A Phase II Trial of Osimertinib (AZD9291) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases
Phase: PHASE2
Conditions: Metastatic Lung Non-Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Stage IV Lung Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

i 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment #10 to: A Phase II trial of Osimertinib (AZD9291) (osimertinib) 
with or without bevacizumab in patients with EGFR mutation positive 
NSCLC and brain metastases 
Protocol Version Date: 03/27/2023 
 
NCI Protocol #: 
10042 
 
Local Protocol #: 
2000021123 
 
I. 
Comments Requiring a Response – Major Issues (CTEP Amendment Review Letter 
dated March 22, 2023):  
 
# 
Section 
Comments 
1. 
Overall 
8.1.1 
Appendix 
C 
Pharmaceutical comments from the last amendment review have not been 
addressed in this amendment.  The PMB-supplied investigational label AZD9291 
(osimertinib) has transitioned to PMB-supplied commercial label osimertinib 
(AZD9291).  The following comments must be addressed: 
 
x Update the primary agent name to the generic name osimertinib.  The 
code name AZD9291 can be retained as a secondary name, such as 
“osimertinib (AZD9291)”. 
x Replace the entire pharmaceutical section with the updated CTEP/PMB 
drug monograph (attached file: Osimertinib (AZD9291) - 781254 – 
1120) for consistency with the FDA approved package insert. 
Remove the current version of Patient Drug Information Appendix and replace 
with the updated CTEP template for marketed agents TEMPLATE B:  
PATIENT CLINICAL TRIAL WALLET CARD (attached file: APPENDIX 
DDI HANDOUT AND WALLET CARD). 
PI Response: The changes have been made as requested.  
 
II. CTEP Request for Rapid Amendment (RRA) dated February 28, 2023: 
  
# 
Section 
Change 
1. 
7.1.1  
Updated AZD9291 CAEPR to Version 2.8, February 9, 2023 as per RRA 
instructions 
x Added New Risk:  
x Rare: Blood and lymphatic system disorders - Other (aplastic 
anemia) 
x Also Reported on Osimertinib Trials But With Insufficient 
Evidence for Attribution: Eye disorders - Other (corneal 
epithelium defect); Eye disorders - Other (corneal erosion); 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
ii 
Eye disorders - Other (eyelids pruritus); Infections and 
infestations - Other (pustule); Skin and subcutaneous tissue 
disorders - Other (onychalgia); Skin and subcutaneous tissue 
disorders - Other (onychomalacia); Urticaria 
 
x Increase in Risk Attribution:  
x Changed to Less Likely from Also Reported on Osimertinib 
Trials But With Insufficient Evidence for Attribution: 
Constipation; Cough; Fatigue 
 
x Decrease in Risk Attribution: 
x Changed to Less Likely from Likely: Diarrhea; Dry skin; 
Mucositis oral; Rash maculo-papular 
x Changed to Also Reported on Osimertinib Trials But With 
Insufficient Evidence from Less Likely: Creatinine increased; 
Epistaxis; Skin and subcutaneous tissue disorders - Other 
(skin fissures) 
x Changed to Also Reported on Osimertinib Trials But With 
Insufficient Evidence from Rare: Ejection fraction decreased 
 
 
 
II. 
Additional Changes by Principal Investigator: 
 
# 
Section 
Change 
1. 
All 
Updated Version Date in Header 
2. 
Title Page 
Updated  Protocol Type / Version # / Version Date 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
2 
 
NCI-Supplied Agents:  Osimertinib (AZD-9291) NSC# 781254; Bevacizumab NSC# 704865 
 
Other Agent(s):  None 
 
IND #:  
 
 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
Revision / Version #2 / January 17, 2017 
 
 
 
 
      Revision /Version #3 /April 10, 2017 
 
 
 
 
      Revision / Version #4 / April 27, 2017 
 
 
 
       
      Revision / Version #5 / May 24, 2017 
 
 
 
 
      Amendment (1) / Version #6 / August 4, 2017 
Amendment (2) / Version #7 / December 6, 
2017 
Amendment (3) / Version #8 / March 8, 2018 
Amendment (4) /Version #9 / June 13, 2018 
Amendment (5) / Version #10 / September 24, 
2018 
Amendment (6) / Version #11 / February 13, 
2019 
Amendment (7)/ Version #12/ October 10, 2019 
Amendment (8)/ Version #13/ June 11, 2020 
Amendment (9)/ Version #14/ December 11, 
2020 
Amendment (10)/ Version #15/ March 27, 2023 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
4 
TABLE OF CONTENTS 
 
SCHEMA .................................................................................................................................. 3 
1. OBJECTIVES .......................................................................................................................... 6 
1.1 
Primary Objectives .............................................................................................................. 6 
1.2 
Secondary Objectives .......................................................................................................... 6 
1.3 
Translational Objectives ...................................................................................................... 6 
2 
BACKGROUND ................................................................................................................. 6 
2.1 
Study Disease: EGFR mutation-positive NSCLC ..................................................................... 6 
2.2 
CTEP IND Agents: ................................................................................................................. 7 
2.3 
Other Agents ..................................................................................................................... 17 
2.4 
Rationale ........................................................................................................................... 17 
2.5 
Correlative Studies Background ......................................................................................... 20 
3 
PATIENT SELECTION ....................................................................................................... 20 
3.1 
Eligibility Criteria ............................................................................................................... 20 
3.2 
Exclusion Criteria ............................................................................................................... 22 
3.2.1 
Symptomatic brain metastases or symptomatic leptomeningeal disease.  Asymptomatic 
leptomeningeal disease is allowed. ................................................................................................ 22 
3.3 
Inclusion of Women and Minorities ................................................................................... 25 
4 
REGISTRATION PROCEDURES ......................................................................................... 25 
4.1 
Investigator and Research Associate Registration with CTEP .............................................. 25 
4.2 
Site Registration ................................................................................................................ 26 
4.3 
Patient Registration ........................................................................................................... 28 
4.4 
General Guidelines ............................................................................................................ 29 
5 
TREATMENT PLAN .......................................................................................................... 29 
5.1 
Agent Administration ........................................................................................................ 29 
5.2 
General Concomitant Medication, Restrictions and Supportive Care Guidelines ................ 32 
5.3 
Duration of Therapy .......................................................................................................... 33 
5.4 
Duration of Follow Up ....................................................................................................... 33 
5.5 
Criteria for Removal from Study ........................................................................................ 33 
6 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................ 34 
6.1 
AZD9291 (osimertinib) ....................................................................................................... 34 
6.2 Bevacizumab ............................................................................................................................ 38 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................................. 42 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) .................................. 42 
7.2 
Adverse Event Characteristics ............................................................................................ 51 
7.3 
Expedited Adverse Event Reporting ................................................................................... 51 
7.4 
Routine Adverse Event Reporting ...................................................................................... 54 
7.5 
Secondary Malignancy ....................................................................................................... 54 
7.6 
Second Malignancy ............................................................................................................ 54 
7.7   Pregnancy .............................................................................................................................. 54 
7.8   Overdose ................................................................................................................................ 55 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
5 
8. 
PHARMACEUTICAL INFORMATION ................................................................................. 56 
8.1 CTEP IND Agents ...................................................................................................................... 56 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................... 60 
9.1 
Integrated Correlative Studies ........................................................................................... 60 
9.2 Exploratory Correlative Studies ................................................................................................ 62 
10 STUDY CALENDAR .......................................................................................................... 70 
11 MEASUREMENT OF EFFECT ............................................................................................ 72 
11.1 
Antitumor Effect ................................................................................................................ 72 
12 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS ................. 81 
12.1 
Data Reporting .................................................................................................................. 82 
12.2 
CTEP Multicenter Guidelines .............................................................................................. 84 
12.3 
Collaborative Agreements Language .................................................................................. 84 
13 STATISTICAL CONSIDERATIONS ...................................................................................... 85 
13.1 
Study Design/Endpoints .................................................................................................... 85 
13.2 
Sample Size/Accrual Rate .................................................................................................. 87 
13.3 
Stratification Factors ......................................................................................................... 88 
13.4 
Analysis of Secondary Endpoints ....................................................................................... 88 
13.5 
Reporting and Exclusions ................................................................................................... 89 
REFERENCES .......................................................................................................................... 90 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ............................................................. 103 
Appendix B 
guidance regarding potential Interactions with concomitant medications .... 104 
drugs inducing cyp3a4 metabolism that astrazeneca strongly recommend are not combined 
with azd9291 (OSIMERTINIB) ............................................................................................... 104 
Medicines whose exposures may be affected by azd9291 (OSIMERTINIB) that astrazeneca 
considers may be allowed with caution ............................................................................... 104 
drugs that may prolong qt interval ...................................................................................... 105 
APPENDIX C INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................................... 107 
APPENDIX D 
FORMALIN-FIXED, Paraffin Embedded (FFPE) Tumor TISSUE Collection, 
HANDLING and Shipment .................................................................................................... 109 
Appendix E Plasma Collection and Shipment ....................................................................... 110 
APPENDIX F 
PATIENT MEDICATION DIARY ........................................................................ 113 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
6 
1. OBJECTIVES 
 
1.1 Primary Objectives 
 
1.1.1 To determine the progression-free survival with Osimertinib (AZD9291) plus bevacizumab 
compared to Osimertinib (AZD9291)  alone 
 
1.2 Secondary Objectives 
 
1.2.1 To assess the safety and tolerability of the combination of Osimertinib (AZD9291) and 
bevacizumab 
1.2.2 To evaluate the time to progression in the CNS with Osimertinib AZD9291  plus 
bevacizumab versus single-agent osimertinib (AZD9291) 
1.2.3 To determine the overall response rate and the intracranial response rate to the combination 
versus single agent 
1.2.4 To assess the overall survival in patients receiving Osimertinib (AZD9291) plus 
bevacizumab compared to Osimertinib (AZD9291)  alone 
 
1.3 Translational Objectives 
1.3.1 To investigate mechanisms of sensitivity and resistance to combination Osimertinib 
(AZD9291)  plus bevacizumab versus Osimertinib (AZD9291)  by molecularly 
characterizing tumor samples including T790M status 
1.3.2 To assess whether circulating tumor DNA in plasma can be used as an indicator of 
sensitivity and resistance to treatment 
1.3.3 To determine whether an angiogenic signature using a multiplex panel array is associated 
with benefit from the combination of Osimertinib (AZD9291) plus bevacizumab  
1.3.4 To investigate angiogenesis, immune and signaling pathway markers in tumor samples to 
determine biomarkers predictive of benefit from combination therapy 
 
2 BACKGROUND 
 
2.1 Study Disease: EGFR mutation-positive NSCLC 
NSCLC is the leading cause of cancer-related death worldwide, and results in over 160,000 deaths 
in the United States per year.(2) In patients with advanced or metastatic disease, platinum-based 
chemotherapy has been the mainstay of management for the past several decades, however 
responses are usually transient and survival is limited for the majority of patients.  More recently, 
identification of oncogenic drivers of NSCLC and targeted therapies that inhibit these drivers have 
revolutionized the way in which lung cancer is treated.  Approximately 15% of all patients with 
NSCLC harbor a somatic mutation in the Epidermal Growth Factor Receptor (EGFR) gene.(3-5)  
Most of these mutations affect discrete regions of the gene within exons 18 to 21 that code for the 
EGFR tyrosine kinase domain. The most common mutations result in an in-frame 15-bp deletion 
in exon 19 and a point mutation resulting in an amino acid substitution at codon 858 (L858R) in 
exon 21.  Several small molecule tyrosine kinase inhibitors (TKIs) have been approved by the US 
FDA for treatment of EGFR-mutation positive NSCLC, including the first-generation TKIs 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
7 
erlotinib and gefitinib and the second-generation TKI afatinib.  These drugs act as ATP analogues 
and compete for the tyrosine kinase catalytic site thus interfering with inhibition of receptor 
activation. EGFR TKIs are extremely effective in treating patients with EGFR-mutated cancers, 
especially compared to chemotherapy(6-8).  However, resistance to these agents inevitably 
develops, resulting in disease progression. Osimertinib (AZD9291)  has been developed as an 
agent to treat EGFR-mutant NSCLC after the development of resistance to first- and second-
generation EGFR TKIs. 
 
2.2 CTEP IND Agents:  
 
2.2.1 Osimertinib (AZD9291)  
 
Osimertinib (AZD9291)  is a potent irreversible tyrosine kinase inhibitor of both sensitizing EGFR 
mutations and the resistance T790M EGFR mutation, with a significant selectivity margin over 
wild-type EGFR. Osimertinib (AZD9291) effectively blocks EGFR signaling in both EGFR single 
mutant cells with activating EGFR mutations and double mutant cells bearing both primary EGFR 
activating and secondary resistance T790M mutation.  Osimertinib (AZD9291)  is currently FDA 
approved for patients with advanced EGFRm+ NSCLC who have previously failed an EGFR TKI 
when the T790M mutation is present, and for the first-line treatment of patients with metastatic 
EGFRm+ NSCLC.    
 
2.2.1.1 Clinical Studies  
 
A phase 1, open-label, multicenter study of Osimertinib (AZD9291) administered once daily was 
conducted to evaluate the safety and tolerability in EGFR-TKI refractory patients (AURA, 
NCT01802632).  Osimertinib (AZD9291)  was given across 5 cohorts from 20mg daily to 240mg 
daily.  The overall confirmed ORR was 51% (123/239; 95% Cl 45, 58) with disease control rate 
(DCR) [complete response (CR) + partial response (PR) + stable disease (SD)] of 84% (201/239; 
95% Cl 79,88).  In patients with T790M mutation identified at time of acquired resistance to EGFR 
TKI, ORR was 61% (78/127; 95% Cl 52, 70) and DCR was 95% (121/127; 95% Cl 90, 98).  
Median progression free survival (PFS) for patients with T790M+ was 9.6 months.  In patients 
without the T790M mutation identified at time of acquired resistance, ORR was 21% (13/61; 95% 
Cl 12, 34) and DCR was 61% (37/61; 95% Cl 47, 73), with median PFS of 2.8 months (9).  
 
An expansion cohort of the AURA trial enrolled 60 additional patients with EGFR TKI naïve 
EGFR mutant NSCLC. Thirty patients received 80mg/day and 30 patients received 160mg/day of 
Osimertinib (AZD9291) .  Across both doses, ORR was 73% with DCR of 97% and PFS rate at 
one year of 75%. ORR was 63% with DCR of 93% and PFS rate at 9 months and 1 year of 83% 
and 73% respectively in the 80mg/day arm.  ORR was 83% with DCR 100% and PFS rate at 9 
months and 1 year of 78% and ‘not calculated’ respectively in the 160mg/day arm(10). 
 
The FLAURA trial (11) enrolled patients with previously-untreated advanced EGFR mutant 
NSCLC and randomized them to Osimertinib (AZD9291)  or standard EGFR TKI (gefitinib or 
erlotinib).  This trial demonstrated a PFS of 18.9 months with Osimertinib (AZD9291) compared 
to 10.2 months in the standard arm (p<0.001), leading to FDA-approval of this agent for patients 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
8 
without prior therapy for metastatic disease.   
 
2.2.1.2 Safety Profile 
 
Safety data from the AURA trial described above are available for 253 patients with advanced 
EGFR-TKI refractory NSCLC.  Overall, 13% of patients had Grade 3 or higher treatment related 
adverse events. There was one treatment related death due to pneumonia. Grade 3 or higher rash 
was observed in 1% of patients and grade 3 diarrhea in 2% of patients. Grade 3 or higher drug-
related adverse events were seen in 10% (2/21) of patients who were dosed at 20mg daily, 3% 
(2/58) at 40mg daily, 11% (10/90) at 80mg daily, 25% (16/63) at 160mg daily, and 14% (3/21) at 
240mg daily. The most common adverse events that occurred in >10% of patients across all doses 
included diarrhea (47%), rash (40%), nausea (22%), decreased appetite (21%), dry skin (20%), 
pruritus (19%), fatigue (17%), paronychia (17%), constipation (15%), cough (15%), stomatitis 
(12%), vomiting (11), anemia (11%), dyspnea (11%), upper respiratory infections (10%), and 
headache (10%).  Less common side effects (<10% of patients), included hyperglycemia (2%), 
QTC prolongation (4%) and pneumonitis-like events (2%). 
 
Safety data is also available from the FLAURA trial (11) for patients with previously-untreated 
EGFR-mutant NSCLC.  34% of patients had grade 3 or greater adverse events and 22% had serious 
adverse events.  The most common adverse events due to any cause were rash or acne (58%), 
diarrhea (58%), and dry skin (36%).  Cardiac events of note included QTc prolongation in 10% of 
patients, of which only 2% were grade 3 or greater.  Interstitial lung disease was observed in 4% 
of patients and none were fatal.   
 
2.2.1.3 Pre-Clinical Studies  
 
Pre-clinical data provides good evidence to support Osimertinib (AZD9291)  as a potentially 
better treatment option for first-line advanced and early stage EGFRm+ NSCLC compared to 
currently approved EGFR TKIs. Unlike gefitinib, erlotinib, and afatinib, emergence of T790M 
does not appear to be a mechanism of preclinical resistance to Osimertinib (AZD9291) (12) and 
in vitro data supports a slower time to resistance in response to AZD9291 treatment than that of 
first and second generation EGFR TKIs. In a pre-clinical mouse model of EGFRm+ NSCLC, 
Osimertinib (AZD9291)  achieved superior durable complete responses compared to those 
achieved with gefitinib.(12) 
 
2.2.1.4 Brain Metastases  
 
Emerging preclinical data indicate that Osimertinib (AZD9291)  may have the potential to target 
brain metastases (a common site of relapse in NSCLC) more effectively than current EGFR 
TKIs(13). Brain metastases are detected in 20 to 30% of patients with advanced NSCLC upon 
initial diagnosis, and are associated with a poor prognosis.(14) Up to 50% of lung cancer patients 
will develop brain metastases at some point during the course of their disease. The first generation 
EGFR-TKI agents have demonstrated only limited efficacy in treating brain metastases(15, 16). 
Preclinical data suggest that Osimertinib (AZD9291)  may be capable of crossing the blood brain 
barrier and may potentially offer better exposure in this anatomically protected location. The 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
9 
central nervous system (CNS) is a common site of first progression for patients receiving 
treatment with a standard TKI, despite concomitant systemic disease control.  Use of a drug 
which may more effectively penetrate the CNS has the potential to control prevent or delay the 
growth of subclinical brain metastases that were below the limits of detection at the time of 
diagnosis.  Results from the FLAURA trial (11) suggested better CNS activity with Osimertinib 
(AZD9291)  compared with first-generation agents, with a median PFS amongst patients with 
CNS metastases of 15.2 months versus 9.6 months in the standard TKI arm (p<0.001).  
Leptomeningeal disease has also been demonstrated to be controlled with Osimertinib 
(AZD9291)  (17).   
 
2.2.2 Bevacizumab (rhuMAb VEGF) 
 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active 
isoforms of human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity 
(Kd=1.1 nM)(18).  The antibody consists of a human IgG1 framework and the antigen-binding 
complementarity-determining regions from the murine anti-VEGF MAb A.4.6.1.(18-20) 
 
2.2.2.1 Mechanism of Action 
 
Of known proangiogenic factors, VEGF is one of the most potent and specific, and has been 
identified as a crucial regulator of both normal and pathological angiogenesis. VEGF is a secreted, 
heparin-binding protein that exists in multiple isoforms.  Action of VEGF is primarily mediated 
through binding to the receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).  
The biological effects of VEGF include endothelial cell mitogenesis and migration, increased 
vascular permeability, induction of proteinases leading to remodeling of the extracellular matrix, 
and suppression of dendritic cell maturation. Neutralization of VEGF by A.4.6.1 or bevacizumab 
has been shown to inhibit the VEGF-induced proliferation of human endothelial cells in vitro, and 
decrease microvessel density and interstitial pressure in tumor xenografts in vivo. In patients, 
preliminary results from a neoadjuvant trial in rectal cancer demonstrated a decrease in blood 
perfusion/permeability and interstitial fluid pressure in tumors after one dose of bevacizumab.(21) 
 
2.2.2.2 Nonclinical Studies 
 
The murine parent MAb of bevacizumab, A4.6.1, has demonstrated potent growth inhibition in 
vivo in a variety of human cancer xenograft and metastasis models, including those for SK-LMS-
1 leiomyosarcoma, G55 glioblastoma multiforme, A673 rhabdomyosarcoma, Calu-6, and MCF-7 
cell lines.(18, 20, 22, 23)  The antitumor activity was enhanced with the combination of A4.6.1 
and chemotherapeutic agents compared to either agent alone.  Combined blockage of the VEGF 
and other growth factor pathways (e.g., epidermal growth factor receptor [EGFR] or Platelet 
Derived Growth Factor Receptor [PDGFR]) has also demonstrated additive effects in vivo.(24, 
25) Associated with the anti-tumor activity of anti-VEGF MAbs were findings of reduced 
intratumoral endothelial cells and microcapillary counts as well as reduced vascular permeability 
and interstitial pressure   
 
Nonclinical toxicology studies have examined the effects of bevacizumab on female reproductive 
function, fetal development, and wound healing.  Fertility may be impaired in cynomolgus 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
10 
monkeys administered bevacizumab, which led to reduced endometrial proliferation and uterine 
weight as well as a decrease in ovarian weight and number of corpora lutea.  Bevacizumab is 
teratogenic in rabbits, with increased frequency of fetal resorption, and specific gross and skeletal 
alterations. In juvenile cynomolgus monkeys with open growth plates, bevacizumab induced 
physeal dysplasia which was partially reversible upon cessation of therapy.  Bevacizumab also 
delays the rate of wound healing in rabbits, and this effect appeared to be dose-dependent and 
characterized by a reduction of wound tensile strength. 
 
2.2.2.3 Clinical Studies 
 
Pharmacokinetics and MTD: The pharmacokinetics (PK) of bevacizumab have been characterized 
in several phase 1 and phase 2 clinical trials, with doses ranging from 1 to 20 mg/kg administered 
weekly, every 2 weeks, or every 3 weeks.  The estimated half-life of bevacizumab is approximately 
21 days (range 11-50 days).  The predicted time to reach steady state was 100 days.  The volume 
of distribution is consistent with limited extravascular distribution.    
 
The maximum tolerated dose (MTD) of bevacizumab has not been determined; however, the dose 
level of 20 mg/kg was associated with severe headaches.(26)  The dose schedule of either 10 mg/kg 
every 2 weeks, or 15 mg/kg every 3 weeks is used in most phase 2 or 3 trials with only a few 
exceptions (e.g., the pivotal phase 3 trial in colorectal cancer, in which bevacizumab was given at 
5 mg/kg every 2 weeks). 
 
Clinical efficacy of bevacizumab: Clinical proof of principle for anti-VEGF therapy with 
bevacizumab has been observed in several solid tumors.  In first- and second-line metastatic 
colorectal cancer (mCRC), the combination of bevacizumab with 5-FU-based chemotherapy 
improved the overall survival (OS), progression-free survival (PFS), and response rate (RR) as 
compared to chemotherapy alone.(27, 28)  There was also improved overall survival in first-line 
NSCLC patients (E4599) treated with carboplatin/paclitaxel with bevacizumab compared with 
chemotherapy alone.  Bevacizumab in combination with chemotherapy has been approved by the 
Food and Drug Administration (FDA) for treatment in mCRC (first and second lines) and in 
NSCLC. 
 
In untreated advanced and metastatic breast cancer, addition of bevacizumab to paclitaxel also 
significantly improved the RR and PFS (E2100)(29).  However, in the phase 3 trial in doxorubicin- 
and paclitaxel-refractory metastatic breast cancer, the addition of bevacizumab to capecitabine did 
not show an improvement in PFS despite an increase in the RR.(30) In locally advanced and 
metastatic pancreatic cancer, a Phase 3 also failed to demonstrate an overall survival (OS) or PFS 
advantage by adding bevacizumab to gemcitabine (CALGB-80303).(31) 
 
Bevacizumab has been studied as monotherapy in renal cell cancer (RCC).  In a three-arm, double-
blind, placebo-controlled phase 2 trial,(32) patients with previously treated stage IV RCC were 
randomized to high-dose (HD) bevacizumab (10 mg/kg every 2 weeks), low-dose (LD) 
bevacizumab (3 mg/kg every 2 weeks), or placebo.  The study demonstrated a highly significant 
prolongation of time to progression (TTP) in the HD arm (4.8 months) as compared with the 
placebo (2.6 months) (hazard ratio [HR]=2.55, P=0.0002); the LD arm was associated with a 
smaller difference in TTP (3.0 months) of borderline significance.  The tumor response rate was 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
11 
10% in the HD arm but 0% in the LD and placebo groups.   
 
A Phase 3 study (BO17705) with bevacizumab (10 mg/kg every 2 weeks) plus interferon-ĮD
versus interferon-ĮD SOXV SODFHER DV ILUVW-line therapy in patients with advanced and/or metastatic 
RCC demonstrated statistically significant and clinically relevant improvements in PFS (10.2 vs. 
5.4 months), and objective response rate (ORR) (31.4 vs. 12.8%).  
 
The Phase 3 study BO17706 indicated no statistically significant improvement in OS when 
bevacizumab (5 mg/kg every 2 weeks) was added to the gemcitabine/erlotinib combination in the 
first-line treatment of advanced pancreatic cancer.  The Phase 3 NCI-sponsored CALGB-80303 
study investigating the use of bevacizumab (10 mg/kg every 2 weeks) combined with gemcitabine 
was prematurely terminated after the CALGB Data Safety Monitoring Board (DSMB) concluded 
that the futility boundary defined for the primary efficacy parameter (OS) had been crossed in a 
protocol-specified interim analysis (dated June 16th, 2006).  
 
Bevacizumab has been extensively studied in patients with NSCLC.  In a large Phase III 
randomized trial of carboplatin/paclitaxel with or without bevacizumab, the addition of 
bevacizumab resulted in an approximately 2 month improvement in overall survival,(33) leading 
to the FDA approval of this agent for use in first-line therapy for patients with non-squamous 
NSCLC.  Bevacizumab has also been combined with EGFR inhibitors with varying degrees of 
success; details of these trials are in Section 2.4.   
 
2.2.2.4 Safety Profile 
 
Based on clinical trials with bevacizumab as monotherapy or in combination with chemotherapy, 
the most common adverse events (AEs) of any severity included asthenia, pain, headache, 
hypertension, diarrhea, stomatitis, constipation, epistaxis, dyspnea, dermatitis, and proteinuria.  
The most common grade 3-4 AEs were asthenia, pain, hypertension, diarrhea, and leukopenia. 
 
The major bevacizumab-associated AEs identified in phase 1 to phase 3 trials include 
hypertension, proteinuria, arterial thromboembolic events (ATEs), hemorrhage, congestive heart 
failure (CHF), gastrointestinal (GI) perforations, and wound healing complications.  Other serious 
AEs (SAEs) observed with bevacizumab therapy include reversible posterior leukoencephalopathy 
syndrome (RPLS) and fistula formation. 
 
The following details a description of major AEs associated with bevacizumab therapy.  In 
addition, a list of Comprehensive Adverse Events and Potential Risks (CAEPR) in NCI-Common 
Terminology Criteria for Adverse Events (CTCAE) terms is included in Section 7.1 of the 
protocol.  Reference may also be made to the Investigators’ Brochure and the FDA package insert 
(www.fda.gov/cder/foi/label/2004/125085lbl.pdf).  
 
Infusion-Related Reactions:  Infusion reactions with bevacizumab were uncommon (<3%) and 
rarely severe (0.2%).  Infusion reactions may include rash, urticaria, fever, rigors, hypertension, 
hypotension, wheezing, or hypoxia.  Currently, there is no adequate information on the safety of 
retreatment with bevacizumab in patients who have experienced severe infusion-related reactions.  
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
12 
Hypertension:  Hypertension is common in patients treated with bevacizumab, with an incidence 
of 20-30% (all grades) across trials, with a mean increase of +5.5mmHg to +8.4mmHg for systolic 
pressure, or +4.1mmHg to +5.4mmHg for diastolic pressure.  Incidence of grade 3 (hypertension 
requiring initiation of or increase in hypertensive medications) ranges from 7.8 to 17.9%.  Grade 
4 hypertension (hypertensive crisis) occurred in up to 0.5% of bevacizumab-treated patients. 
 
Hypertension associated with bevacizumab can generally be controlled with routine oral drugs 
while bevacizumab is continued.  However, incidents of hypertensive crisis with encephalopathy 
(including RPLS) or cardiovascular sequelae have been rarely reported.  Blood pressure (BP) 
should be closely monitored during bevacizumab therapy and the goal of BP control should be 
consistent with standard medical practice.(34)  Bevacizumab therapy should be suspended in the 
event of uncontrolled hypertension. 
 
Proteinuria:  Proteinuria has been seen in all bevacizumab studies to date, ranging in severity from 
mild asymptomatic increase in urine protein (incidence of about 38%) to rare instances of grade 3 
proteinuria (>3.5gm/24 hour urine) (3%) or nephrotic syndrome (1.4%).  Pathologic findings on 
renal biopsies in two patients showed proliferative glomerulonephritis.  The risk of protenuria may 
be higher in patients with advanced RCC or history of hypertension.  There is also evidence from 
dose-finding trials that the rate of proteinuria may be dose related.   
 
Renal thrombotic microangiopathy:  Thrombotic microangiopathy (TMA) has been described in 
biopsy samples from case reports of patients treated with bevacizumab and other anti-VEGF 
agents.  The presentation was mostly localized to the kidney, and systemic manifestations (e.g., 
thrombocytopenia or schistocytosis) were present only in some of these patients.  As renal biopsies 
were rarely performed in patients with proteinuria or renal insufficiency, the true rate of renal-
localized or subclinical TMA is not assessable. Available data indicate that systemically evident 
TMA (i.e., with evidence of hemolysis or thrombocytopenia) is very rare. However, the use of 
more than one anti-VEGF agent in combination might enhance the risk.  In a phase 1 dose 
escalation trial of concurrent bevacizumab (10 mg/kg every 2 weeks) and escalating doses of 
sunitinib (25 mg, 37.5 mg or 50 mg daily for 4 out of 6 weeks) in patients with RCC, 5 of the 12 
patients at the highest dose level developed systemic TMA, or microangiopathic hemolytic 
anemia; clinical presentations in these cases included thrombocytopenia, schistocytes, 
hypertension, and varying degrees of proteinuria. 
 
Hemorrhage:  Overall, grade 3 and 4 events associated with bleeding or hemorrhage were observed 
in 4.0% of 1,132 patients treated with bevacizumab in a pooled database from eight phase 1, 2, 
and 3 clinical trials in multiple tumor types.  The hemorrhagic events that have been observed in 
bevacizumab clinical studies were predominantly tumor-associated hemorrhage and minor 
mucocutaneous hemorrhage. 
 
Tumor-associated hemorrhage - Major or massive pulmonary hemorrhage/hemoptysis has been 
observed primarily in patients with NSCLC.  In a phase 2 study in NSCLC, 6 cases of life-
threatening (4 fatal) hemoptysis were reported among 66 patients treated with bevacizumab and 
chemotherapy(35); squamous cell histology was identified as the risk factor.  In the phase 3 trial 
in non-VTXDPRXV 16&/& ( WKH UDWH RI *UDGH  EURQFKR-pulmonary hemorrhage was <1% 
in the control arm (carboplatin/paclitaxel) versus 2.3% in the chemotherapy plus bevacizumab arm 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
13 
(10/427 patients, including 7 deaths).  Of patients experiencing pulmonary hemorrhages requiring 
medical intervention, many had cavitation and/or necrosis of the tumor, either pre-existing or 
developing during bevacizumab therapy.  Patients developing lung cavitation on treatment should 
be assessed by the treating physician for risk-benefit. 
 
GI hemorrhages, including rectal bleeding and melena have been reported in patients with CRC, 
and have been assessed as tumor-associated hemorrhages.  In the pivotal phase 3 trial in advanced 
CRC, the rate of GI (duodenal, ileal, cecal and colonic) hemorrhage (all grades) was 24% in the 
irinotecan, fluorouracil, and leucovorin (IFL)/bevacizumab arm compared to 6% in the IFL alone 
arm; grade 3-4 hemorrhage was 3.1% for IFL/bevacizumab and 2.5% for IFL.   
 
Serious tumor associated bleedings have also been observed in patients with pancreatic cancer, 
gastric cancer, central nervous system (CNS) metastases, hepatoma, or varices treated with 
bevacizumab.  
 
Mucocutaneous hemorrhage - Across all bevacizumab clinical trials, mucocutaneous hemorrhage 
has been seen in 20%-40% of patients treated.   
 
These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved 
without medical intervention, and did not require any changes in bevacizumab treatment regimen. 
 
There have also been less common events of minor mucocutaneous hemorrhage in other locations, 
such as gingival bleeding and vaginal bleeding. 
 
Thromboembolic Events, Arterial (ATE):  The risk of ATEs is increased with bevacizumab 
therapy; such events included cerebral infarction, transient ischemic attack (TIA), myocardial 
infarction (MI), and other peripheral or visceral arterial thrombosis.  A pooled analysis of five 
randomized studies showed a two-fold increase in these events (3.8% vs. 1.7%).  ATE led to a 
fatal outcome in 0.8% patients with bevacizumab (vs. 0.5% without bevacizumab).  The rate of 
cerebrovascular accidents (including TIA) was 2.3% vs. 0.5%, and the rates of MI 1.7% vs. 0.7%.  
Certain baseline characteristics, such as age and prior arterial ischemic events, appear to confer 
additional risk.(36)  In patients >65 years treated with bevacizumab and chemotherapy, the rate of 
ATE was approximately 8.5%.  
 
Aspirin is a standard therapy for primary and secondary prophylaxis of ATE in patients at high 
ULVN RI VXFK HYHQWV DQG WKH XVH RI DVSLULQ  PJ GDLO\ ZDV DOORZHG LQ WKH ILYH UDQGRPL]HG
studies discussed above though safety analyses specifically regarding aspirin use were not 
preplanned.  Due to the relatively small numbers of aspirin users and ATE events, retrospective 
analyses of the ability of aspirin to affect the risk of ATE were inconclusive.  Further analyses of 
the effects of concomitant use of bevacizumab and aspirin are ongoing. 
 
Thromboembolic Events, Venous (VTE) (including deep venous thrombosis, pulmonary 
embolism, and thrombophlebitis):  In the phase 3 pivotal trial in mCRC, there was a slightly higher 
rate of VTE in patients treated with chemotherapy plus bevacizumab compared with chemotherapy 
alone (19% vs. 16%).  The incidence of NCI-CTC Grade>3 VTEs in one NSCLC trial (E4599) 
was higher in the bevacizumab-containing arm compared to the chemotherapy control arm (5.6% 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
14 
vs. 3.2%). 
In clinical trials across all indications, the overall incidence of VTEs ranged from 2.8% to 17.3% 
in the bevacizumab-containing arms compared to 3.2% to 15.6% in the chemotherapy control 
arms. The use of bevacizumab with chemotherapy does not substantially increase the risk of VTE 
compared with chemotherapy alone. However, patients with mCRC who receive bevacizumab and 
experienced VTE may be at higher risk for recurrence of VTE. 
Perforations of GI tract:  GI perforations/fistula are rare but have occurred at an increased rate in 
bevacizumab-containing therapies.  The majority of such events required surgical intervention, 
and some were associated with a fatal outcome.  In the pivotal phase 3 trial in CRC (AVF2107), 
the incidence of bowel perforation was 2% in patients receiving IFL/bevacizumab and 4% in 
patients receiving fluorouracil (5-FU)/bevacizumab compared to 0.3% in patients receiving IFL 
alone.  GI perforation has also been reported in non-CRC tumors (e.g., gastric/esophageal, 
pancreatic, and ovarian cancers) or nonmalignant conditions such as diverticulitis and gastric ulcer. 
GI perforation should be included in the differential diagnosis of patients on bevacizumab therapy 
presenting with abdominal pain or rectal/abdominal abscess. 
GI Fistula:  Fistula formations, including events resulting in death, have been observed in patients 
receiving bevacizumab in clinical studies and post-marketing reports.  Fistulae in the GI tract are 
common (1-10% incidence) in patients with certain metastatic tumors such as CRC or cervical, 
but uncommon (0.1-1%) or rare (0.01-0.1%) in other indications.  
In addition, fistulae that involve areas other than the GI tract have also been observed (e.g. 
tracheoesophageal, bronchopleural, urogenital, and biliary).  Events were reported at various 
timepoints during treatment, ranging from 1 week to 1 year following initiation of bevacizumab, 
with most events occurring within the first 6 months of therapy. 
Tracheoesophageal (TE) fistula:  Life-threatening or fatal TE fistula has been reported in patients 
with small cell lung cancer (SCLC) treated with concurrent chemoradiation and bevacizumab.  In 
a phase 2 trial of bevacizumab plus irinotecan, carboplatin, and radiation therapy (RT) followed 
by maintenance bevacizumab that accrued 25 patients, there have been two confirmed cases of TE 
fistula (one fatal) and a third case of fatal upper aerodigestive tract hemorrhage, with TE fistula 
suspected but not confirmed.  All three events occurred during the bevacizumab maintenance 
phase (1.5 to 4 months after completion of chemoradiation).  While pulmonary fistula (including 
TE fistula) has also been observed in advanced NSCLC or SCLC patients receiving bevacizumab 
and chemotherapy (without RT), the incidence was extremely low.   
Wound Healing Complications:  Bevacizumab delays wound healing in rabbits, and it may also 
compromise or delay wound healing in patients.  Bowel anastomotic dehiscence and skin wound 
dehiscence have been reported in clinical trials with bevacizumab.   
The appropriate interval between surgery and initiation of bevacizumab required to avoid the risk 
of impaired wound healing has not been determined.  Across mCRC trials, at least 28 days must 
have elapsed following major surgery before bevacizumab could be initiated; data suggested 
initiation of bevacizumab 29-60 days following surgery did not appear to increase the risk of 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
15 
wound healing complications compared to those treated with chemotherapy alone.   
 
The optimal interval between termination of bevacizumab and subsequent elective surgery has not 
been determined.  In the pivotal study in CRC, among patients who underwent major surgery while 
on study therapy, there was an increased rate of significant post-operative bleeding or wound 
healing complications in the IFL plus bevacizumab arms vs. IFL alone [10% (4/40) vs. 0% 
(0/25)].(37)  Decisions on the timing of elective surgery should take into consideration the half-
life of bevacizumab (average 21 days, range 11-50 days). 
 
If patients receiving treatment with bevacizumab require elective major surgery, it is recommended 
that bevacizumab be held for 4–8 weeks prior to the surgical procedure.  Patients undergoing a 
major surgical procedure should not begin/restart bevacizumab until 4 weeks after that procedure 
In the case of high risk procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that chemotherapy be restarted no earlier than 6 weeks and bevacizumab no earlier 
than 8 weeks after surgery. 
 
Heart failure (HF):  The risk of left ventricular dysfunction may be increased in patients with prior 
or concurrent anthracycline treatment.  In phase 3 trials in metastatic breast cancer (AVF 2119g) 
in which all patients had received prior anthracyclines, congestive heart failure (CHF) or 
cardiomyopathy were reported in 3% in the bevacizumab plus capecitabine arm compared to 1% 
in the capecitabine-only arm.(29)  In a Phase 3 trial of patients with previously untreated metastatic 
breast cancer (E2100), the incidence of left ventricular ejection fraction (LVEF) decrease (defined 
as NCI CTC Grade 3 or 4) in the paclitaxel plus bevacizumab arm was 0.3% versus 0% for the 
paclitaxel alone arm  
 
In phase 2 study of 48 patients with refractory acute myelogenous leukemia treated with 
cytarabine, mitoxantrone, and bevacizumab, five cases of cardiac dysfunction (CHF) or LVEF 
decreases to <40% were reported. All but one of these subjects had significant prior exposure to 
anthracyclines as well.  Two additional studies investigated concurrent administration of 
anthracyclines and bevacizumab.  In 21 patients with inflammatory breast cancer treated with 
neoadjuvant docetaxel, doxorubicin (cumulative doses at 240 mg/m2), and bevacizumab, no 
patients developed clinically apparent CHF; however, patients had asymptomatic decreases in 
LVEF to <40%.(38)  In a small phase 2 study in patients with soft tissue sarcoma, 2 of the 17 
patients treated with bevacizumab and high-dose doxorubicin (75 mg/m2) developed CHF (one 
Grade 3 event after a cumulative doxorubicin dose of 591 mg/m2 and one Grade 4 event after a 
cumulative doxorubicin dose of 420 mg/m2); an additional 4 patients had asymptomatic decreases 
in LVEF.(39)  Patients receiving anthracyclines or with prior exposure to anthracyclines should 
have a baseline Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO) with a normal 
ejection fraction.   
 
Reversible 
Posterior 
Leukoencephalopathy 
Syndrome 
(RPLS), 
Posterior 
Reversible 
Encephalopathy Syndrome (PRES), or similar leukoencephalopathy syndrome:  RPLS/PRES are 
clinical syndromes related to vasogenic edema of the white matter and have rarely reported in 
association with bevacizumab therapy (<1%).  Clinical presentations may include altered mental 
status, seizure, visual disturbance or cortical blindness, with or without associated hypertension.  
MRI scans are required for diagnosis. Typical findings are vasogenic edema (enhanced intensity 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
16 
in T2 and FLAIR sequences on non-contrast magnetic resonance imaging [MRI]) predominantly 
in the white matter of the posterior parietal and occipital lobes, and less frequently, in the anterior 
distributions and the gray matter.   
 
RPLS/PRES is potentially reversible, but timely correction of the underlying causes, including 
control of BP and interruption of the offending drug, is important in order to prevent irreversible 
tissue damage.  The safety of reinitiating bevacizumab therapy in patients previously experiencing 
RPLS is not known.(40, 41)   
 
Neutropenia:  In the phase 3 trial with IFL plus or minus bevacizumab in CRC, Grade 3-4 
neutropenia was 21% with bevacizumab plus IFL vs. 14% with IFL alone (Grade 4 neutropenia 
was 3% vs. 2%).  Increased rates of severe neutropenia, febrile neutropenia, or infection with 
severe neutropenia (including some fatalities) have been observed in patients treated with some 
myelotoxic chemotherapy regimens plus bevacizumab.  In a phase 3 trial in NSCLC, the 
carboplatin and paclitaxel plus bevacizumab arm was associated with increased rate of Grade 4 
neutropenia (27% vs. 17%), febrile neutropenia (5.4% vs. 1.8%), and infection with neutropenia 
(4.4% vs. 2.0%) with three fatal cases.(33) 
 
Bone metaphyseal dysplasia in children with active (open) growth plates:  Inhibitors of 
VEGF/VEGFR pathways have been shown to induce physeal dysplasia in juvenile cynomolgus 
monkeys with open growth plates.  Asymptomatic metaphyseal bone lesions were also observed 
in a 4.5-month old infant after 4 doses (8 weeks) of bevacizumab for treatment of cutaneovisceral 
angiomatosis with thrombocytopenia (CAT).  The radiographic findings included lytic lesions in 
the metaphyses of upper and lower extremity long bones, which reversed following cessation of 
bevacizumab.(42)  In a phase 1 pediatric study with bevacizumab, metaphyseal expansion was not 
observed in the three patients with open growth plates at baseline; however, the duration of 
treatment was limited.(43)  At this time, experience is limited for prolonged treatment with 
bevacizumab in children, and no data are available for the long term impact of bevacizumab on 
growth.    
 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for additional details 
regarding the safety experience with bevacizumab. 
 
Fertility and Pregnancy:  Clinical data are lacking regarding the immediate or long-term effect of 
bevacizumab on fertility and pregnancy.  However, bevacizumab is known to be teratogenic and 
detrimental to fetal development in animal models.  In addition, bevacizumab may alter corpus 
luteum development and endometrial proliferation, thereby having a negative effect on fertility.  
As an IgG1, it may also be secreted in human milk.  Therefore, fertile men and women on 
bevacizumab studies must use adequate contraceptive measures and women should avoid breast 
feeding.  The duration of such precautions after discontinuation of bevacizumab should take into 
consideration the half-life of the agent (average 21 days, ranging from 11 to 50 days). 
 
Immunogenicity:  As a therapeutic protein, there is a potential for immunogenicity with 
bevacizumab.  With the currently available assay with limited sensitivity, high titer human anti-
bevacizumab antibodies have not been detected in approximately 500 patients treated with 
bevacizumab. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
18 
For patients who are EGFR TKI-naïve, only a few trials have included (or focused on) patients 
with untreated brain metastases to determine efficacy of EGFR TKIs in the CNS.  One trial studied 
the use of erlotinib in patients with lung adenocarcinoma with disease progression in the brain, 
and demonstrated an overall response rate of 58% and PFS of about 10 months.(48)  Although 
about 30% of patients in this trial were wild-type for EGFR, the ORR and PFS was similar to that 
seen with erlotinib in trials of EGFR-mutant patients that required local therapy of brain metastases 
prior to enrollment.6 In a retrospective study of 110 patients with EGFR mutation positive NSCLC, 
upfront erlotinib was compared to WBRT or SRS in patients with brain metastases.(49)  There 
was a longer time to intracranial progression for patients treated with radiation compared to 
erlotinib alone, however overall survival was similar.   
 
Although the use of an EGFR inhibitor has not been formally compared to radiation therapy in a 
prospective randomized trial, there is clearly CNS activity with first-generation EGFR inhibitors 
and they are often used in lieu of local therapy in patients with newly-diagnosed EGFR-mutant 
NSCLC with small, asymptomatic brain metastases.  However, patients with EGFR TKI resistance 
with disease progression in the brain often present a clinical challenge as there are no studies (to 
our knowledge) that specifically assess activity of third-generation EGFR inhibitors in the CNS.  
Interestingly, the prevalence of T790M in brain metastases after treatment with a first-generation 
EGFR TKIs is 16% whereas in systemic metastases the prevalence is 50-60%, indicating a 
different etiology of drug resistance in the CNS.(50) 
 
Activity of Osimertinib (AZD9291)  for brain metastases 
Preclinical data suggests that Osimertinib (AZD9291)  has better activity in brain metastases in 
animal models of EGFR-mutant NSCLC compared to several other EGFR TKIs (51).  Osimertinib 
(AZD9291)  has been studied in patients with brain metastases from lung cancer, and early data 
suggests that there is activity in the CNS.  Among 3 EGFR-mutant patients who developed new 
brain metastases during treatment with rociletinib (another EGFR inhibitor), all of them had a CNS 
response to Osimertinib (AZD9291).(52) Additionally, a Phase I trial of patients with EGFR-
mutant lung cancer and leptomeningeal disease found that Osimertinib (AZD9291)  resulted in a 
radiographic improvement in 8 of 11 patients.(53)  Although this suggests that there is penetration 
of the drug into the CNS, most of these patients had prior brain radiation, so the independent effect 
of the drug in the CNS remains unknown. The largest study to date of Osimertinib (AZD9291)  in 
patients with CNS disease from EGFR mutant NSCLC is the BLOOM trial(54) which included 20 
patients with leptomeningeal disease who had progressed on a prior EGFR TKI.  Patients were 
treated with Osimertinib (AZD9291) 160mg daily.  Of the 12 patients who reached imaging 
assessment, 7 had radiographic improvement, 2 had stable disease, and 3 were not evaluable.  Of 
the 7 symptomatic patients, 3 had improvement in symptoms, 1 had no change and 2 were not 
evaluable; of the 5 asymptomatic patients, 2 had worsening symptoms and 3 remained 
asymptomatic.  Toxicity was consistent with that of other studies of Osimertinib (AZD9291) with 
no unexpected AEs.  This study demonstrated that Osimertinib (AZD9291) can have activity in 
the CNS in patients with previously treated EGFR-mutant NSCLC in a subset of patients.  The 
FLAURA trial (11) also demonstrated a superior PFS with Osimertinib (AZD9291) compared to 
standard EGFR TKIs among patients with brain metastases, indicating that there is superior CNS 
activity with this agent. 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
20 
patients enrolled on the trial, and the maximally tolerated doses were the standard doses of both 
drugs (Osimertinib (AZD9291) 80mg po daily and bevacizumab 15mg/kg IV every 21 days).  
There were no dose reductions or treatment discontinuations due to toxicity required.  There was 
only one SAE of hypertension that resolved with therapy.  In this trial, there were 12 patients with 
brain metastases, 8 of whom had untreated brain metastases at study initiation.  Among the 8 
patients with untreated brain metastases, there were 3 SAEs: one of grade 3 dyspnea that was 
considered possibly related to therapy, and 2 SAEs that were considered unrelated to study therapy.  
There were no neurologic SAEs (personal communication, unpublished data). 
 
There is no data available specifically for the activity of combination EGFR and VEGF therapy in 
the CNS.  Additionally, there is currently no data available for the combination of a third-
generation EGFR inhibitor with activity against T790M such as Osimertinib (AZD9291) plus a 
VEGF inhibitor.  Therefore, this trial aims to test the combination of Osimertinib (AZD9291)  plus 
bevacizumab in patients with EGFR-mutant NSCLC with brain metastases as initial treatment of 
advanced disease. 
 
We hypothesize that the addition of bevacizumab to Osimertinib (AZD9291) will improve the 
progression-free survival in patients with EGFR-mutant NSCLC and brain metastases. 
 
Additionally, we hypothesize that the combination of Osimertinib (AZD9291)  plus bevacizumab 
will be safe and tolerable, and will improve other markers of clinical benefit including time to CNS 
progression, overall response rate, intracranial response rate, and overall survival.   
 
2.5 Correlative Studies Background 
 
The goal of the correlative studies that accompany this trial is to identify factors associated with 
benefit from Osimertinib (AZD9291)  +/- bevacizumab in patients with EGFR mutant lung 
cancer and brain metastases. To achieve this goal we will perform a comprehensive set 
experiments that will evaluate the genomic landscape, angiogenesis markers, expression 
signatures and immune infiltrates of tumors on each arm of the study. Detailed information on 
the correlative studies is provided in Section 9. 
 
 
 
3 PATIENT SELECTION 
 
3.1 Eligibility Criteria  
 
3.1.1 NSCLC with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or 
any other mutation known to be associated with EGFR TKI sensitivity).  Presence of an 
activating EGFR mutation may be documented in tumor tissue or by plasma testing if 
performed in a CLIA-certified laboratory. 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
21 
3.1.2 No prior treatment with an EGFR TKI.  Patient may have received prior chemotherapy 
for early-stage or advanced disease but this is not required.  Prior immunotherapy is not 
allowed. 
 
3.1.3 Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, 
and does not require local therapy at the time of enrollment.  Measurable CNS disease is 
defined as a brain metastasis that can be accurately measured in at least one dimension 
ORQJHVW GLDPHWHU WR EH UHFRUGHG DV  PP  FP ZLWK EUDLQ 05, ,I WKH OHVLRQ LV -
10mm in size and is the only measurable disease, MRI imaging must be performed with 
1.5 mm slice thickness or less. 
 
A history of previously treated brain metastases is allowed, however any lesion present at 
the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or 
within 2mm of the treated lesion) will NOT be considered “untreated” unless it is new or 
documented to have progressed unequivocally since treatment. 
 
See Section 11 for the evaluation of measurable disease. 
 
3.1.4 Patients are not required to have measurable systemic (i.e. non-CNS) disease.  If present, 
measurable systemic disease must be able to be accurately measured in at least one 
dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal 
OHVLRQV DV  PP  FP ZLWK FRQYHQWLRQDO WHFKQLTXHV RU DV  PP  FP ZLWK
spiral CT scan, MRI, or calipers by clinical exam.  See Section 11 for the evaluation of 
measurable disease. 
 
3.1.5 $JH  \HDUV  
 
3.1.6 (&2* SHUIRUPDQFH VWDWXV 2.  
 
3.1.7 Life expectancy of greater than 3 months. 
 
 
3.1.8 The use of anti-convulsants is allowed, as long as the patient is on a stable dose with no 
seizure activity for at least 2 weeks prior to initiating trial therapy. 
 
3.1.9 Female subjects should be using highly effective contraceptive measures, and must have 
a negative pregnancy test and not be breast-feeding prior to start of dosing if of child- 
bearing potential or must have evidence of non-child-bearing potential by fulfilling one 
of the following criteria at screening:  
 
• 
Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 
months following cessation of all exogenous hormonal treatments 
• 
Women under 50 years old would be consider postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range for the institution 
• 
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
22 
oophorectomy or bilateral salpingectomy but not tubal ligation 
 
Fertile men should be willing to use barrier contraception. during and for 4 months after 
Osimertinib (AZD9291) , and fertile women must agree to use adequate contraceptive 
measures during and for 6 weeks after Osimertinib (AZD9291) .  Fertile men and women 
must agree to use adequate contraceptive measures during study therapy and for at least 6 
months after the completion of bevacizumab therapy.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, the patient 
should inform the treating physician immediately. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 Exclusion Criteria 
 
3.2.1 Symptomatic brain metastases or symptomatic leptomeningeal disease.  
Asymptomatic leptomeningeal disease is allowed.  
 
3.2.2 Patients with brain metastases for whom complete surgical resection is clinically 
appropriate.  
 
3.2.3 Prior treatment with any EGFR TKI. 
 
3.2.4 Prior treatment with agents targeting the VEGF pathway, including bevacizumab. 
 
3.2.5 The use of corticosteroids to control cerebral edema or treat neurologic symptoms 
will not be allowed, and patients who previously required corticosteroids for symptom 
control must be off steroids for at least 3 days without recurrence of symptoms prior to 
starting trial therapy.  Corticosteroids for other indications is allowed. 
 
3.2.6 Patients may not be receiving any other investigational agents and may not have 
participated in a study of an investigational agent or using an investigational device 
within five half-lives of the compound or 3 months, whichever is greater. 
 
3.2.7 Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time 
of starting study treatment with the exception of alopecia and grade 2 platinum-therapy 
related neuropathy. 
 
3.2.8 Concurrent, active malignancies in addition to that being studied (other than 
cutaneous squamous cell carcinoma or basal cell carcinoma). 
 
3.2.9 Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted 
medical devices).   
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
23 
3.2.10 Past medical history of interstitial lung disease, drug-induced interstitial lung disease, 
radiation pneumonitis which required steroid treatment, or any evidence of clinically 
active interstitial lung disease 
 
3.2.11 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Osimertinib (AZD9291)  or bevacizumab. 
 
3.2.12 Urine protein should be screened by urine analysis.  If protein is 2+ or higher, 24-
hour urine protein should be obtained.  Patients with 24-hour urine protein > 1000 mg are 
excluded. 
 
3.2.13 Serious or non-healing wound, ulcer or bone fracture. 
 
3.2.14 History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess 
within 6 months prior to day 1.  
 
3.2.15 Invasive procedures defined as follows: 
 
a. Major surgical procedure, open biopsy or significant traumatic injury within 28 
days prior to Day 1 therapy 
 
b. Anticipation of need for major surgical procedures during the course of the study 
 
c. Core biopsy within 7 days prior to D1 therapy 
 
3.2.16 Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Day 1. 
 
3.2.17 Patients with clinically significant cardiovascular disease are excluded. 
 
a. Inadequately controlled HTN (SBP >160mmHg and/or DBP >90 mmHg despite 
antihypertensive medication) 
 
b. History of CVA within 6 months (see additional requirement for adjuvant 
protocols) 
c. Myocardial infarction or unstable angina within 6 months (see additional 
requirement for adjuvant protocols) 
d. New York heart association grade II or greater congestive heart failure  
e. Serious and inadequately controlled cardiac arrhythmia 
f. Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection) 
g. Clinically significant peripheral vascular disease  
 
3.2.18 Any of the following cardiac criteria: 
a. Mean resting corrected QT interval (QTcF) > 470 ms obtained from 3 
electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc 
value 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
24 
b. Any clinically important abnormalities in rhythm, conduction or 
morphology of resting ECG (e.g., complete left bundle branch block, 
third degree heart block, second degree heart block) 
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history 
of long QT syndrome or unexplained sudden death under 40 years of age in first 
degree relatives or any concomitant medication known to prolong the QT interval. 
 
3.2.19 Evidence of bleeding diathesis or coagulopathy (including clinically significant 
hemoptysis). 
 
3.2.20 Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow 
the formulated product or previous significant bowel resection that would preclude 
adequate absorption of Osimertinib (AZD9291) . 
 
3.2.21 Patients with known hypersensitivity to Chinese hamster ovary cell products or other 
recombinant human antibodies.  
 
3.2.22 Patients currently receiving (or unable to stop use prior to receiving the first dose of 
study treatment) medications or herbal supplements known to be potent inducers of 
CYP3A4 (at least 3 week prior). All patients must try to avoid concomitant use of any 
medications, herbal supplements and/or ingestion of foods with known inducer effects on 
CYP3A4.  
 
3.2.23 Any evidence of severe or uncontrolled systemic diseases, including, but not limited 
to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the 
investigator’s opinion makes it undesirable for the patient to participate in the trial or which 
would jeopardise compliance with the protocol, or active infection including hepatitis B, 
hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is 
not required. 
 
3.2.24 History of hypersensitivity active or inactive excipients of Osimertinib (AZD9291) or 
drugs with a similar chemical structure or class to Osimertinib (AZD9291). 
 
3.2.25 Inadequate bone marrow reserve or organ function (as demonstrated by any of the 
following laboratory values: absolute neutrophil count <1.5 x 109/L; platelet count <100 x 
109/L; haemoglobin <90 g/L; alanine aminotransferase >2.5 times ULN if no demonstrable 
liver metastases or >5 times ULN in the presence of liver metastases; aspartate 
aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in 
the presence of liver metastases; total bilirubin >1.5 times ULN if no liver metastases or 
>3 times ULN in the presence of documented Gilbert’s Syndrome [unconjugated 
hyperbilirubinaemia] or liver metastases; serum creatinine >1.5 times ULN concurrent 
with creatinine clearance <50 mL/min [measured or calculated by Cockcroft and Gault 
equation]—confirmation of creatinine clearance is only required when creatinine is >1.5 
times ULN. 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
27 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI protocol #10042 protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is restricted 
and is based on person and site roster data housed in the CTSU RSS.  To participate, 
Investigators and Associates must be associated with the Corresponding or Participating 
protocol organization in the RSS.  
 
x Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
x Click on the Protocols tab in the upper left of your screen.  
x Either enter the protocol # in the search field at the top of the protocol tree, or 
x Click on the By Lead Organization folder to expand, then select LAO-CT018, and 
protocol #10042. 
x Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org (members’ area) Æ Regulatory Tab 
ÆRegulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
4.2.3 Requirements For 10042 Site Registration 
x IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
28 
website. 
x Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
x Click on the Regulatory tab at the top of your screen. 
x Click on the Site Registration subtab. 
x Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks.  
 
4.3 Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It is 
integrated with the CTSU Enterprise System for regulatory and roster data interchange and 
with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type.  
x To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
x Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes. 
x If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
29 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 General Guidelines 
 
Following registration, patients should begin protocol treatment within 10-14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient does 
not receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5 TREATMENT PLAN 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Arm 1: Osimertinib (AZD9291)  80mg PO QD plus bevacizumab 15mg/kg IV q3w 
Arm 2: Osimertinib (AZD9291)  80mg PO QD  
 
Patients will be randomized in a 1:1 fashion to Arm 1 (osimertinib plus bevacizumab) or Arm 2 
(osimertinib alone).   
Treatment in all arms will continue unless one of the follow criteria applies: 
x Disease progression as per RECIST 1.1 or RANO-BM and absence of clinical benefit 
x Symptomatic deterioration 
x Unmanageable toxicity 
 
 
Patients who experience either CNS or systemic progression but have documented response in the other 
site (systemic or CNS), and who are otherwise benefiting from treatment, are allowed to undergo local 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
30 
therapy to the progressive disease followed by continuation on study treatment; if the best response in the 
other site is only stable disease, the evidence of clinical benefit and decision to continue study therapy 
should be discussed with the Study Chair and the sponsor (CTEP).  Patients who experience tumor 
progression in both the CNS and in an extracranial site will come off therapy due to disease progression 
 
Patients who discontinue trial therapy will be followed off trial for survival endpoints. 
 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Osimertinib 
(AZD9291)  
None 
80mg 
PO  
Daily  
Days 1-21 
21 days  
(3 weeks) 
 
 
 
Bevacizumab 
(arm 1 only) 
None* 
15mg/kg 
IV 
IV 
Day 1 Q21 
days  
 
* If infusional reactions occur, acetaminophen, diphenhydramine, steroids, or other medications 
may be given for symptom control and for premedication as needed.  Anaphylactic precautions 
should be observed during bevacizumab administration. 
 
The patient will be requested to maintain a medication diary (Appendix F) of each dose of 
Osimertinib (AZD9291).  The medication diary will be returned to clinic staff at the end of each 
cycle. 
 
5.1.1 CTEP IND Agents 
 
5.1.1.1 Osimertinib (AZD9291)   
Osimertinib (AZD9291)  will be provided as tablets for oral administration as a single daily dose 
of 80 mg.  A desiccant is included with the tablets. 
Patients should swallow 1 tablet once daily, commencing on Day 1 but no later than within 2 days 
from randomization day. Tablets should be taken whole with water. 
 
The initial dose of Osimertinib (AZD9291)  80 mg once daily can be reduced to 40 mg once daily. 
Doses should be taken approximately 24 hours apart at the same time point each day. Doses should 
not be missed. If a patient misses taking a scheduled dose, within a window of 12 hours, it is 
acceptable to take the dose.  If it is more than 12 hours after the scheduled dose time, the missed 
dose should not be taken, and patients should be instructed to take the next dose at the next 
scheduled time. If a patient vomits after taking their study drug, they should not make up for this 
dose, but should take the next scheduled dose. 
 
Any change from the dosing schedule, dose interruptions, or dose reductions should be recorded 
in the eCRF. 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
31 
Additional information about Osimertinib (AZD9291)  may be found in the Investigator’s 
Brochure 
 
5.1.1.2 Bevacizumab 
 
Bevacizumab is administered by intravenous (IV) infusion.  The dose should be based on the 
patient’s actual body weight; the dose will be recalculated if there is a weight change of >10% 
from baseline.   
 
The first dose of bevacizumab should be given over a minimum of 90 minutes.  If well tolerated, 
the second dose can be given over a minimum of 60 minutes.  If this dose is well-tolerated, then 
all subsequent infusions can be administered over a minimum of 30 minutes.  If an infusion 
reaction occurs, subsequent doses of bevacizumab should be administered over the shortest period 
that was well tolerated.   
 
Special Precautions/Safety Issues: 
 
Prior to each treatment, the patient should be carefully assessed with special attention to blood 
pressure, proteinuria, bleeding and cardiovascular events, as well as symptoms or signs of bowel 
perforation and RPLS.  Decisions for retreatment or dose modification/interruption should follow 
the dose modification guidelines in Section 6.1. 
 
Patients who have an ongoing study agent-related SAE upon study completion or at 
discontinuation from the study will be contacted by the investigator or his/her designee 
periodically until the event is resolved or determined to be irreversible. 
 
Infusional reactions:  Routine premedication is not required for the first dose of bevacizumab.  If 
infusional reactions occur, acetaminophen, diphenhydramine, steroids, or other medications may 
be given for symptom control and for premedication as needed.  Anaphylactic precautions should 
be observed during bevacizumab administration. 
 
Hypertension:   Patients should have BP monitored prior to each infusion of bevacizumab.  
Hypertensive medication should be initiated or increased for optimal BP control according to 
standard public heath guidelines. 
 
Proteinuria:  Proteinuria should be monitored by dipstick at least every 6 weeks.    
 
Surgery and wound complication issues and surgery:  The appropriate interval from 
discontinuation of bevacizumab to subsequent elective surgery required to reduce the risk of 
impaired wound healing has not been determined.  Decision on such an interval should take into 
consideration the half-life of bevacizumab.  It is generally recommended that bevacizumab should 
be discontinued at least 4-8 weeks prior to major elective surgery.  In addition, bevacizumab should 
not be restarted until at least 4 weeks after major surgery provided that the wound has adequately 
healed; in cases of high risk procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that bevacizumab be resumed no earlier than 8 weeks after surgery. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
32 
 
5.2 General Concomitant Medication, Restrictions and Supportive Care Guidelines 
 
Once enrolled, guidelines regarding concomitant medications listed in Appendix B must be 
followed.  Patients may receive any medication that is clinically indicated for treatment of AEs. 
 
Drugs that are not allowed must have been discontinued for an appropriate period before they enter 
screening (as indicated in Appendix B). All concomitant medications should be captured on the 
electronic case report form (eCRF).  
 
1. Female patients of child-bearing potential should use reliable methods of contraception from the 
time of screening until 6 weeks after discontinuing Osimertinib (AZD9291)  and 6 months after 
discontinuing bevacizumab.  
2.   Male patients should be asked to use barrier contraceptives (i.e., by use of condoms) during sex 
with all partners during the trial and for a washout period of 4  months after Osimertinib 
(AZD9291)  or 6 months after bevacizumab. Male patients should avoid procreation for 4 months 
after Osimertinib (AZD9291)  or 6 months after bevacizumab. Patients should refrain from 
donating sperm from the start of dosing until 4 months after discontinuing Osimertinib (AZD9291)  
and 6 months after discontinuing bevacizumab. 
3.   Once enrolled all patients must try to avoid concomitant use of medications, herbal supplements 
and/or ingestion of foods that are known to be potent inducers of CYP3A4 whenever feasible, but 
patients may receive any medication that is clinically indicated for treatment of adverse events. 
Such drugs must have been discontinued for an appropriate period before they enter screening and 
for a period of 3 months after the last dose of Osimertinib (AZD9291). All concomitant 
medications should be captured on the eCRF. Guidance on medicines to avoid, medications that 
require close monitoring and on washout periods is provided (see Appendix B). 
4.   If medically feasible, patients taking regular medication, with the exception of potent inducers of 
CYP3A4 (see above), should be maintained on it throughout the study period. Patients taking 
concomitant medications whose disposition is dependent upon BCRP and/or P-glycoprotein (P-
gp) and which have a narrow therapeutic index should be closely monitored for signs of changed 
tolerability as a result of increased exposure of the concomitant medication whilst receiving 
Osimertinib (AZD9291). Guidance on medications to avoid, medications that require close 
monitoring and on washout periods is provided (see Appendix B).   
 
Patients taking rosuvastatin should have creatine phosphokinase levels monitored (due to BCRP-
mediated increase in exposure). If the patient experiences any potentially relevant AEs suggestive 
of muscle toxicity including unexplained muscle pain, tenderness, or weakness, particularly if 
accompanied by malaise or fever, rosuvastatin must be stopped and any appropriate further 
management should be taken.  
 
 
Appendix C presents guidelines for patients, their caregivers and non-study healthcare team 
members on identifying medications/substances that could potentially interact with the study 
agent(s). 
 
Patients taking warfarin should be monitored regularly for changes in prothrombin time or 
International Normalized Ratio (INR). 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
33 
 
Other anti-cancer therapies including investigational agents, and radiotherapy should not be given 
while the patient is still on study drug.   
 
5.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
 
x 
Disease progression in the absence of clinical benefit, 
 
x 
Intercurrent illness that prevents further administration of treatment, 
 
x 
Unacceptable adverse event(s), 
 
x 
Patient decides to withdraw from the study, or 
 
x 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
Subjects may be discontinued from investigational product (IP) in the following situations: 
 
x Subject decision. The subject is at any time free to discontinue treatment, without 
predjudice to further treatment 
x Adverse Event 
x Severe non-compliance with the study protocol 
 
Patients experiencing any of the following adverse events will not be permitted to restart study 
treatment: 
 
x Interstitial Lung Disease (ILD) 
x QTc interval prolongation with signs/symptoms of serious arrhythmia 
 
 
5.4 Duration of Follow Up 
 
Patients will be followed for a minimum of 4 weeks after removal from study treatment or until 
death, whichever occurs first.  As a minimum, telephone contact should be made with the patient 
28 days following the discontinuation of Osimertinib (AZD9291) to collect new AEs and follow 
up on any ongoing AEs and concomitant medications (including any subsequent cancer therapy). 
Patients removed from study for unacceptable adverse event(s) will be followed until resolution 
or staELOL]DWLRQ RI WKH DGYHUVH HYHQW  JUDGH . Survival data will be followed until death from 
any cause. 
 
5.5 Criteria for Removal from Study 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
34 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 Osimertinib (AZD9291)  
 
6.1.1 Dose reduction levels for Osimertinib (AZD9291)  are provided in Table 6.1. 
 
Table 6.1 Dose reduction levels 
 
 
Osimertinib 
Starting dose 
Osimertinib (AZD9291)  80 mg 
Reduced dose 
Osimertinib (AZD9291)  40 mg 
 
 
6.1.2 General dose adjustments on adverse events 
All patients to commence treatment of Osimertinib (AZD9291)  at the starting dose level of 80mg 
daily as shown in Table 6.1. 
 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), 
where the clinician considers the event of concern to be specifically associated with Osimertinib 
(AZD9291) (and not attributable to the disease or disease-related processes for which patient is 
being treated), dosing will be interrupted and supportive therapy administered as required in 
accordance with local practice/guidelines.  If a toxicity resolves or reverWV WR &7&$( JUDGH 
within 3 weeks of onset, treatment with Osimertinib (AZD9291) may be restarted at the same dose 
(80 mg) or a lower dose (40 mg) using the rules above for dose modifications (Table 6.1) and with 
discussion and agreement with the Sponsor Study Team Physician as needed. There will be no 
individual modifications to dosing schedule in response to toxicity, only potential dose reduction 
or dose interruption. 
 
,I WKH WR[LFLW\ GRHV QRW UHVROYH WR &7&$( JUDGH  DIWHU  ZHHNV WKHQ WKH SDWLHQW VKRXOG EH
withdrawn from the study and observed until resolution of the toxicity. 
 
Dose adjustment for adverse events should be in accordance with the following table: 
 
Table 6.2. Dose adjustment information for adverse reactions 
Target Organ 
Adverse Reaction 
Dose Modification 
Pulmonary 
ILD/Pneumonitis 
Permanently discontinue 
osimertinib 
Cardiac 
QTc interval greater than 500 
Withold osimertinib until 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
35 
msec on at least 2 separate 
ECGs 
QTc interval is less than 481 
msec or recovery to baseline 
if baseline QTc is greater than 
or equal to 481 msec, then 
restart at a reduced dose (40 
mg) 
 
QTc interval prolongation 
with signs/symptoms of 
serious arrhythmia 
Permanently discontinue 
osimertinib 
Other 
Grade 3 or higher adverse 
reaction 
Withhold osimertinib for up 
to 3 weeks 
 
If Grade 3 or higher adverse 
reaction improves to Grade 0-
2 after withholding of 
osimertinib for up to 3 weeks 
Osimertinib may be restarted 
at the same dose (80 mg) or a 
lower dose (40 mg) 
 
Grade 3 or higher adverse 
reaction that does not 
improve to Grade 0-2 after 
withholding for up to 3 weeks 
Permanently discontinue 
osimertinib 
 
 
On resolution of toxicity within 3 weeks: 
x If an AE subsequently requires dose interruption, Osimertinib (AZD9291)  may restart 
at the same dose or the reduced dose, on resolution/improvement of the AE at the 
discretion of the Investigator. 
 
Patients experiencing any of the following adverse events will not be permitted to restart study 
treatment: 
x Interstitial Lung Disease (ILD) 
x QTc interval prolongation with signs/symptoms of serious arrhythmia 
 
There is no dose reduction allowed below 40mg.  If a patient experiences toxicity such that 40mg 
is no longer considered tolerable, the patient should discontinue study treatment. 
Skin reactions 
It is recommended that all patients follow a program of sun protective measures while receiving 
study drug and for 3 to 4 weeks after discontinuing study drug. 
 
The aim is to reduce the risk of development of skin reactions or minimize the severity of skin 
reactions and minimize the requirement for dose reduction of study drug. T o x i c i t y  w i l l  
b e  m a n a g e d  a c c o r d i n g  t o  l o c a l  g u i d e l i n e s .    
Skin reactions are to be reported as AEs in the eCRF, with additional details captured in the 
"SKNREAC" eCRF such as: 
x Changes in the characteristics of skin reactions will be collected in the "SKNREAC" eCRF. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
37 
Life threatening 
(Grade 4) 
Life-threatening 
consequences (e.g. 
haemodynamic collapse)  
Dose interruption 
until recovered to 
Grade 1 
followed by dose 
reduction 
Toxicity will be managed as per local guidelines.  
 
 
Appropriate management of diarrhea, including dose adjustments for AEs of diarrhea that are of 
CTCAE Grade  RU WKDW DUH FOLQLFDOO\ significant and/or intolerable and considered by the 
Investigator to be causally related to Osimertinib (AZD9291) , should be undertaken as per standard 
practice and guidelines for dose adjustments above. Changes in CTCAE grade of diarrhea will be 
captured in the AE eCRF. 
 
QTc prolongation 
Patients with QTcF prolongation to >500 msec should have study treatment interrupted and regular 
ECGs performed until resolution to <481 msec or recovery to baseline if baseline QTcF is >481 
msec and then restarted at a reduced dose of 40mg. If the toxicity does not resolve WR  JUDGH 
within 21 days the patient will be permanently withdrawn from study treatment.  
Interstitial lung disease (ILD)/Pneumonitis-like toxicity 
If a new or worsening of pulmonary symptoms (e.g., dyspnea) or occurrence of a radiological 
abnormality suggestive of ILD is observed, an interruption in study drug dosing is recommended, 
and the Study Physician should be informed. It is strongly recommended to perform a full 
diagnostic workup to exclude alternative causes such as lymphangitic carcinomatosis, infection, 
allergy, cardiogenic edema, or pulmonary hemorrhage.  In the presence of confirmatory HRCT 
scans where other causes of respiratory symptoms have been excluded, a diagnosis of ILD should 
be considered and study drug permanently discontinued. In the absence of a diagnosis of ILD, 
study drug may be restarted following consultation with the Study Physician. 
 
Note: Patients experiencing ILD will not be permitted to restart study drug. 
 
Keratitis 
Keratitis was reported in 0.7% (n=6) of the 833 patients treated with Osimertinib (AZD9291)  
in the AURA studies. Patients presenting with signs and symptoms suggestive of keratitis such 
as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain 
and/or red eye should be referred  promptly to an ophthalmology specialist. 
 
Changes in cardiac contractility 
Across clinical trials, Left Ventricular Ejection Fraction (LVEF) decreases greater than or equal 
to 10% and a drop to less than 50% occurred in 4.0% (26/655) of patients treated with 
Osimertinib (AZD9291)  who had baseline and at least one follow-up LVEF assessment. Based 
on the available clinical trial data, a causal relationship between effects on changes in cardiac 
contractility and Osimertinib (AZD9291) has not been established. Whilst Osimertinib 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
45 
Adverse events reported on Osimertinib (AZD9291) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Osimertinib 
(AZD9291) caused the adverse event: 
  
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Myocardial infarction; 
Supraventricular tachycardia 
EYE DISORDERS - Eye disorders - Other (corneal erosion); Eye disorders - Other (eyelids 
pruritus); Eye disorders - Other (corneal epithelium defect); Vision decreased 
GASTROINTESTINAL DISORDERS - Dry mouth; Dyspepsia; Dysphagia; Gastritis; 
Gastrointestinal disorders - Other (intestinal ischemia); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever2; 
Flu like symptoms; Generalized edema; Malaise; Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Folliculitis; Infections and infestations - Other (pustule); 
Lung infection; Nail infection; Papulopustular rash; Rash pustular; Shingles; Upper respiratory 
infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (drug eruption) 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase 
increased; CPK increased; Creatinine increased; Ejection fraction decreased; GGT increased; 
Investigations - Other (electrocardiogram QT interval abnormal); Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; 
Hypermagnesemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -; Back pain; Generalized 
muscle weakness; Neck pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Ischemia cerebrovascular; Stroke 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS -; Dyspnea2; Epistaxis; 
Hypoxia; Pleural effusion; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (skin fissures); 
Skin and subcutaneous tissue disorders - Other (onychomalacia); Skin and subcutaneous tissue 
disorders - Other (onychalgia); Skin and subcutaneous tissue disorders - Other (skin erosion); 
Urticaria 
VASCULAR DISORDERS - Hematoma; Thromboembolic event 
 
 
Note: Osimertinib (AZD9291) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
 
 
   
 
 
 
 
 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
49 
2Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and atrial flutter. 
 
3The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in patients 
with a history of diabetes. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric 
fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large intestinal 
anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic 
leak. 
 
11There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the age of 18 
treated with bevacizumab. 
 
12Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
13Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab 
treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates. 
 
14Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and 
chemotherapy compared to chemotherapy alone.  
 
15Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
HOHYDWLRQ  P,8P/ ZDV LQFUHDVHG LQ SDWLHQWV UHFHLYLQJ DGMXYDQW EHYDFL]XPDE SOXV P)2/)2; FRPSDUHG WR
mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and an FSH level 
<30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on 
fertility are unknown. 
 
16Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack, and 
stroke. 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
50 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that bevacizumab (rhuMAb VEGF) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac arrest; 
Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane perforation); 
Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye 
disorders - Other (ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient 
increased IOP > or =30 mm Hg); Eye pain; Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal 
detachment; Retinal tear; Retinopathy; Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral 
pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema 
limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site reaction; Localized 
edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic failure; 
Hepatic necrosis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; Dermatitis 
radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone abnormal; 
CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Electrocardiogram 
QT corrected interval prolonged; Forced expiratory volume decreased; GGT increased; INR increased; Lipase 
increased; Lymphocyte count decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest 
wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; Muscle weakness lower limb; 
Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); 
Neck pain; Osteonecrosis; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; Cerebrospinal fluid 
leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; 
Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; Leukoencephalopathy; Memory 
impairment; Myasthenia gravis; Nervous system disorders - Other (increased intracranial pressure); Paresthesia; 
Peripheral motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; Dysuria; 
Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular 
menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders - Other (pulmonary 
infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain of skin; 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
51 
Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin 
and subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin 
induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.2   Adverse Event Characteristics  
 
x CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 7.3.4. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
53 
Not resulting in 
Hospitalization  
  KUV 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.3.4   Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
Not applicable 
 
7.3.5 Adverse Events of Special Interest in Bevacizumab Studies 
 
The following AEs are considered of special interest in patients receiving bevacizumab 
and must be reported expeditiously through CTEP-AERS: 
• Hypertension > Grade 3 
• Proteinuria > Grade 3· 
• GI perforation, abscesses and fistulae, any grade 
• Wound healing complications > Grade 3 
• Haemorrhage > Grade 3  
• CNS bleeding, any grade 
• Hemoptysis > Grade 2  
•Arterial Thromboembolic event, anygrade 
• Venous thromboembolic events > Grade 3 
• Posterior Reversible Encephalopathy Syndrome (PRES), any grade 
• CHF  > Grade 3 
• Non-GI fistula or abscess  > Grade 2 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
54 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times during 
the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to describe 
the event:  
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS)  
x Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE reporting 
unless otherwise specified. 
 
7.7   Pregnancy 
 
All pregnancies and outcomes of pregnancy should be reported to the Sponsor and the Company 
during the course of the study and within 6 weeks of the last dose of Osimertinib (AZD9291). 
 
Maternal exposure 
 
If a subject becomes pregnant during the course of the study Osimertinib (AZD9291) and 
bevacizumab should be discontinued immediately. 
 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
55 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs.  Elective abortions without complications should not be handled as 
AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the subject was discontinued from the study. 
 
If any pregnancy occurs in the course of the study or within 6 weeks of the final dose of the 
investigational product, then the Investigator or other site personnel informs the appropriate 
Sponsor/Sponsor representatives within 1 day i.e., immediately but no later than 24 hours of when 
he or she becomes aware of it. 
 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor data entry site within 1 or 5 calendar days for SAEs and 
within 30 days for all other pregnancies. 
 
The same timelines apply when outcome information is available. 
 
Paternal exposure 
 
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should if possible be followed up and documented. 
 
To capture information about a pregnancy from the partner of a male subject, the male subject’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; the 
male subject should not be asked to provide this information. A consent form specific to this 
situation must be used. The outcome of any conception occurring from the date of the first dose 
until 4 months after dosing ends should be followed up and documented. 
 
7.8   Overdose 
 
In the context of a clinical study, an overdose is any dose which exceeds the daily dose that is 
defined in the clinical study protocol.  
 
A maximum tolerated dose has not been established for Osimertinib (AZD9291). 
 
Such overdoses should be recorded as follows: 
Standard mandatory text in CSP template 
 
There is no specific treatment in the event of Osimertinib (AZD9291) overdose, and symptoms of 
overdose are not established. In the event of an overdose, physicians should follow general 
supportive measures and should treat symptomatically 
 
If an overdose on a Company study drug occurs in the course of the study, then the Investigator or 
other site personnel inform the appropriate Sponsor representatives immediately, or no later than 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
56 
24 hours of when he or she becomes aware of it. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 7.3. 
For other overdoses, reporting must occur within 30 days. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 CTEP IND Agents 
 
8.1.1 Osimertinib (AZD9291) 
 
Chemical Name: N-(2-{[2-(Dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-
1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate 
 
Other Names: Tagrisso™, AZD9291 mesylate 
 
Classification: Epidermal growth factor receptor (EGFR) inhibitor 
 
Molecular Formula: C28H33N7O2.CH4O3S   
M.W.: 595.71 (mesylate salt) 
 
 
 
 
 
 
 
 
499.61 
(free base) 
 
Approximate Solubility: The solubility of osimertinib free base has been measured as 7.2 
mg/mL in Simulated Gastric Fluid (pH 1.4) and 0.2 mg/mL in Fasted State Simulated Intestinal 
Fluid (pH 6.5). 
 
Mode of Action: Osimertinib (AZD9291) is a potent, oral, irreversible, tyrosine kinase inhibitor 
(TKI) of epidermal growth factor receptor (EGFR) mutation-positive (EGFRm) and T790M 
mutation-positive forms of EGFR. 
 
Description: Osimertinib mesylate is a crystalline powder. 
 
How Supplied: Osimertinib (AZD9291) tablets are supplied by AstraZeneca and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Tablets are packaged in 30-count 
bottles with mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and 
sodium stearyl fumarate as inactive ingredients in the following strengths: 
x 80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain 
on the reverse. 
x 40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain 
on the reverse. 
 
The tablet coating contains polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric oxide 
yellow, ferric oxide red and ferric oxide black. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
57 
 
Storage: Store at room temperature 20° to 25°C (68° to 77°F), excursions permitted between 15 to 
30°C (59 to 85°F). 
 
If a storage temperature excursion is identified, promptly return osimertinib (AZD9291) to 
controlled room temperature and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the excursion) 
to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Refer to the package label for expiration.   
 
Route of Administration:  Take by mouth with or without food.  If a dose of osimertinib (AZD9291) 
is missed or vomited, do not make up the missed dose and take the next dose as scheduled. 
 
Potential Drug Interactions:  The main metabolic pathways of osimertinib (AZD9291) are 
oxidation (predominantly CYP3A4) and dealkylation in vitro.  Avoid concomitant use of strong 
CYP3A4 inducers.  CYP3A4 inhibitors are not likely to affect the exposure of osimertinib 
(AZD9291).  Based on in vitro studies, osimertinib (AZD9291) is a competitive inhibitor of CYP 
3A4/5 but not CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at clinically relevant 
concentrations. Osimertinib (AZD9291) is an inducer of CYP1A2.  Use caution with 
coadministration of CYP 3A4/5 and 1A2 substrates. 
 
Osimertinib (AZD9291) is a substrate of BCRP and P-gp but is unlikely to result in clinically 
relevant drug interactions.  Osimertinib (AZD9291) is not a substrate of OATP1B1 and OATP1B3 
and does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MATE1 and MATE2K at 
clinically relevant concentrations.  Based on in vitro data, osimertinib (AZD9291) is an inhibitor 
of BCRP and may increase the exposure of BCRP substrates.  Osimertinib (AZD9291) does not 
inhibit P-gp at clinically relevant concentrations but has the potential to increase exposure of 
sensitive substrates. 
 
Avoid use of osimertinib (AZD9291) in patients with congenital long QT syndrome. For patients 
with normal QT interval at the trial enrollment, avoid use of concomitant drugs that are known to 
prolong QT interval and use caution with drugs that may prolong QT interval. Refer to a frequently 
updated drug information reference and to the protocol for appropriate cardiac monitoring.  
 
 
 
Patient Care Implications: Advise women of reproductive potential to use effective contraception 
while receiving study treatment and for 6 weeks after the last dose of Osimertinib 
(AZD9291). Men should use effective contraception while receiving study treatment and 
for 4 months after the last dose of Osimertinib (AZD9291). Refer to the protocol document 
for specific guidance. 
 
8.1.2 Bevacizumab (NSC 704865) 
 
Other Names:  
rhuMAb VEGF, Avastin® 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
58 
 
Classification:  
Recombinant humanized monoclonal antibody 
 
Molecular Weight: 
Approximate molecular weight is 149,000 daltons 
 
Mode of Action:  
Bevacizumab blocks the binding of vascular endothelial 
growth factor (VEGF) to its receptors resulting in inhibition 
of angiogenesis. 
 
Description:  
Bevacizumab is a recombinant humanized anti-VEGF 
monoclonal antibody consisting of 93% human and 7% 
murine amino acid sequences. The agent is composed of 
human IgG framework and murine antigen-binding 
complementarity-determining regions 
 
How Supplied:  
Genentech supplies and the PMB/CTEP/DCTD/NCI 
distributes bevacizumab as a clear to slightly opalescent, 
sterile liquid for parenteral administration.    Each 400 mg 
(25mg/ml – 16 mL fill) glass vial contains bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for 
Injection, USP. 
   
Preparation:   
Vials contain no preservatives and are intended for single 
use only. Place the calculated dose in 100 mL of 0.9% 
sodium chloride for injection. The concentration of the final 
bevacizumab solution should be kept within the range of 1.4 
– 16.5 mg/ml. 
 
Storage:  
8SRQ UHFHLSW UHIULJHUDWH EHYDFL]XPDE Û WR Û & 'R QRW
freeze.  Do not shake.  If a storage excursion is identified, 
promptly return bevacizumab to 2°C-8°C (36°F-46°F) and 
quarantine the supplies.  Provide a detailed report of the 
excursion 
(including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov 
for 
determination 
of 
suitability. 
 
Stability:  
Shelf-life studies of rhuMAb VEGF are ongoing.  The sterile 
single use vials contain no antibacterial preservatives.  
Discard vials 8 hours after initial entry. 
 
Once diluted in 0.9% sodium chloride, administer solutions 
of bevacizumab within 8 hours. 
   
Route of Administration:  Intravenous 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
59 
Method of Administration: Administer the initial dose over a minimum of 90 minutes.  
If no adverse reactions occur, administer the second dose 
over a minimum of 60 minutes. If no adverse reactions occur 
after the second dose, administer subsequent doses over a 
minimum of 30 minutes. If infusion-related adverse 
reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated.  
 
 
Availability: Bevacizumab is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational agents 
for the study should be ordered under the name of one lead investigator at that institution. 
 
 Study agent must be ordered after patient is registered to the treatment arm as no starter 
supplies are available for this study. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   
 
8.1.4 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
Investigator Brochure Availability–   
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
60 
8.1.5 The current versions of the IBs for PMB-supplied agents will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity 
and Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  Questions about 
IB access may be directed to the PMB IB coordinator via email.    
 
8.1.6 Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/  
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/   
x CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
x IB Coordinator:  IBCoordinator@mail.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
x PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
We will perform correlative studies including the use of 1 integrated biomarker to be measured in 
the tumor and 3 exploratory biomarkers to be measured in the tumor or plasma.  
 
Integrated biomarker: 
1. Molecular profiling using the Oncomine Comprehensive Research Panel; 
 
Exploratory biomarkers 
1. Angiogenesis, Immune and Signaling Pathway Markers; 
2. Circulating Tumor DNA; 
3. Markers of Angiogenesis and Inflammation. 
 
Tumor tissue will be obtained by a surgical or biopsy procedure. Tissue will be required from all 
patients at baseline unless not considered feasible (i.e. in the case of disease progression in the 
CNS only).  Tissue will also be collected at the time of disease progression when the patient is 
undergoing biopsy for clinical purposes. Blood will be collected from patients at the following 
timepoints: baseline, every 6 weeks on trial therapy, and at progression.   
 
The subject’s consent to the use of donated biological samples is mandatory. 
 
9.1 
Integrated Correlative Studies 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
61 
9.1.1 Molecular Profiling using the Oncomine Comprehensive Research Panel 
 
The genomic landscape of EGFR mutant lung cancers 
 
Using the Oncomine next generation sequencing assay, we will centrally confirm the presence of 
the specific sensitizing mutation in EGFR.  This will be done after the patient is enrolled and 
treated on trial for the purposes of analyzing the data.  Additionally, co-occurring mutations are 
often detected with EGFR mutations and little is known about how these affect response to 
therapies. For example, mutations in tumor suppressors like TP53 occur in >50% of EGFR mutant 
tumors. Tumors that do not have TP53 mutations however, have mutations in other tumor 
suppressor genes such as ATM, CDKN2B and RB1. The data that we collect from the Oncomine 
panel provide us with the unique opportunity to analyze the relationship between co-occurring 
mutations, response to therapy and drug resistance. We hypothesize that co-occurring mutations 
may impact the PFS and response to Osimertinib (AZD9291) with or without bevacizumab.  The 
objective of this analysis is to identify genes that when altered modulate the response to 
Osimertinib (AZD9291)  +/- bevacizumab either by affecting extracranial and CNS response rates, 
PFS or OS. We hypothesize that: 1) tumors with mutations in TP53 at baseline will have a worse 
outcome as compared to those with intact TP53, 2) mutations in genes that potentiate angiogenic 
signaling will be associated with reduced response to bevacizumab. In addition, to testing these 
specific hypotheses, this assay data will allow us to identify novel genes and pathways that may 
play a role in response and resistance to these drugs. To perform these experiments, we will 
comprehensively assess mutations and/or copy number alterations in 143 genes cancer genes using 
the Oncomine panel. 
 
The Oncomine™ Comprehensive Assay is composed of primer pools for highly multiplex PCR 
amplification of DNA to provide substrate for next generation sequencing to detect single 
nucleotide variants (SNVs), small insertions and deletions (indels), copy number variants (CNVs), 
and gene fusions within tissue samples.  The assay was developed and is manufactured by 
ThermoFisher Scientific for use with Ion Torrent sequencing instruments and data analysis 
software.  The assay simultaneously interrogates DNA sequence in 143 cancer-related genes.  Full 
coding sequences or selected regions of the genes (hotspots) are analyzed, based on the most 
frequent sites of alterations in cancer.  Gene fusions are assayed by analysis of cDNA generated 
from RNA by reverse transcription prior to amplification with the Oncomine primers (RNAseq).  
The assay calls for 20ng of DNA and 10ng of RNA per tumor, extracted from formalin-fixed, 
paraffin-embedded or fresh tissue samples.   
 
The Oncomine workflow has been extensively validated by the NCI-MATCH Trial, and the Yale 
Clinical Molecular Pathology Laboratory (YCMPL), which participated in this validation and is a 
MATCH sequencing center, has been performing sequencing of tumor DNA and RNA with the 
Oncomine assay for several years.  The system has been optimized and updated several times 
during that period. 
 
Paraffin blocks containing tissue biopsy specimens will be sent to the YCMPL for pre-analytic 
work up and processing.  The blocks will be sectioned and one section stained with hemotoxylin 
and eosin for examination under the light microscope of tumor content and quality (e.g., amount 
of necrosis).  Regions of the tissue section containing tumor will be circled on the stained slide 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
62 
and corresponding regions on unstained slides bearing sections from tissue adjacent to the stained 
section will be manually microdissected from the sections.  If the tumor cells on the slide are 
scattered or clustered in small clumps within normal tissue, laser capture microdissection will be 
used to collect the tissue for analysis. 
 
DNA and RNA will be extracted from the deparaffinized tissue and subjected to analysis using the 
Oncomine primer pools and sequencing on an Ion Torrent personal genome machine (PGM), 
followed by a data analysis using Torrent Suite, Ion Reporter, and custom software developed at 
Yale.  The data will be assessed by automated and manual quality control procedures, and any 
variants that pass filters will be evaluated manually to eliminate known artifacts and confirm 
accuracy.   
 
 
9.1.1.1 Collection of specimen(s) 
Tumor tissue will be obtained by a surgical or biopsy procedure. Tissue will be required 
from all patients at baseline unless not considered feasible (i.e. in the case of disease 
progression in the CNS only).  Tissue will also be collected at the time of disease 
progression when the patient is undergoing biopsy for clinical purposes. 
 
9.1.1.2 Handling of specimen(s) 
See Appendix D for details. 
 
9.1.1.3 Shipping of specimen(s) 
See Appendix D for details. 
 
9.1.1.4 Site(s) Performing Correlative Study 
This assay will be performed under the direction of Dr. 
 at the Yale School of 
Medicine. 
 
9.2 Exploratory Correlative Studies 
 
9.2.1 Angiogenesis, Immune and Signaling Pathway Markers 
 
The major target of bevacizumab is VEGF, which can bind to receptors expressed by endothelial 
cells. In addition to its known ability to modulate of endothelial cell function, angiogenesis and 
vascular permeability, VEGF can also regulate the mobilization of leukocytes, in particular 
immune cells of the myeloid lineage such as macrophages, which also express VEGF receptors. 
While biomarkers for bevacizumab in NSCLC are lacking, it is notable that in pre-clinical models 
of EGFR mutant lung adenocarcinoma, tumor derived VEGF production is induced by TKI 
resistant xenografts.(74) Moreover, combining bevacizumab with erlotinib improves progression 
free survival in patients with EGFR mutant tumors, including those with acquired drug 
resistance.(63) 
  
In pre-clinical models of brain tumors, peri-vascular tumor associated macrophages can also confer 
acquired resistance to bevacizumab treatment. Biomarkers for bevacizumab and osimeritinb may 
therefore be expressed by lung cancer cells, vascular cells, or myeloid cells in the tumor 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
64 
images is captured using the PM2000 image workstation. For each field of view (FOV) on a whole 
tissue section images for three different channels are obtained. Signal from DAPI stain visualizes 
the nuclei, cytokeratin is visualized with Alexa 546 and the protein of interest with Cy5. Binarizing 
the cytokeratin signal creates a tumor mask which allows the measurement of pixels of the target 
of interest within this defined tumor area and/or within subcellular compartments. This method of 
biomarker quantification can be applied to tissue micro arrays (TMAs) and to whole tissue sections 
(WTSs).  
 
For quality control purposes and standardization, each antibody is validated using a previously 
described antibody validation protocol (76). Antibodies are titrated on test TMAs consisting of 40 
cancer specimens and the optimal titer is chosen according to an expression range graph, which 
allows objective assessment of the optimal dynamic range and the signal to noise ratio of a given 
protein of interest. Specificity is evaluated by Western Blots for every protein-specific antibody to 
confirm the recognition of a single band at the correct molecular weight. These assays are followed 
by staining and AQUA analysis of a cell line TMA and protein expression of a given antibody on 
cell lines on the TMA are correlated with the Western Blot result. Reproducibility of the antibody 
is assessed with AQUA analysis of serial sections of test arrays stained under the same conditions 
on different days. An r2 of 0.75 and above is defined as sufficient antibody reproducibility. Only 
antibodies that validate by this protocol are used for assessment of clinical specimens.  
 
Antibodies to be used in panel are: CD34, Cytokeratin, CD68 and VEGF. A second panel will 
include PD-L1 clone E1L3N from CST. 
 
All assays are standardized and automated after validation. This approach will allow us to 
standardize the assays and offer them as CLIA certified tests for clinical evaluation. 
 
In addition to performing IHC on tumor samples, we will also perform RNA sequencing.  The 
Yale Center for Genome Analysis has expertise in performing RNA sequencing on FFPE 
specimens. These studies will allow us to establish whether we can identify signatures of 
angiogenesis, hypoxia and inflammation and to determine whether these correlate with sensitivity 
to Osimertinib (AZD9291)  +/- bevacizumab.  
 
9.2.1.1 Collection of specimen(s) 
Tumor tissue will be obtained by a surgical or biopsy procedure. Tissue will be required from all 
patients at baseline unless not considered feasible (i.e. in the case of disease progression in 
the CNS only).  Tissue will also be collected at the time of disease progression when the 
patient is undergoing biopsy for clinical purposes. 
 
9.2.1.2 Handling of specimen(s) 
See Appendix D for details. 
 
9.2.1.3 Shipping of specimen(s) 
See Appendix D for details. 
 
9.2.1.4 Site(s) Performing Correlative Study 
These assays will be performed at the Yale School of Medicine in the following laboratories: Dr. 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
66 
when a patient exhibits a good treatment response (based on imaging), and rise when disease 
progression occurs.   
 
We will utilize this assay for non-invasive mutation profiling at baseline, longitudinally during 
therapy with Osimertinib (AZD9291) with or without bevacizumab, and at progression on study 
therapy to determine whether plasma-based biomarkers can predict for treatment benefit.  We aim 
to test the hypothesis that circulating tumor DNA can be used as a quantitative biomarker of 
treatment response and resistance.  We expect levels of mutant ctDNA to decline within a few 
weeks after initiation of treatment if the patient has a good therapeutic response.  Such declines 
have been observed anecdotally in previous studies, but the timing and magnitude of decline would 
be important to characterize in the setting of a clinical trial where all patients are receiving a 
uniform therapy.  Also, the development of the resistance mutation C797S has been documented 
in patients treated with third-generation EGFR inhibitors, and this mutation has been reported to 
be detectable in ctDNA.  In this study, we aim to collect serial blood samples during therapy to 
assess whether the C797S mutation (and possibly other mutations) can be detected in the plasma 
of patients who progress, and whether such mutations are detectable prior to clinical evidence of 
progression. 
 
9.2.2.1 Collection of specimen(s) 
10 ML of blood will be collected from patients in purple top EDTA tubes at the following 
timepoints: baseline, every 6 weeks on trial, and at progression.   
 
9.2.2.2Handling of specimen(s) 
See Appendix E for details. 
 
9.2.2.3 Shipping of specimen(s) 
See Appendix E for details. 
 
9.2.2.4 Site(s) Performing Correlative Study 
This assay will be performed by Dr. 
, MD, PhD at Yale School of Medicine. 
 
9.2.3 Blood-based Markers of Angiogenesis and Inflammation 
 
Blood-based biomarkers 
To date, the effort to identify candidate predictive blood-based markers for anti-angiogenic 
inhibitors has been challenging for many reasons. These include biological complexity, limitations 
of available reagents, limited sample collection in most trials, and a lack of randomization, which 
is needed to deal with the potential confounding of prognostic and predictive markers. Many of 
these barriers have now been overcome.  Compared to tissue-based biomarkers, blood-based 
biomarkers have the significant advantages of low cost, universal applicability, and the ability to 
be followed over the course of a patient’s treatment.   By focusing on soluble factors of known 
biological relevance, further scientific, diagnostic, and therapeutic efforts are greatly facilitated.   
 
Anti-VEGF therapies 
Recently, our multiplex ELISA approach has identified several strong candidate predictors of 
benefit from bevacizumab. In CALGB80303, a phase III study of gemcitabine ± bevacizumab, our 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
67 
group identified VEGF-D as a candidate predictor for benefit from bevacizumab(80). VEGF-D, as 
measured by IHC in FFPE tumor samples, was also a predictive marker for bevacizumab in the 
randomized phase II MAX study(81). The related factor, VEGF-C, has also been implicated as a 
predictive marker for bevacizumab in a non-randomized cohort comparison study(82).   Processed 
forms of VEGF-D and VEGF-C, which are abundant in tumor tissues, can bind and activate 
VEGFR-2, potentially bypassing VEGF-A blockade.  In addition, recent work has implicated 
processed forms of VEGF-A as predictive markers for bevacizumab(83, 84).  While there is 
considerable biological overlap, processed or short isoforms of VEGF-A are generally associated 
with pathological angiogenesis while longer isoforms tend to be associated with physiological 
angiogenesis. Taken together, these findings suggest that VEGF family ligands may mediate 
sensitivity and resistance to the VEGF-A binder bevacizumab.  Importantly, many limitations in 
the quality of reagents, particularly around VEGF-A and VEGF-C, have now been overcome.  
 
Another recent and instructive success is the identification of IL-6 as a strong candidate predictive 
biomarker for anti-VEGF therapy in renal cell carcinoma.  This marker was found to be a 
predictive marker in two independent phase III studies, each of which used a different VEGF 
inhibitor.  VEG105192 was a phase III study of BSC +/- pazopanib in refractory mRCC(85) and 
CALGB90206 was a phase III study of IFN +/- bevacizumab in 1st line mRCC (86).   Both of 
these studies found that high levels of IL6 predicted for greater benefit from these VEGF 
inhibitors(65, 87).  The CALGB study with bevacizumab also found a predictive role for HGF that 
was IL-6 dependent (i.e., a 3-way treatment interaction)(87). The role of the IL6-Jak-Stat axis is 
particularly intriguing given its role in tumor associated inflammation and anti-tumor immunity. 
Numerous other inflammatory mediators have been shown to regulate tumor angiogenesis and 
sensitivity to anti-VEGF therapy(88, 89). Tumor angiogenesis, inflammation, and anti-tumor 
immunity have highly interconnected biologies, a topic that has been extensively reviewed(90-92). 
However, to date, these factors have not been systematically interrogated in most anti-VEGF 
therapy trials.   Analysis of the role of inflammation in mediating resistance to anti-VEGF therapy 
is now highly clinically relevant, particularly since most of these factors are now targetable in the 
clinic with agents either FDA approved or in clinical trials.   
 
Anti-EGFR therapies 
Blood-based biomarkers for predicting benefit from anti-EGFR therapy have also been recently 
identified.  Currently, in colorectal cancer treatment, RAS mutation status in the patient’s tumor 
sample is the widely accepted gold standard predictive marker for cetuximab, as well as 
panitumumab.  However, for a variety reasons, blood-based markers have not been extensively 
evaluated in large, randomized anti-EGFR trials.  In the phase III trial of best supportive care ± 
erlotinib in non-small cell lung cancer, VHUXP 7*)Į ZDV LGHQtified as a candidate predictor(93). 
In colorectal cancer, several EGFR ligands have been identified as candidate predictors for 
cetuximab in non-randomized studies(94). Using FFPE tumor samples from the randomized phase 
II study CALGB80203 evaluating FOLFOX or FOLFIRI +/- cetuximab, our group recently 
identified gene expression of HER3 and CD73 as candidate predictors of benefit from cetuximab 
(95).  These results are particularly intriguing since CD73 is a well-recognized modulator of 
inflammation and immunity and anti-EGFR therapies are well known to be associated with 
inflammatory responses to treatment (i.e, acneiform rash).  Moreover, CD73 expression also 
identified a group of patients whose tumors were KRAS mutated that benefited from cetuximab; 
if confirmed, this finding has major implications for our understanding of RAS mutations and anti-
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
68 
EGFR therapies. Other mRNA markers that showed modest trends in either PFS or OS included 
HER2, HER4, BTC, DUSP4, and HB-EGF.  
 
We have recently optimized methods for the use of multiplex ELISA methods for the majority of 
HER axis ligands and soluble receptors in the plasma of cancer patients.  We have also recently 
developed completely novel ELISAs that are not commercially available for both soluble HER3 
and soluble CD73.  Initial analyses of the plasma samples from CALGB80203 were presented at 
ASCO in 2014(96).  In this analysis, plasma levels of EGF and sHER3 were potential predictive 
biomarkers for benefit from cetuximab. Low levels of EGF predicted for OS benefit from 
cetuximab in KRAS WT tumors and lack of benefit in KRAS mutant patients (codons 12 and 13 
only), but were not predictive across all patients combined. Patients with higher sHER3 levels had 
significant OS benefit from cetuximab treatment.  The consistent finding that HER3 is predictive 
in both tissue and plasma justifies further investigation.   
 
We have also recently completed our analysis of CD73 levels in plasma samples from patients 
treated in CALGB80203. This analysis found plasma CD73 was strongly predictive of overall 
survival for cetuximab (unpublished data). The finding in CALGB80203 that both tissue and 
plasma CD73 are also predictive of benefit from cetuximab suggests the importance of CD73, and 
by extension ADCC and inflammation, as mediators of cetuximab sensitivity and resistance; these 
results also merit further investigation.  
 
The application of multiplex ELISA approaches in clinical samples is rapidly evolving, having 
only recently shown positive results. The design of our multiplex panel array to interrogate diverse 
biologies related to angiogenesis is novel. Many of the analytes in our multiplex array were 
developed specifically for our use and have been carefully optimized for performance in plasma 
and serum samples from cancer patients. Our approach utilizes the Searchlight™ platform from 
Aushon BioSystems Inc.  We have worked in tandem with the team at Aushon for over 7 years to 
develop multiple new assays and optimize the performance of our specific panel design (see Table 
9.3.4).  All antibody pairs have been validated to limit cross-reactivity and optimal dilutions were 
identified for every panel.  Specific blocking buffers were identified, cross-reactivity of antibodies 
was tested and non-specific binding was minimized. Preliminary testing and plate validation were 
performed by both groups independently. Freeze/thaw stability tests were done for all individual 
analytes. Lastly, assay performance across the different tissue types (citrated plasma, EDTA 
plasma and serum) was evaluated. 
 
 
  Table 9.3.4.  Plasma-based marker identification 
Soluble 
Angiogenic 
Factors 
Matrix-Derived  
Factors 
Markers of 
Vascular 
Activation and 
Inflammation 
Anti-EGFR 
therapies 
 
ANG-2 
PDGF-BB 
sEndoglin 
CRP 
EGF 
bFGF 
PlGF 
Osteopontin 
ICAM-1 
HB-EGF 
HGF 
VEGF-A 
TGFE1 
IL-6 
7*)Į  
IGFBP1 
VEGF-D 
TGFE2 
PAI-1 Active 
s-EGFR 
IGFBP2 
sVEGFR1 
TGFERIII 
PAI-1 Total 
s-HER2 
IGFBP3 
sVEGFR2 
TIMP1 
SDF-1 
s-HER3 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
69 
PDGF-AA 
sVEGFR3 
TSP2 
VCAM-1 
s-CD73 
 
We plan to use this approach to analyze plasma samples obtained longitudinally from patients 
treated with AZD9291 (osimertinib) plus bevacizumab versus Osimertinib (AZD9291)  alone.  Our 
hypothesis is that VEGF- and EGFR-related candidate markers will predict for benefit or lack of 
benefit from bevacizumab and Osimertinib (AZD9291), respectively. Additionally, we 
hypothesize that early changes in VEGF- and EGFR-related candidate markers will predict for 
greater or lesser benefit from bevacizumab and Osimertinib (AZD9291), respectively. Our 
approach is technically robust and readily adaptable to clinical practice.   Because this data will be 
derived from patients, even preliminary data may significantly improve our understanding of how 
angiogenesis and tumor growth factors are regulated in cancer patients. Promising findings can be 
followed up in future clinical studies and in preclinical models. Because our lab serves as the core 
lab for multiplex ELISA analyses within the Alliance, the current profiling can be compared to the 
profiles seen in other studies, helping to optimize future profiling approaches and provide the 
disease specific context needed for clinically meaningful companion diagnostics. Given the results 
of our prior work and the work of others, we anticipate being able to identify and validate or refute 
candidate markers of benefit that are specific for anti-angiogenic agents. We also anticipate that 
we will identify multiple prognostic factors.  
 
The characteristics of blood analytes will be investigated using a variety of statistical approaches. 
Baseline and on-treatment levels will be quantified and change from baseline will be determined 
for all analytes at the desired time points (waterfall plots).   Linear mixed-effects model will be 
performed to understand the longitudinal trends of the analytes over the different time points. 
Coefficients of variation will be used to assess the dispersion of each analyte.  Pair-wise 
correlations among the analytes will be estimated using Spearman’s rank correlation. Descriptive 
statistics will also be presented.  
 
Blood analytes will be correlated with progression-free survival (PFS) and/or overall survival, and 
correlations with response rate can also be explored for consistency with those seen with PFS using 
Cox regression analysis.  Continuous analytes intensities for baseline measures and log ratios of 
on-treatment over baseline intensities [log(on-treatment/baseline)] will be used. For each analyte, 
linear regression and Pearson coefficient correlations will be used for assessing the associations 
with continuous response measure. Summary statistics will include, but are not limited to, the 
hazard ratios and associated confidence intervals. Kaplan-Meier plots and log-rank tests will be 
presented and performed to compare candidate biomarker groups. 
 
9.2.3.1 Collection of specimen(s) 
10 ML of blood will be collected from patients in purple top EDTA tubes at the 
following time points: baseline, every 6 weeks on trial therapy, and at progression.   
 
9.2.3.2 Handling of specimen(s) 
See Appendix E for details. 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
70 
9.2.3.3 Shipping of specimen(s) 
See Appendix E for details. 
 
9.2.3.4 Site(s) Performing Correlative Study 
These assays will be performed by Dr. 
, MBA, PhD, at Duke 
University. 
 
10 STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy except 
where indicated.  Scans and x-rays (including echocardiogram) must be done <4 weeks prior to 
the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory evaluations 
should be repeated within 48 hours prior to initiation of the next cycle of therapy.  All evaluations 
and visits can be +/- 3 days except where indicated. 
 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 n 
Disease 
Progression 
Off 
Study 
 
 
Day 
1 
Day 
8 
Day 
15 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
 
 
Osimertinib 
(AZD9291) a 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Bevacizumabb 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical examc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistryd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urine proteine 
X 
 
 
 
 
X 
 
X 
 
 
 
ECGf 
X 
 
 
 
X 
X 
 
X 
 
 
 
Echocardiogramg 
X 
 
 
 
 
 
 
X 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
B-HCGh 
X 
 
 
 
 
 
 
 
 
 
 
CT chest/abdomen/pelvis and 
MRI brain with associated 
tumor measurementsi 
X 
 
 
 
 
X 
 
X 
 
 
X 
Tumor biopsy 
Xj 
 
 
 
 
 
 
 
 
Xk 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
71 
Blood for correlative studiesl 
X 
 
 
 
 
X 
 
X 
 
X 
 
Ophthalmic Examm 
 
At any time if patient experiences visual symptoms 
a. Osimertinib (AZD9291) : 80mg PO daily continuously in 21-day cycles for patients randomized to the combination or 
monotherapy arm.  Drug is dispensed on Day 1 of each cycle. 
b. Bevacizumab: 15mg/kg IV every 21 days (Day 1 of each cycle) for those patients randomized to the combination arm. 
c. Physical exam will include assessment of the following: general appearance, skin, head and neck (including ears, eyes, nose, 
and throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurologic systems. 
d. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
e. Urine protein should be screened by urine analysis every 6 weeks while the patient is on study treatment.  At the pre-study 
visit, if protein is 2+ or higher, 24-hour urine protein should be obtained and the level should be <1000 mg for patient enrollment.  
f. ECG to evaluate the QTc must be obtained pre-study and prior to treatment and on day 1 of cycles 2, 3 and 5. After cycle 5, 
ECG should be obtained every other cycle (i.e. every 6 weeks) while patient is on study therapy, or more frequently if QTc 
prolongation is observed.  See below for details. 
g. Left ventricular ejection fraction must be assessed by echocardiogram prior to treatment and every 3 months while on 
treatment.  Evaluation can be +/- 7 days.  See below for details. 
h. Serum or urine pregnancy test (for women of childbearing potential). 
i. CT chest/abdomen/pelvis and MRI brain must be repeated every 6 weeks while on study.  Evaluation can be - 7 days.  Tumor 
measurements include RECIST 1.1 and RANO-BM. 
j. Tumor tissue must be obtained prior to treatment by a surgical or biopsy procedure. Tissue will be required from all patients 
unless not considered feasible (i.e. in the case of disease progression in the CNS only).  Core biopsies must be performed at least 
7 days prior to treatment start.  Archival tissue is acceptable if no systemic therapy has been administered in the interim and 
sufficient material is present to meet the requirements listed in Appendix D.  
k. Tumor tissue should be collected when a biopsy is occurring for clinical purposes at the time of disease progression. 
l. Blood will be collected for correlative studies from patients at the following timepoints: pre-treatment (can be on C1D1 prior to 
administration of study treatment), every 6 weeks while on trial therapy, and at disease progression.   
m.  Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, 
lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. 
n. Procedures beyond Cycle 6 should follow the procedures specified for Cycles 5 and 6 on an alternating basis (i.e. Cycle 7 
should be consistent with Cycle 5, Cycle 8 should be consistent with Cycle 6, Cycle 9 should be consistent with Cycle 5, etc.). 
 
 
Resting 12-lead ECG 
 
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 10 
minutes prior to assessment. All ECGs should be recorded with the patient in the same physical 
position. A standardized ECG machine should be used and the patient should be examined using 
the same machine throughout the study if possible. 
 
After paper ECGs have been recorded, the investigator or designated physician will review each 
of the ECGs and may refer to a local cardiologist if appropriate. A paper copy should be filed in 
the patient’s medical records. If an abnormal ECG finding at screening or baseline is considered 
to be clinically significant by the investigator, it should be reported as a concurrent condition. For 
all ECGs details of rhythm, ECG intervals and an overall evaluation will be recorded. 
 
 
If there is a clinically significant abnormal ECG finding during the Treatment period, this should 
be recorded on the AE eCRF, according to standard adverse events collection and reporting 
processes. A 28-day follow-up assessment will be required if an on treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm reversibility of the 
abnormality. 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
72 
 
Echocardiogram 
 
An Echocardiogram to assess LVEF will be performed at screening (prior to first dose of 
osimertinib) and at least every 3 months throughout the treatment period. The patients should also 
be examined using the same machine and operator whenever possible, and quantitative 
measurements should be taken. A 28-day follow- up assessment will be required if an on treatment 
assessment was abnormal at the time of discontinuation of study therapy, to confirm reversibility 
of the abnormality. 
 
 
11 MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect  
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks with CT 
scans of the chest/abdomen/pelvis and MRI of the brain.  In addition to a baseline scan, 
confirmatory scans should also be obtained 6 (not less than 4) weeks following initial 
documentation of objective response. 
 
Response and progression of systemic disease will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1).(71)  Response and progression of intracranial disease will be 
evaluated in this study using the RANO-Brain Metastases Criteria.(72)  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria.   
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with Osimertinib (AZD9291)  +/- bevacizumab. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline and received at least one cycle of therapy will be considered evaluable for 
response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
73 
Measurable disease - Non-CNS.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 20 mm 
 Fm) by chest x-ray or as 10 mm  Fm) with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if they show unequivocal progression on two consecutive scans.   
 
Measurable disease - CNS.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as  mm  Fm) 
by brain MRI with 1.5 mm slice thickness or less.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if they show unequivocal progression on two consecutive scans.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm  Fm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or SDWKRORJLFDO O\PSK QRGHV ZLWK 10 to <15 mm >1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions – non-CNS.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
74 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
non-CNS disease. 
 
Non-target lesions– non-CNS.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should 
be noted throughout follow-up.  
 
Target lesions – CNS.  All measurable brain lesions up to a maximum of 5 lesions, should 
be identified as target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) and should 
be those that lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the longest diameters for all target lesions will be calculated and 
reported as the baseline sum diameters.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of CNS disease. 
 
 
Non-target lesions– CNS.  All other lesions in the brain including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm  FP diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
75 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have 
slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed.   
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
 
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
76 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria for Non-CNS Disease Using RECIST 1.1 
 
11.1.4.1 Evaluation of Non-CNS Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 
cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance 
of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
 11.1.4.2 Evaluation of Non-CNS Non-Target Lesions 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
77 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 
cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time. 
 
 11.1.4.3 Evaluation of Best Overall Non-CNS Response 
 
The best overall non-CNS response is the best response recorded from the start of the 
treatment until systemic disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started).  
The patient's best non-CNS response assignment will depend on the achievement of 
both measurement and confirmation criteria. 
 
For Patients with Measurable Non-CNS Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
78 
beaccepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Non-CNS Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Response Criteria for CNS Disease Using RANO-BM 
 
11.1.5.1 Evaluation of CNS Target Lesions 
 
Complete Response (CR):  Disappearance of all CNS target lesions for at least 4 weeks 
with no new lesions, no use of corticosteroids, and patient is stable or improved 
clinically.   
 
Partial Response (PR):  At least a 30% decrease in the sum of the longest diameters of 
CNS target lesions, taking as reference the baseline sum longest diameters sustained 
for at least 4 weeks, no new lesions, stable to decreased corticosteroid dose, stable or 
improved clinically. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of CNS 
target lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  (Note:  the 
appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.5.2 Evaluation of CNS Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all enchancing CNS non-target lesions 
and no new CNS lesions. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
79 
 
Non-CR/Non-PD:  Persistence of one or more non-target CNS lesion(s). 
 
Progressive Disease (PD):  Appearance of one or more new CNS lesions, unequivocal 
progression of existing non-target CNS lesions, and/or unequivocal progression of 
existing tumor-related non-enhancing (T2/FLAIR) CNS lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be representative 
of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time. 
 
11.1.5.3 Evaluation of Best Overall CNS Response 
 
The best overall CNS response is the best response recorded in the CNS from the start 
of the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started).  
The patient's best CNS response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
For Patients with Measurable CNS Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Cortico-
steroids*** 
Neurologic 
Status 
Overall CNS 
Response 
Best Overall 
CNS Response 
when 
Confirmation is 
Required* 
CR 
CR 
No 
None 
Stable or 
improved 
CR 
>4 wks. 
Confirmation* 
CR 
Non-
CR/Non-PD 
No 
Stable or 
decreased 
Stable or 
improved 
PR 
>4 wks. 
Confirmation* 
CR 
Not 
evaluated 
No 
Stable or 
decreased 
Stable or 
improved 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
Stable or 
decreased 
Stable or 
improved 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
Stable or 
decreased 
Stable or 
improved 
SD 
Documented at 
least once >4 
wks. from 
baseline* 
PD 
Any 
Yes or No 
Any 
Any 
PD 
no prior SD, PR 
or CR 
Any 
PD** 
Yes or No 
Any 
Any 
PD 
Any 
Any 
Yes 
Any 
Worse**** 
PD 
Any 
Any 
Yes or No 
Any 
Any 
PD 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
80 
 
See RANO-BM manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
*** Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration. 
**** Patients with worsening clinical status without objective evidence of disease progression can qualify 
for PD.  Patients with a global deterioration of neurologic status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic CNS 
deterioration.”  Every effort should be made to document the objective CNS progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable CNS Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall CNS Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
11.1.5.4 Evaluation of Best Overall Response (non-CNS and CNS disease) 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started), taking into account both 
non-CNS and CNS disease.  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Best Overall Response Assessment 
 
Non-CNS (RECIST 1.1) 
CNS (RANO-BM) 
Best Overall Response 
CR, PR, or SD 
CR, PR, or SD 
Log as CNS and non-CNS 
CR, PR, or SD 
PD 
CR, PR, or SD 
Log as CNS CR, PR, or SD; 
log as non-CNS PD 
CR, PR, or SD 
PD 
Log as CNS PD; log as non-
CNS CR, PR, or SD 
PD 
PD 
Log as both CNS and non-
CNS PD 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
81 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression (in 
CNS or non-CNS disease) or death, whichever occurs first.   
 
Bi-compartmental PFS 
 
Non-CNS 
(RECIST 1.1) 
CNS 
(RANO-BM) 
Bi-compartmental PFS 
 
Note 
PD 
CR, PR, or 
SD 
Log as a PFS event 
Log as non-CNS PD 
CR, PR, or SD 
PD 
Log as a PFS event 
Log as CNS PD 
PD 
PD 
Log as a PFS event 
Log as both CNS and non-CNS PD 
 
 
11.1.7 Time to CNS Progression 
 
Time to CNS Progression is defined as the duration of time from start of treatment to 
time of progression in the CNS. 
 
11.1.8 Overall Survival 
 
OS is defined as the duration of time from start of treatment to death. 
 
 
12 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious 
adverse events; reporting of expedited adverse events; and accumulation of reported adverse 
events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
82 
12.1 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the trial 
in Rave is granted through the iMedidata application to all persons with the appropriate roles 
assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site user 
must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role 
or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold the 
Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page.  Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane 
of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail 
at ctsucontact@westat.com. 
 
12.1.1 Method 
 
CTMS Routine Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will 
be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality 
if approved by CTEP).  Information on CTMS reporting is available at:   
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users have 
activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by 
email at CTMSSupport@theradex.com for additional support with Rave and completion 
of CRFs. 
 
 
12.1.2 Responsibility for Data Submission 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
83 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than 
once every 2 weeks.  The timeliness of data submissions and timeliness in resolving data 
queries will be tracked by CTMS.  Metrics for timeliness will be followed and assessed on 
a quarterly basis.  For the purpose of Institutional Performance Monitoring, data will be 
considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis 
as data is received.  Queries will be issued by CTMS directly within Rave.  The queries 
will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  
Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP.  
Onsite audits will be conducted by the CTMS to ensure compliance with regulatory 
requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring 
the integrity of data generated from NCI-sponsored clinical trials, as described in the 
ETCTN 
Program 
Guidelines, 
which 
may 
be 
found 
on 
the 
CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials), the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged to 
review the eCRFs, working closely with CTMS to ensure prospectively that all required 
items are appropriately captured in the eCRFs prior to study activation.  CTMS will prepare 
the eCRFs with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
See Section 12.1.1 for details on CDUS reporting.  As the data management center for this 
trial, Theradex is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review.   
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
84 
 
12.2 CTEP Multicenter Guidelines 
N/A 
 
12.3 Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
85 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings.  Press releases and 
other media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
Patients will be randomized 1:1 to receive the combination of Osimertinib (AZD9291) plus 
bevacizumab or Osimertinib (AZD9291) alone. Treatment will continue until disease progression 
or the occurrence of one of the criteria listed in Section 5.3.  However, if a patient has disease 
progression but is considered to be deriving clinical benefit (i.e. progression at one site of disease 
with other sites well-controlled) they may receive local therapy (such as radiation therapy) to the 
progressing lesion and continue on trial therapy. 
 
Power analysis and sample size estimation:  
The primary objective of this multi-center, randomized Phase II trial is to compare the progression 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
86 
free survival (PFS) between two study arms, i.e. Osimertinib (AZD9291)  alone versus Osimertinib 
(AZD9291)  plus bevacizumab. The secondary objectives of this study are to estimate and compare 
the response rate (RR), intracranial response rate (IRR), time to intracranial progression, overall 
survival (OS), and safety profile.  
 
The sample size estimation is completed using the log rank test. With the proposed sample size of 
110 evaluable patients (55 patients for combination arm and 55 patients for Osimertinib 
(AZD9291)  arm; 83 events are required at the final analysis), it provides at least 80% power to 
detect a 9 month improvement in the median PFS for the combination arm, i.e., estimated median 
3)6 §  24.2 months for the combination arm and median PFS = 15.2 months for Osimertinib 
(AZD9291)  arm (HR = 0.63), with one-sided type I error = 10%. This calculation is based on the 
assumption of accrual time = 36 months, additional follow-up time = 24 months, the number of 
total estimated PFS events in the two arms is 84 (46 events in the single-agent arm and 38 events 
in the combination arm), and the accrual rate is about 3 patients / months. In addition, it is estimated 
that about 2% of patients of enrolled patients will not begin protocol therapy.  Therefore, 112 
patients will be enrolled to provide at least  110 evaluable patients which will provide sufficient 
statistical power to detect clinically significant difference between the combination arm and single 
arm. 
 
Randomization: 
The eligible patients will be randomized according to a stratified permuted block randomization 
scheme.  Stratification will be based on EGFR mutation type (exon 19 deletion or L858R/other), 
number of untreated new or progressing brain metastases (>4 or <4), and performance status (0-1 
vs 2).  Randomization will be proceeded within strata according to a permuted block scheme with 
a block size, or balancing interval, varying randomly between 3 or 6 according to the outcome of 
a computer generated random number.  This will ensure that the cumulative number of assignments 
to each treatment will be in balance in 1:1 ratio after each block of assignments has been made. 
 
Interim analysis:  
The futility analysis will be based on the method proposed by Wieand et al.(99) If after 42 events 
(50% of the targeted information) are observed and the observed hazard ratios for combination vs. 
single-agent arm comparisons favor the single-agent arm (i.e. HR>1), then the combination arm 
will be terminated for futility and the study will be closed to accrual. We do not plan to perform a 
superiority test during the interim analysis as part of this study design.  Accrual will not be 
suspended during safety and interim analyses. 
 
Statistical analysis plan:  
Demographic information, such as age and race, will be tabulated.  Descriptive statistics, including 
means, standard deviations, and ranges for continuous parameters, as well as percents and 
frequencies for categorical parameters, will be presented.  Adverse medical events will be 
tabulated.  NCI toxicity Grade 1 to Grade 4 laboratory abnormalities will be listed.   
 
For lifetime data analyses, e.g., PFS and OS, the two study arms will be compared for progression 
free survival with Kaplan-Meier estimates and stratified log-rank tests. The Rothman confidence 
interval (CI) will be reported. In addition, the possible risk factors will be compared for survival 
with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
89 
13.4.2 Data analysis plan for secondary omics endpoints 
 The Omics biomarker data, e.g., RNA-seq, analysis will be completed using Lasso-based elastic 
net method. The elastic net method is a variable selection procedure by L1 and L2 penalized 
estimation that enforces variable selection and shrinkage simultaneously. The penalty parameter 
that controls the shrinkage of fixed terms and the variable selection will be determined by k-fold 
cross validation.  Because of the limited sample size, other biomarker data analysis is for 
exploratory research only. The statistical analyses will be completed by either R 3.2.1 or SAS 9.4 
statistical program in this project.   
 
13.5 Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Osimertinib (AZD9291) with or without Bevacizumab.   
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the exception of those who received 
no study medication) will be included in analysis of the response rate and other efficacy 
analyses.  Patients in response categories 4-9 should be considered to have a treatment 
failure (disease progression).  Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate.  For PFS, OS, and other 
time-to-event endpoints, censoring is defined as (1) lost to follow-up or (2) event-free at 
the end of the study. 
 
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation 
of treatment, major protocol violations, etc.).  However, these subanalyses may not serve 
as the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported.  The 95% confidence 
intervals should also be provided.  
 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
90 
 REFERENCES 
1. 
Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, 
Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth 
B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G, et al. 
Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate 
cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 
1999;17(11):3461-7. Epub 1999/11/05. PubMed PMID: 10550143. 
2. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 
2013;63(1):11-30. Epub 2013/01/22. doi: 10.3322/caac.21166. PubMed PMID: 23335087. 
3. 
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, 
Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber 
DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of 
non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-39. Epub 2004/05/01. 
doi: 10.1056/NEJMoa040938. PubMed PMID: 15118073. 
4. 
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, 
Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson 
M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 
2004;304(5676):1497-500. Epub 2004/05/01. doi: 10.1126/science.1099314. PubMed PMID: 
15118125. 
5. 
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, 
Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene 
mutations are common in lung cancers from "never smokers" and are associated with sensitivity 
of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-11. Epub 
2004/08/27. doi: 10.1073/pnas.0405220101. PubMed PMID: 15329413; PMCID: PMC516528. 
6. 
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han 
B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield 
EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. 
N 
Engl 
J 
Med. 
2009;361(10):947-57. 
Epub 
2009/08/21. 
doi: 
10.1056/NEJMoa0810699. PubMed PMID: 19692680. 
7. 
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, 
Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa 
A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla 
G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine 
M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-
Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, 
Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, 
Molina MA, Taron M, Paz-Ares L. Erlotinib versus standard chemotherapy as first-line treatment 
for European patients with advanced EGFR mutation-positive non-small-cell lung cancer 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
91 
(EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-
46. Epub 2012/01/31. doi: 10.1016/s1470-2045(11)70393-x. PubMed PMID: 22285168. 
8. 
Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, 
O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, 
Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina 
V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung 
adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two 
randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-51. Epub 2015/01/16. doi: 
10.1016/s1470-2045(14)71173-8. PubMed PMID: 25589191. 
9. 
P.A. Jänne M-JA, D.-W. Kim, S.-W. Kim, D. Planchard, S.S. Ramalingam, P. Frewer, 
M. Cantarini, S. Ghiorghiu, J.C.-H. Yang A PHASE I STUDY OF AZD9291 IN PATIENTS 
WITH EGFR-TKI-RESISTANT ADVANCED NSCLC – UPDATED PROGRESSION FREE 
SURVIVAL AND DURATION OF RESPONSE DATA,  . Annals of Oncology  2015;26(suppl 
1):Pp.i60. 
10. 
S.S. Ramalingam YO, N. Nogami, J. Yang, C. Eberlein, S. Ashton, M. Mellor, P. 
Spitzler, C. Meador, E. Ichihara, D. Cross, W. Pao, P. Ballard, G. Hughes, M. Cantarini, P. Frewer, 
S. Ghiorghiu, P.A. Janne. Preclinical and clinical evaluation of AZD9291, a mutation-specific 
inhibitor, in treatment- naïve EGFR-mutated NSCLC Poster 454P. Annals of Oncology, Vol. 25, 
Sppl. 4.  34th Congress of the European Society for Medical Oncology: Annals of Oncology; 2014. 
11. 
 Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, 
Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, et al. Osimertinib in 
untreated EGFR-mutated advanced non-small cell lung cancer. N Enl J Med 2018; 378:113-125. 
12. 
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, 
Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun 
J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim 
DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated 
resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-61. Epub 
2014/06/05. doi: 10.1158/2159-8290.cd-14-0337. PubMed PMID: 24893891; PMCID: 
PMC4315625. 
13. 
D. Kim JY, D. Cross, P. Ballard, P. Yang, J. Yates, L. Xie, M. Cantarini, S. Ghiorghiu, 
P.A. Janne. Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-
small cell lung cancer (NSCLC) brain metastases (BM).  39th European Society for Medical 
Oncology Congress; Annals of Oncology (2014) 25 (suppl_4): iv146-iv164 2014. 
14. 
Porta R, Sanchez-Torres JM, Paz-Ares L, Massuti B, Reguart N, Mayo C, Lianes P, 
Queralt C, Guillem V, Salinas P, Catot S, Isla D, Pradas A, Gurpide A, de Castro J, Polo E, Puig 
T, Taron M, Colomer R, Rosell R. Brain metastases from lung cancer responding to erlotinib: the 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
92 
importance of EGFR mutation. Eur Respir J. 2011;37(3):624-31. Epub 2010/07/03. doi: 
10.1183/09031936.00195609. PubMed PMID: 20595147. 
15. 
Bai H, Han B. The effectiveness of erlotinib against brain metastases in non-small cell 
lung cancer patients. Am J Clin Oncol. 2013;36(2):110-5. Epub 2012/03/07. doi: 
10.1097/COC.0b013e3182438c91. PubMed PMID: 22391431. 
16. 
Shimato S, Mitsudomi T, Kosaka T, Yatabe Y, Wakabayashi T, Mizuno M, Nakahara 
N, Hatano H, Natsume A, Ishii D, Yoshida J. EGFR mutations in patients with brain metastases 
from lung cancer: association with the efficacy of gefitinib. Neuro Oncol. 2006;8(2):137-44. Epub 
2006/03/03. 
doi: 
10.1215/15228517-2005-002. 
PubMed 
PMID: 
16510849; 
PMCID: 
PMC1871943. 
17. 
Ahn, MJ, Chiu CH, Cheng Y, Han JY, Goldberg SB, Greystoke A, Crawford J, Zhao 
Y, Huang X, Jonson M, Vishwanathan K, Mendoza-Naranjo A, Mok T. Osimertinib for patients 
with leptomeningeal metastases associated with EGFRm advanced NSCLC. Annals of Oncology 
(2018) 29 (Suppl_9):ix150-ix169. 
18. 
Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, 
Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for 
the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593-9. Epub 
1997/10/23. PubMed PMID: 9377574. 
19. 
Genentech I. Avastin™ (bevacizumab) Investigator’s Brochure. . 2008. 
20. 
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of 
vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. 
Nature. 1993;362(6423):841-4. Epub 1993/04/29. doi: 10.1038/362841a0. PubMed PMID: 
7683111. 
21. 
Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, 
Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, 
Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK. 
Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human 
rectal cancer. Nat Med. 2004;10(2):145-7. Epub 2004/01/28. doi: 10.1038/nm988. PubMed PMID: 
14745444; PMCID: PMC2693485. 
22. 
Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer 
angiogenesis in vivo: implications from intravital microscopy of combination treatments with an 
anti-VEGF 
neutralizing 
monoclonal 
antibody 
and 
doxorubicin. 
Anticancer 
Res. 
1999;19(5B):4203-14. Epub 2000/01/11. PubMed PMID: 10628376. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
93 
23. 
Kabbinavar F, J.T. Wong, R.E. Ayala. The effect of antibody to vascular endothelial 
growth factor and cisplatin on the growth of lung tumors in nude mice. Proc Am Assoc Cancer 
Res  1995;36:A488. 
24. 
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting 
both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 
2003;111(9):1287-95. Epub 2003/05/03. doi: 10.1172/jci17929. PubMed PMID: 12727920; 
PMCID: PMC154450. 
25. 
Shaheen RM, Ahmad SA, Liu W, Reinmuth N, Jung YD, Tseng WW, Drazan KE, 
Bucana CD, Hicklin DJ, Ellis LM. Inhibited growth of colon cancer carcinomatosis by antibodies 
to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001;85(4):584-9. 
Epub 2001/08/17. doi: 10.1054/bjoc.2001.1936. PubMed PMID: 11506500; PMCID: 
PMC2364099. 
26. 
Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, 
Reimann JD, Vassel A. A phase I/II dose-escalation trial of bevacizumab in previously treated 
metastatic breast cancer. Semin Oncol. 2003;30(5 Suppl 16):117-24. Epub 2003/11/13. PubMed 
PMID: 14613032. 
27. 
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, 
Schwartz MA, Benson AB, 3rd. Bevacizumab in combination with oxaliplatin, fluorouracil, and 
leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the 
Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539-44. Epub 
2007/04/20. doi: 10.1200/jco.2006.09.6305. PubMed PMID: 17442997. 
28. 
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin 
J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. 
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl 
J Med. 2004;350(23):2335-42. Epub 2004/06/04. doi: 10.1056/NEJMoa032691. PubMed PMID: 
15175435. 
29. 
, 
, 
, 
. E2100: A randomized phase III trial of 
paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or 
metastatic breast cancer.  . 41st Annual Meeting of the American Society of Clinical Oncology. 
2005. 
30. 
Miller K, H.S. Rugo, M.A. Cobleigh Phase III trial of capecitabine (Xeloda®) plus 
bevacizumab (Avastin™) versus capecitabine alone in women with metastatic breast cancer 
(MBC) previously treated with an anthracycline and a taxane. Breast Cancer Res Treat 76:S37. 
2002. 
31. 
HL Kindler DN, D Hollis, E Oraefo, D Schrag, H Hurwitz, HL McLeod, MF Mulcahy, 
RL Schilsky, RM Goldberg Cancer and Leukemia Group B A double-blind, placebo-controlled, 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
94 
randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus 
placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of 
Cancer and Leukemia Group B (CALGB) 80303. Journal of Clinical Oncology, 2007 ASCO 
Annual Meeting Proceedings. 2007;Vol 25, No 18S (June 20 Supplement), 2007: 4508. 
32. 
Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, 
Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular 
endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427-
34. Epub 2003/08/02. doi: 10.1056/NEJMoa021491. PubMed PMID: 12890841; PMCID: 
PMC2275324. 
33. 
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, 
Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N 
Engl J Med. 2006;355(24):2542-50. Epub 2006/12/15. doi: 10.1056/NEJMoa061884. PubMed 
PMID: 17167137. 
34. 
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., Jones 
DW, Materson BJ, Oparil S, Wright JT, Jr., Roccella EJ. The Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 
7 report. JAMA. 2003;289(19):2560-72. Epub 2003/05/16. doi: 10.1001/jama.289.19.2560. 
PubMed PMID: 12748199. 
35. 
Novotny W HE, Griffing S, et al. . Identification of squamous cell histology and central, 
cavitary tumors as possible risk factors for pulmonary hemorrhage in patients with advanced 
NSCLC receiving bevacizumab.  . Proc Am Soc Clin Oncol  20:A1318. 2001. 
36. 
JR Skillings DJ, K Miller. Arterial thromboembolic events (ATEs) in a pooled analysis 
of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy. Proc Am Soc 
Clin Oncol  24:A3019. 2005. 
37. 
Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin J, 
Kabbinavar F, Novotny W, Sarkar S, Hurwitz H. Surgical wound healing complications in 
metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91(3):173-80. 
Epub 2005/08/25. doi: 10.1002/jso.20301. PubMed PMID: 16118771. 
38. 
Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, Hewitt SM, Berman 
A, Steinberg SM, Liewehr DJ, Plehn J, Doshi A, Thomasson D, McCarthy N, Koeppen H, 
Sherman M, Zujewski J, Camphausen K, Chen H, Swain SM. Antiangiogenic and antitumor 
effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin 
Oncol. 2006;24(5):769-77. Epub 2006/01/05. doi: 10.1200/jco.2005.03.4645. PubMed PMID: 
16391297. 
39. 
D'Adamo DR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K, Schwartz GK, 
Chen H, Maki RG. Phase II study of doxorubicin and bevacizumab for patients with metastatic 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
95 
soft-tissue 
sarcomas. 
J 
Clin 
Oncol. 
2005;23(28):7135-42. 
Epub 
2005/09/30. 
doi: 
10.1200/jco.2005.16.139. PubMed PMID: 16192597. 
40. 
Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med. 2006;354(9):980-2; discussion -2. Epub 2006/03/03. doi: 
10.1056/NEJMc052954. PubMed PMID: 16510760. 
41. 
Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med. 2006;354(9):980-2; discussion -2. Epub 2006/03/04. PubMed PMID: 
16514715. 
42. 
Smith AR, Hennessy JM, Kurth MA, Nelson SC. Reversible skeletal changes after 
treatment with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia 
syndrome. Pediatr Blood Cancer. 2008;51(3):418-20. Epub 2008/05/22. doi: 10.1002/pbc.21597. 
PubMed PMID: 18493993. 
43. 
Glade Bender JL, Adamson PC, Reid JM, Xu L, Baruchel S, Shaked Y, Kerbel RS, 
Cooney-Qualter EM, Stempak D, Chen HX, Nelson MD, Krailo MD, Ingle AM, Blaney SM, 
Kandel JJ, Yamashiro DJ. Phase I trial and pharmacokinetic study of bevacizumab in pediatric 
patients with refractory solid tumors: a Children's Oncology Group Study. J Clin Oncol. 
2008;26(3):399-405. Epub 2008/01/19. doi: 10.1200/jco.2007.11.9230. PubMed PMID: 
18202416. 
44. 
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus 
H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second 
mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73. Epub 2005/03/02. doi: 
10.1371/journal.pmed.0020073. PubMed PMID: 15737014; PMCID: PMC549606. 
45. 
Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New strategies 
in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors 
in lung cancer. Clin Cancer Res. 2011;17(17):5530-7. Epub 2011/07/22. doi: 10.1158/1078-
0432.ccr-10-2571. PubMed PMID: 21775534; PMCID: PMC3166976. 
46. 
Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim 
SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, 
Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung 
cancer. N Engl J Med. 2015;372(18):1689-99. Epub 2015/04/30. doi: 10.1056/NEJMoa1411817. 
PubMed PMID: 25923549. 
47. 
Heon S, Yeap BY, Lindeman NI, Joshi VA, Butaney M, Britt GJ, Costa DB, Rabin 
MS, Jackman DM, Johnson BE. The impact of initial gefitinib or erlotinib versus chemotherapy 
on central nervous system progression in advanced non-small cell lung cancer with EGFR 
mutations. Clin Cancer Res. 2012;18(16):4406-14. Epub 2012/06/27. doi: 10.1158/1078-0432.ccr-
12-0357. PubMed PMID: 22733536; PMCID: PMC3682221. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
96 
48. 
Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu 
Y, Yang JJ. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer 
and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013;24(4):993-
9. Epub 2012/11/07. doi: 10.1093/annonc/mds529. PubMed PMID: 23129122. 
49. 
Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang 
Z, Wu AJ. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant 
lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89(2):322-9. Epub 2014/04/01. doi: 
10.1016/j.ijrobp.2014.02.022. PubMed PMID: 24679729. 
50. 
Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Masago K, Fujita S, Kaji R, 
Imai Y, Monden K, Matsumoto T, Nagata K, Otsuka K, Tachikawa R, Tomii K, Kunimasa K, 
Iwasaku M, Nishiyama A, Ishida T, Nishimura Y. Prognostic impact of central nervous system 
metastases after acquired resistance to EGFR-TKI: poorer prognosis associated with T790M-
negative status and leptomeningeal metastases. Anticancer Res. 2015;35(2):1025-31. Epub 
2015/02/11. PubMed PMID: 25667490. 
51. 
Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, Pickup K, Jordan A, 
Hickey M, Grist M, Box M, Johnstrom P, Varnas K, Malmquist J, Thress KS, Janne PA, Cross D. 
Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain 
Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 
2016;22(20):5130-40. Epub 2016/07/21. doi: 10.1158/1078-0432.ccr-16-0399. PubMed PMID: 
27435396. 
52. 
Sequist LV, Piotrowska Z, Niederst MJ, Heist RS, Digumarthy S, Shaw AT, Engelman 
JA. Osimertinib Responses After Disease Progression in Patients Who Had Been Receiving 
Rociletinib. 
JAMA 
Oncol. 
2016;2(4):541-3. 
Epub 
2016/01/01. 
doi: 
10.1001/jamaoncol.2015.5009. PubMed PMID: 26720284. 
53. 
Lee DH KD-W, Ahn M-J, et al. AZD9291 activity in patients with leptomeningeal 
disease from non-small cell lung cancer: a Phase I study.  AACR-NCI-EORTC International 
Conference on Molecular Targets and Cancer Therapeutics. Abstract PR07.2015. 
54. 
Yang J C-H KD-W, Kim S-W, Cho BC, Lee J-S, Ye X, Yin X, Yang Z, Jiang H, Ahn 
M-J. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell 
lung cancer (NSCLC): Updated results from BLOOM, a phase I study. 2016 ASCO Annual 
Meeting J Clin Oncol 34, 2016 (suppl; abstr 9002). 2016. 
55. 
Besse B, Le Moulec S, Mazieres J, Senellart H, Barlesi F, Chouaid C, Dansin E, Berard 
H, Falchero L, Gervais R, Robinet G, Ruppert AM, Schott R, Lena H, Clement-Duchene C, 
Quantin X, Souquet PJ, Tredaniel J, Moro-Sibilot D, Perol M, Madroszyk AC, Soria JC. 
Bevacizumab in Patients with Nonsquamous Non-Small Cell Lung Cancer and Asymptomatic, 
Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study. Clin Cancer Res. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
97 
2015;21(8):1896-903. Epub 2015/01/24. doi: 10.1158/1078-0432.ccr-14-2082. PubMed PMID: 
25614446. 
56. 
Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety 
in patients with central nervous system metastases. Clin Cancer Res. 2010;16(1):269-78. Epub 
2009/12/24. doi: 10.1158/1078-0432.ccr-09-2439. PubMed PMID: 20028762. 
57. 
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, 
Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab 
plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 
2014;370(8):709-22. Epub 2014/02/21. doi: 10.1056/NEJMoa1308345. PubMed PMID: 
24552318. 
58. 
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch 
during tumorigenesis. Cell. 1996;86(3):353-64. Epub 1996/08/09. PubMed PMID: 8756718. 
59. 
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor 
growth and angiogenesis. J Clin Oncol. 2005;23(5):1011-27. Epub 2004/12/09. doi: 
10.1200/jco.2005.06.081. PubMed PMID: 15585754. 
60. 
Elamin YY, Rafee S, Toomey S, Hennessy BT. Immune effects of bevacizumab: 
killing two birds with one stone. Cancer Microenviron. 2015;8(1):15-21. Epub 2014/10/19. doi: 
10.1007/s12307-014-0160-8. PubMed PMID: 25326055; PMCID: PMC4449343. 
61. 
Naumov GN, Nilsson MB, Cascone T, Briggs A, Straume O, Akslen LA, Lifshits E, 
Byers LA, Xu L, Wu HK, Janne P, Kobayashi S, Halmos B, Tenen D, Tang XM, Engelman J, 
Yeap B, Folkman J, Johnson BE, Heymach JV. Combined vascular endothelial growth factor 
receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in 
xenograft models of EGFR inhibitor resistance. Clin Cancer Res. 2009;15(10):3484-94. Epub 
2009/05/19. doi: 10.1158/1078-0432.ccr-08-2904. PubMed PMID: 19447865; PMCID: 
PMC2893040. 
62. 
Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh CH, 
O'Connor P, Hainsworth J. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in 
advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a 
double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846-54. Epub 
2011/05/31. doi: 10.1016/s0140-6736(11)60545-x. PubMed PMID: 21621716; PMCID: 
PMC4134127. 
63. 
Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, 
Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka 
M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with 
advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
98 
open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-44. Epub 
2014/09/02. doi: 10.1016/s1470-2045(14)70381-x. PubMed PMID: 25175099. 
64. 
 Yu HA, Hayes SA, Young RJ, Ni A, Rodriguez C, Makhnin A, Riely GJ, Kris MG. A 
phase I study of osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant 
lung cancers. J Clin Oncol 35, no.15_suppl (May 2017). 
65. 
Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson 
TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV. Prognostic or predictive plasma 
cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell 
cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;13:827-37. Epub 
2012/07/05. doi: S1470-2045(12)70241-3 [pii] 
10.1016/S1470-2045(12)70241-3. PubMed PMID: 22759480. 
66. 
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, 
Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen 
JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, 
Engelman JA. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to 
EGFR 
Inhibitors. 
Science 
Translational 
Medicine. 
2011;3(75):75ra26-75ra26. 
doi: 
10.1126/scitranslmed.3002003. 
67. 
Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, Okimoto 
RA, Lin L, Neel DS, Sabnis A, Flanagan J, Chan E, Varella-Garcia M, Aisner DL, Vaishnavi A, 
Ou SH, Collisson EA, Ichihara E, Mack PC, Lovly CM, Karachaliou N, Rosell R, Riess JW, 
Doebele RC, Bivona TG. RAS-MAPK dependence underlies a rational polytherapy strategy in 
EML4-ALK-positive lung cancer. Nat Med. 2015;21(9):1038-47. Epub 2015/08/25. doi: 
10.1038/nm.3930. PubMed PMID: 26301689; PMCID: PMC4734742. 
68. 
Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, 
Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, 
Yang PC, Miller V, Ladanyi M, Yang CH, Pao W. MET amplification occurs with or without 
T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. 
Proc 
Natl 
Acad 
Sci 
U 
S 
A. 
2007;104(52):20932-7. 
Epub 
2007/12/21. 
doi: 
10.1073/pnas.0710370104. PubMed PMID: 18093943; PMCID: PMC2409244. 
69. 
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst 
RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell 
lung cancer. Lab Invest. 2014;94(1):107-16. Epub 2013/11/13. doi: 10.1038/labinvest.2013.130. 
PubMed PMID: 24217091. 
70. 
Schalper KA, Carvajal-Hausdorf D, McLaughlin J, Altan M, Velcheti V, Gaule P, 
Sanmamed MF, Chen L, Herbst RS, Rimm DL. Differential expression and significance of PD-
L1, IDO-1 and B7-H4 in human lung cancer. Clin Cancer Res. 2016. Epub 2016/07/22. doi: 
10.1158/1078-0432.ccr-16-0150. PubMed PMID: 27440266. 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
99 
71. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 
Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer. 2009;45(2):228-47. Epub 2008/12/23. doi: 10.1016/j.ejca.2008.10.026. 
PubMed PMID: 19097774. 
72. 
Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M, 
Brown PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi FS, 
Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, Mehta MP, Schiff D, Soffietti R, Suh JH, 
van den Bent MJ, Vogelbaum MA, Wen PY. Response assessment criteria for brain metastases: 
proposal from the RANO group. Lancet Oncol. 2015;16(6):e270-8. Epub 2015/06/13. doi: 
10.1016/s1470-2045(15)70057-4. PubMed PMID: 26065612. 
73. 
Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, 
Eisenhauer E, Sagae S, Greven K, Vergote I, Cervantes A, Vermorken J. Re: New guidelines to 
evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst. 
2004;96(6):487-8. Epub 2004/03/18. PubMed PMID: 15026475. 
74. 
Rolff J, Becker M, Merk J, Hoffmann J, Fichtner I. Preclinical Study of a Combination 
of Erlotinib and Bevacizumab in Early Stages of Unselected Non-Small Cell Lung Cancer Patient-
Derived Xenografts. Target Oncol. 2016;11(4):507-14. Epub 2016/01/29. doi: 10.1007/s11523-
015-0415-4. PubMed PMID: 26817645. 
75. 
Camp RL, Chung GG, Rimm DL. Automated subcellular localization and 
quantification of protein expression in tissue microarrays. Nat Med. 2002;8(11):1323-7. doi: 
10.1038/nm791. PubMed PMID: 12389040. 
76. 
Bordeaux J, Welsh A, Agarwal S, Killiam E, Baquero M, Hanna J, Anagnostou V, 
Rimm D. Antibody validation. Biotechniques. 2010;48(3):197-209. doi: 10.2144/000113382. 
PubMed PMID: 20359301; PMCID: 3891910. 
77. 
Narayan A, Carriero NJ, Gettinger SN, Kluytenaar J, Kozak KR, Yock TI, Muscato 
NE, Ugarelli P, Decker RH, Patel AA. Ultrasensitive measurement of hotspot mutations in tumor 
DNA in blood using error-suppressed multiplexed deep sequencing. Cancer Res. 
2012;72(14):3492-8. Epub 2012/05/15. doi: 10.1158/0008-5472.can-11-4037. PubMed PMID: 
22581825; PMCID: PMC3426449. 
78. 
Narayan A, Bommakanti A, Patel AA. High-throughput RNA profiling via up-front 
sample 
parallelization. 
Nat 
Methods. 
2015;12(4):343-6. 
Epub 
2015/03/03. 
doi: 
10.1038/nmeth.3311. PubMed PMID: 25730493; PMCID: PMC4451056. 
79. 
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael 
JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, 
Wilson RK, Raphael BJ, Ding L. Mutational landscape and significance across 12 major cancer 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
100 
types. Nature. 2013;502(7471):333-9. Epub 2013/10/18. doi: 10.1038/nature12634. PubMed 
PMID: 24132290; PMCID: PMC3927368. 
80. 
Nixon AB, Pang H, Starr MD, Friedman PN, Bertagnolli MM, Kindler HL, Goldberg 
RM, Venook AP, Hurwitz HI, Alliance for Clinical Trials In O. Prognostic and Predictive Blood-
Based Biomarkers in Patients with Advanced Pancreatic Cancer: Results from CALGB80303 
(Alliance). Clin Cancer Res. 2013;19(24):6957-66. doi: 10.1158/1078-0432.CCR-13-0926. 
PubMed PMID: 24097873. 
81. 
Weickhardt AJ, Williams D, Lee C, Simes J, Murone C, Wilson K, Cummins M, Asadi 
K, Price TJ, Mariadason J, Tebbutt NC, Group AGT. Vascular endothelial growth factors (VEGF) 
and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in 
metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study. J Clin Oncol. 
2011;29:3531 (suppl; abstr). 
82. 
Lieu CH, Tran H, Jiang ZQ, Mao M, Overman MJ, Lin E, Eng C, Morris J, Ellis L, 
Heymach JV, Kopetz S. The association of alternate VEGF ligands with resistance to anti-VEGF 
therapy 
in 
metastatic 
colorectal 
cancer. 
PLoS 
One. 
2013;8(10):e77117. 
doi: 
10.1371/journal.pone.0077117. PubMed PMID: 24143206; PMCID: 3797099. 
83. 
Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for 
the 
antiangiogenic 
agent 
bevacizumab. 
J 
Clin 
Oncol. 
2013;31(9):1219-30. 
doi: 
10.1200/JCO.2012.46.2762. PubMed PMID: 23401453. 
84. 
Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, Tomczak P, Provencher 
L, Cortes J, Delmar PR, Scherer SJ. Biomarker results from the AVADO phase 3 trial of first-line 
bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer. 
2013;108(5):1052-60. doi: 10.1038/bjc.2013.69. PubMed PMID: 23422754; PMCID: 3619079. 
85. 
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman 
P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins 
RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized 
phase III trial. J Clin Oncol. 2010;28(6):1061-8. doi: 10.1200/JCO.2009.23.9764. PubMed PMID: 
20100962. 
86. 
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus 
J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus 
interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of 
CALGB 90206. J Clin Oncol. 2010;28(13):2137-43. doi: 10.1200/JCO.2009.26.5561. PubMed 
PMID: 20368558; PMCID: 2860433. 
87. 
Nixon AB, Halabi S, Shterev I, Starr MD, Brady JC, Dutcher J, Hopkins J, Hurwitz HI, 
Small E, Rini B, Febbo PG, George D. Identification of predictive biomarkers of overall survival 
(OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
101 
+/- bevacizumab (B): Results from CALGB 90206 (Alliance) J Clin Oncol. 2013;31:Suppl; abstr 
4520. 
88. 
Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng 
YG, Peale FV, Ouyang W, Ferrara N. An interleukin-17-mediated paracrine network promotes 
tumor resistance to anti-angiogenic therapy. Nat Med. 2013;19(9):1114-23. doi: 10.1038/nm.3291. 
PubMed PMID: 23913124. 
89. 
Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, 
Ferrara N. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid 
cells. Nat Biotechnol. 2007;25(8):911-20. doi: 10.1038/nbt1323. PubMed PMID: 17664940. 
90. 
Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 
2011;364(7):656-65. doi: 10.1056/NEJMra0910283. PubMed PMID: 21323543. 
91. 
Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev 
Cancer. 2004;4(2):97-105. doi: 10.1038/nrc1275. PubMed PMID: 14964307. 
92. 
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of 
STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7(1):41-51. doi: 
10.1038/nri1995. PubMed PMID: 17186030. 
93. 
Addison CL, Ding K, Zhao H, Le Maitre A, Goss GD, Seymour L, Tsao MS, Shepherd 
FA, Bradbury PA. Plasma transforming growth factor alpha and amphiregulin protein levels in 
NCIC 
Clinical 
Trials 
Group 
BR.21. 
J 
Clin 
Oncol. 
2010;28(36):5247-56. 
doi: 
10.1200/JCO.2010.31.0805. PubMed PMID: 21079146. 
94. 
Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S, Rowinsky EK, Xu 
LA, Harbison CT, Clark EA, Mauro DJ, Khambata-Ford S. Tumour gene expression predicts 
response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer. 
2011;104(3):488-95. doi: 10.1038/sj.bjc.6606054. PubMed PMID: 21206494; PMCID: 3049558. 
95. 
Cushman SM, Jiang C, Hatch AJ, Shterev I, Sibley AB, Niedzwiecki D, Venook AP, 
Owzar K, Hurwitz HI, Nixon AB. Gene expression markers of efficacy and resistance to cetuximab 
treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). Clin Cancer Res. 
2015;21(5):1078-86. doi: 10.1158/1078-0432.CCR-14-2313. PubMed PMID: 25520391. 
96. 
Hatch AJ, Pang H, Starr MD, Brady JC, Jia J, Niedzwiecki D, Venook AP, Cushman 
SM, Hurwitz H, Nixon AB. Prognostic and predictive blood-based biomarkers of overall survival 
(OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results 
from CALGB 80203 (Alliance). J Clin Oncol. 2014;32(5):11022 (suppl; abstract). 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
102 
97. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger 
MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small 
EJ, Beer TM, Wilding G, Martin A, Hussain M. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-59. Epub 
2008/03/04. doi: 10.1200/jco.2007.12.4487. PubMed PMID: 18309951; PMCID: PMC4010133. 
98. 
Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, 
Friedlander M, Jakobsen A, Vermorken JB. Re: new guidelines to evaluate the response to 
treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst. 
2000;92(18):1534-5. Epub 2000/09/21. PubMed PMID: 10995813. 
99. 
Wieand S SG, O'Fallon JR. Stopping when the experimental regimen does not appear 
to help. Stat Med 13:1453-1458. 1994. 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
103 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
104 
APPENDIX B 
GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use 
of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF. 
 
DRUGS INDUCING CYP3A4 METABOLISM THAT ASTRAZENECA 
STRONGLY RECOMMEND ARE NOT COMBINED WITH OSIMERTINIB 
(AZD9291)  
Osimertinib (AZD9291)  is metabolised by CYP3A4 and CYP3A5 enzymes. 
A drug-drug interaction study of AZD9291 evaluated in patients showed that there is potential 
for Osimertinib (AZD9291) being a victim when co-administered with strong inducers of 
CYP3A4 Osimertinib (AZD9291) concentrations are decreased when co-dosed with rifampicin). 
The following potent inducers of CYP3A4 must not be used during this study for any patient 
receiving Osimertinib (AZD9291). 
 
Table 1 
Drugs inducing CYP3A4 
 
Contraindicated drugs 
 
Withdrawal period prior to Osimertinib 
(AZD9291)  start 
Carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentin 
St John’s Wort 
3 weeks 
Phenobarbitone 
5 weeks 
 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that 
are known to strongly modulate CYP3A4 activity.  Appropriate medical judgment is required.  
Please contact the study PI with any queries you have on this issue. 
 
MEDICINES WHOSE EXPOSURES MAY BE AFFECTED BY AZD9291 
(OSIMERTINIB) THAT ASTRAZENECA CONSIDERS MAY BE ALLOWED 
WITH CAUTION 
Osimertinib (AZD9291) may increase the concentration of sensitive BCRP and Pgp substrates 
(concentration of the sensitive BCRP substrate, rosuvastatin and sensitive Pgp substrate, 
fexofenadine, are increased). 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
105 
Table 2 
Exposure, pharmacological action and toxicity may be increased by 
Osimertinib (AZD9291)  
Warning of possible interaction 
Advice 
Rosuvastatin 
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions.  Please refer to full 
prescribing information for all drugs prior to co-
administration with Osimertinib (AZD9291). 
Sulfasalazine 
Doxorubicin 
Daunorubicin 
Topotecan 
Dabigatran 
Aliskiren 
Digoxin 
 
DRUGS THAT MAY PROLONG QT INTERVAL 
The drugs listed in this section are taken from information provided by The Arizona Center for 
Education and Research website: https://www.crediblemeds.org/.  The website characterizes 
drugs based on the risk of inducing Torsades de Pointes (TdP).   
During screening the drugs that patients are currently prescribed should be checked opposite the 
ArizonaCert website.   
 
 
Drugs with a known risk of Torsades de Pointes 
The following drugs prolong the QT interval and are clearly associated with a known risk of 
TdP, even when taken as recommended.  These drugs must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in Table 3 and 
should not be co-administered with study treatment Osimertinib (AZD9291) and for a period of 
two weeks after discontinuing study treatment.  The list of drugs may not be exhaustive and is 
subject to change as new information becomes available.  As such investigators are 
recommended to search the website to provide the most up to date information. 
 
Table 3 
Drugs with a known risk of TdP 
Drug name 
 
Withdrawal period prior to Osimertinib 
(AZD9291) start 
Anagrelide, ciprofloxacin, clarithromycin, 
cocaine, droperidol, erythromycin, 
levofloxacin, ondansentron, papaverine, 
hydrochloride, procainamide, sulpiride, 
sulropride, terfenadine, terlipressin 
2 days 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
106 
Table 3 
Drugs with a known risk of TdP 
Drug name 
 
Withdrawal period prior to Osimertinib 
(AZD9291) start 
Cilostazol, Cisapride, disopyramide, 
dofetilide, domperidone, flecanide, 
gatifloxacine, grepafloxacin, ibutilide, 
moxifloxacin, oxaliplatin, Propofol, 
quinidine, roxithromycin, sevoflurane, 
sotalol, sparfloxacin, thioridazine 
7 days 
Azithromycin, bepridil, citalopram, 
chlorpromazine, dronedarone, escitalopram, 
fluconazole, halofantrine, haloperidol, 
levomepromazine, levosulpiride, 
mesoridazine 
14 days 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide*, Ibogaine 
  
6 weeks 
Pentamidine 
Astemizole, Probucol, vandetanib 
8 weeks 
4 months 
Amiodarone, chloroquine 
1 year 
* 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
 
Other TdP risk Categories 
Patients receiving drugs that prolong QT interval or may increase the risk of TdP from other TdP 
risk categories can be enrolled, notwithstanding other exclusions and restrictions, if these drugs 
are considered essential for patient management and the patient has been stable on therapy.  
Close monitoring with ECGs and electrolytes is recommended. 
 
Patients with congenital long QT syndrome (CLQTS) are excluded from this study. 
 
Guidance regardless of TdP risk category 
Following study treatment initiation if it is considered essential for patient management to give 
drugs known to prolong QTc interval, regardless of TdP risk category, close monitoring with 
ECGs and electrolytes is recommended. 
 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
107 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, Osimertinib (AZD9291).  This clinical trial is sponsored by the National Cancer 
Institute (NCI).  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Osimertinib (AZD9291)  interacts with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells. 
 
 
 
 
x Osimertinib (AZD9291) is metabolized by CYP3A4 and CYP3A5 enzymes.  A drug-drug 
interaction study of Osimertinib (AZD9291)  evaluated in patients showed that there is 
potential for Osimertinib (AZD9291) being a victim when co-administered with strong 
inducers of CYP3A4 
x Osimertinib (AZD9291) may increase the concentration of sensitive BCRP and Pgp 
substrates 
  
 
 
 
 
 
 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Osimertinib (AZD9291) interacts with many drugs which can cause side effects. Because of this, 
it is very important to tell your study doctors about all of your medicines before you enroll on this 
clinical trial.  It is also very important to tell them if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study.  When you talk about your 
medications with your doctors, include medicine you buy without a prescription (over-the-counter 
remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication 
bottles or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  
 
These are the things that you and they need to know: 
 
Osimertinib (AZD9291) must be used very carefully with other medicines that need certain liver 
enzymes and transport proteins to be effective or to be cleared from your system. Before you enroll 
onto the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements that are considered “strong inducers of CYP 3A4 or 
substrates of P-gp and BCRP.”  
 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
109 
APPENDIX D 
FORMALIN-FIXED, PARAFFIN EMBEDDED (FFPE) TUMOR 
TISSUE COLLECTION, HANDLING AND SHIPMENT 
The purpose of this Standard Operating Procedure (SOP) is to outline the process for formalin-
fixing and paraffin embedding tissue for processing and shipping to the laboratory of Dr. 
 at Yale. Tissue samples will be collected from participants who have been 
properly consented and who have agreed to participate in the research study. Tumor tissues are 
only suitable for molecular studies if fixed in a timely and appropriate manner. The purpose of 
this document is to outline standardized procedures for collection sites to follow for formalin 
fixing/paraffin embedding tissue. 
 
The tumor tissue will be obtained by surgical resection or biopsy procedure. Tissue will be 
obtained prior to the start of trial therapy.  Patients with only CNS progression are not required 
to undergo a tissue biopsy.  Immediately after acquisition, tissue cores (preferably three) will 
be placed into separate pre-labeled 30mL tubes of 10% neutral buffered formalin (NBF). Let 
fix for 16-24 hours. Pathology at the site will paraffin block the core biopsies. 
 
Ship FFPE blocks, once embedded, for overnight delivery (Mon-Thur).  If blocks are not 
available, 15-20 unstained slides are acceptable alternatives (15 slides minimum, 20 slides 
strongly encouraged). Once slides are cut, they should be shipped within 7 days. 
Shipping Instructions  
1. Label the samples with the following information: 
CTEP Protocol Number (NCI#10020) 
Description (FFPE block) 
Patient Study ID Number 
Date of Collection  
Time of Collection  
2. Place the FFPE blocks or unstained slides in a ziplock bag and wrap in bubble 
wrap or another type of padded material prior to shipping.  The zip lock bag can 
be placed into a FedEx envelope or small shipping box. 
3. Verify that the FedEx air bill is marked Standard Overnight Shipping. 
4. Call Courier Service to pick up specimens. 
5. Ship overnight (Mon-Thur). No shipments will occur over weekends or holidays.  
Prior to any shipment, please notify 
 via email and/or 
telephone. The samples will be shipped to the following address: 
 
C/O
Lab 
Yale School of Medicine 
Yale Comprehensive Cancer Center 
333 Cedar Street, NSB 287B 
New Haven, CT  06510 
lab:
fax: 203-785-7531 
Email:
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
110 
 
APPENDIX E PLASMA COLLECTION AND SHIPMENT 
 
At each required timepoint, one 10 mL purple-top tube is to be sent to the 
 
Laboratory and one 10 mL purple-top tube is to be sent to the 
 Laboratory as per 
instructions below. 
 
 
Plasma Collection/Processing/Storage SOP – 
 Laboratory 
 
1. Collect blood in 10 mL purple-top EDTA-containing Vacutainer tubes and gently 
turn tubes end over end 3-4 times upon collection to dissolve the EDTA and prevent 
coagulation.  If blood is collected from a port-a-cath instead of by venipuncture, an 
appropriate volume should first be discarded as waste to avoid contamination with 
saline and/or heparin. 
 
2. Tubes should be kept at room temperature and transported to the laboratory without 
excessive agitation (preferably not via hospital’s pneumatic tube system).   
 
3. Spin tubes at 1000 x g for 15 minutes in a clinical centrifuge ideally within 1 hour 
of collection, and not more than 4 hours.  Tubes should be carefully balanced in the 
centrifuge to avoid vibrations, which might disrupt WBCs and increase background 
DNA in the plasma.  The centrifuge should be stopped in "brake off" mode.  It is 
important to handle tube very gently to avoid bringing cells back into the plasma 
when transporting the tube from the centrifuge back to the lab bench and when 
opening the rubber plug at the top of the tube.   
 
4. Plasma should be dispensed into cryovials in 1mL aliquots (the final aliquot can be 
less than 1mL).  From a 10 mL tube, we typically obtain about 4.5 mL of plasma.  
Care should be taken to avoid any white blood cells by not pipetting the last ~0.5 
mL of plasma above the buffy coat layer.  Plasma should be frozen at -70oC to -
80oC for long-term storage 
 
5. The buffy coat layer should be preserved in a separate cryovial as a source of 
germline DNA.  It is acceptable for some plasma and RBCs to be taken up by the 
pipette along with the buffy coat.  This can be kept in long-term storage at -70oC to 
-80oC. 
 
6. Once the plasma is frozen, it should not be thawed until it is ready to be processed 
for sequencing.  
 
7. Samples should be shipped on dry ice overnight to the analyzing lab.  Samples can 
be stored locally for several months and shipped in batches once several samples 
have been collected.  Please email Dr. 
prior to 
shipping so that we know to expect the shipment.  The shipping address is: 
 Lab 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
111 
Yale School of Medicine 
15 York Street, Room HRT 210 
New Haven, CT 06510 
 
 
Plasma Collection/Processing/Storage SOP – 
 Laboratory 
 
x Biomarker assays are time sensitive.  Samples must be processed within 90 minutes of 
collection.  Complete the Biomarker Flowsheet, insert a copy of the flowsheet with 
shipment, and fax to ATTN: BIOMARKER LABORATORY at 919-668-3925.  
x For any questions regarding biomarker processing, supplies and shipping, please call 919-
681-2239 
 
 
For plasma samples: 
 
1. Draw one 10ml purple-top (K2EDTA) tube (BD Vacutainer, Catalog no. 366643) 
2. Invert tubes 10 times to mix blood 
3. Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
4. Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
5. Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
6. Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml cryovial.  For the 
EDTA, aliquot into pink capped cryovial.  Total of 4 pink capped cryovials needed for 
EDTA plasma.  
7. Label and freeze at -80°C* (see labeling instructions below) 
 
*Please note:  If your site does not have a -80°C freezer, samples should be shipped on dry ice 
on the day of collection.  If unable to ship samples on the day of collection, please place 
the samples on dry ice until they can be shipped.  Samples can be stored on dry ice for 
no more than 48 hours prior to shipping.  Please replenish dry ice as needed to ensure 
samples stay frozen and there is enough to last throughout shipment. 
 
LABELING INSTRUCTIONS:   
 
x Plasma-containing tubes need to be labeled with the following information (using a Sharpie or 
Cryopen): 
 
1. Protocol Name  
2. Subject Study Number 
3. Subject Initials 
4. Sample Date and Time 
5. Sample Type (ie. whole blood, EDTA plasma, citrate plasma, serum, urine) 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
112 
SHIPPING INSTRUCTIONS:   
 
x Ship biomarker samples within 48 to 72 hours of completed processing. 
x Please include complete the Biomarker Flowsheet with shipment.  
x All biomarker samples (whole blood, plasma, serum and urine) must be shipped on dry ice by 
overnight delivery Monday through Thursday (no holidays) to the following address: 
 
Attention: 
Phase I Biomarker Laboratory 
 
 
 
ATTN:  
, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
 
 
 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
113 
 
 
 
 
 
 
APPENDIX F 
PATIENT MEDICATION DIARY 
 
Today’s date ______________Cycle Number: __________     Agent:  Osimertinib (AZD9291) 
 
Patient Name_____________________(initials acceptable)  
             
 
Patient Study ID ________________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take Osimertinib (AZD9291) tablets daily.  Take tablets with or without food and take with 8 
ounces of water.  Tablets should be swallowed whole, do not chew or crush.  Take ________ mg tablet at 
the same time each day.  If you miss a dose (i.e. if you do not take it within 12 hours of scheduled time), 
skip the dose and resume taking Osimertinib (AZD9291) at the next scheduled time on the next day.  If 
you vomit after taking Osimertinib, do not retake the dose; you should take Osimertinib (AZD9291) at the 
next scheduled time on the next day. 
4. 
Record the date, and when you took the tablet.   
5. 
If you have any comments or notice any side effects, please record them in the Comments column.   
6. 
Please bring this form and your bottles of Osimertinib (AZD9291) tablets when you return for each 
appointment. 
7.    Please store Osimertinib (AZD9291) tablets at room temperature. 
Day 
Date 
Time of dose  AM/PM 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
 
 
CTEP-assigned Protocol # 10042 
 
Local Protocol # ___________________ 
Use of this document is governed by the terms of use on the first page of this document.

NCI Protocol #:10042 
Version Date: 03/27/2023 
 
114 
 
Patient’s signature _____________________________________________________________ 
 
   Physician’s Office will complete this section: 
1. Date patient started protocol treatment______________      
2. Date patient was removed from study_______________ 
3. Patient’s planned total daily dose
 _________________________________________________________________________________________  
3. Total number of tablets taken this cycle of Osimertinib (AZD9291)_________________   
4. Physician/Nurse/Data Manager’s Signature 
 _________________________________________________________________________________________  
 
Use of this document is governed by the terms of use on the first page of this document.