MATCH Treatment Subprotocol E: Osimertinib (AZD9291) in Patients With Tumors Having EGFR T790M Mutations or Rare Activating Mutations of EGFR
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f: 617. 589.0914
ecog-acrin.org
July 16, 2021
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD 20892
Dear Ms. Kruhm:
Enclosed is Addendum #29 to EAY131-E, MATCH Treatment Subprotocol E: AZD9291 in 
Patients with Tumors Having EGFR T790M Mutations or Rare Activating Mutations of EGFR
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements:
This addendum has been reviewed and approved by the Central IRB, which is the sole 
IRB of record for this study. Local IRB review and approval is unnecessary.
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum.
Re: Review of Amendment #39 of Protocol #EAY131-E: “MATCH Treatment Subprotocol E: 
AZD9291 in Patients with Tumors Having EGFR T790M Mutations (Except Non-Small Cell Lung 
Cancer) or Rare Activating Mutations of EGFR” dated 4/15/2021. The principal investigators 
responses appear in bold below. 
I.
Recommendations:
Section
Comments
1.
Global
5.1
Within approximately 6 months the PMB-supplied investigational label AZD9291 
(osimertinib) will transition to PMB-supplied commercial label osimertinib 
(AZD9291). There are no manufacturing differences between the 
investigational clinical supply and the marketed commercial supply.  At the 
time of the next amendment please make the following administrative updates 
to facilitate the planned transition:
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)”.

ii
Section
Comments
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.
PI Response: This has been revised throughout the documents.
The following revisions to the EAY131-E protocol have been made in this addendum:
Section
Change
1.
Global
Administrative edits made throughout document. 
2.
Cover Page
Updated study title.
3.
Cover Page
Updated Version Date and addendum number.
4.
2.1.2.1
Revised eligibility criteria regarding eligible mutations for study. 
5.
2.1.4
First sentence, line 2; revised ‘prior to registration to treatment’ to “prior to
registration’. 
6.
2.1.10
Revised ‘Male patients’ to ‘Patients’. 
7.
3.2.2
Updated template language regarding the ‘Second Cancer Reporting 
Requirements.’
8.
3.4
Under ‘Adverse Events of Special Interest’, in item 1, 1st paragraph, lines 5&6; 
revised ‘eCRF’ to ‘eCRF in Medidata Rave’ 
9.
4
In footnote C, revised ‘women’ to ‘patients’.
10.
5.1
Updated the primary agent name to the generic name Osimertinib throughout 
section.
The following revisions to the EAY131-E Informed Consent Document have been made in this 
addendum:
Section
Change
1.
Global
Updated the primary agent name to the generic name Osimertinib (AZD9291) 
throughout document.
2.
Cover Page
Updated Version Date.
If you have any questions regarding this addendum, please contact aaagu@ecog-acrin.org or 
857-504-2900.
We request review and approval of this addendum to EAY131-E so ECOG-ACRIN may activate 
it promptly.  
Thank you.
Sincerely,
Pamela Cogliano
Senior Director of Protocol Development

EAY131-E
1
Molecular Analysis for Therapy 
Choice (MATCH)
MATCH Treatment Subprotocol E: Osimertinib 
(AZD9291) in Patients with Tumors Having EGFR T790M 
Mutations or Rare Activating Mutations of EGFR
TREATMENT SUBPROTOCOL CHAIR:
Lecia V. Sequist, MD
TREATMENT SUBPROTOCOL CO-CHAIR:
Helena Yu, MD
TRANSLATIONAL CHAIR:
Christine Lovly, MD
Version Date: July 16, 2021
NCI Update Date: August 12, 2015
NOTE: This subprotocol (EAY131-E) should 
be used in conjunction with the 
MATCH Master Protocol (EAY131).
SUBPROTOCOL ACTIVATION DATE
August 12, 2015 (incorporated in Addendum #1)
Update #2 – 8/15
NOTE: As of 11/17, all protocol changes will
be noted by addendum number.
Addendum #2 – 2/16
Addendum #3 – 5/16
Addendum #4 – 7/16
Addendum #5 – 12/16
Addendum #7 – 3/17
Addendum #12
Addendum #13
Addendum #14
Addendum #23
Addendum #25
Addendum #27
Addendum #29
Agent
IND#
NSC#
Supply
Osimertinib 
(AZD9291)
IND Sponsor: DCTD, NCI
781254
NCI Supplied
Rev. Add12
Rev. Add25

ECOG-ACRIN
EAY131-E
Cancer Research Group
Version Date: July 16, 2021
NCI Update Date: August 12, 2015
2
Table of Contents
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol E: Osimertinib (AZD9291) in Patients with Tumors 
Having EGFR T790M Mutations or Rare Activating Mutations of EGFR ............. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Supporting Preliminary Data ..................................................................... 5 
2. Selection of Patients ........................................................................................... 8 
2.1 Eligibility Criteria ....................................................................................... 8 
3. Osimertinib (AZD9291) Treatment Plan ........................................................... 10 
3.1 Administration Schedule ......................................................................... 10 
3.2 Adverse Event Reporting Requirements ................................................. 10 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Osimertinib (AZD9291) (osimertinib, NSC 781254) ................................ 13 
3.4 Dose Modifications ................................................................................. 16 
3.5 Supportive Care ....................................................................................... 17 
3.6 Duration of Agent-specific treatment ..................................................... 17 
3.7 Duration of Follow-Up ............................................................................. 18 
4. Study Parameters .............................................................................................. 19 
4.1 Therapeutic Parameters for Osimertinib (AZD9291) Treatment ............ 19 
5. Drug Formulation and Procurement ................................................................. 21 
5.1 Osimertinib (NSC #781254) ..................................................................... 22 
6. Translational Studies ......................................................................................... 24 
7. References ........................................................................................................ 24 
Appendix I  Patient Pill Calendar ............................................................................. 25 
Appendix II  Guidance Regarding Potential Interactions with Concomitant 
Medications ...................................................................................................... 27 
Appendix III  PATIENT CLINICAL TRIAL WALLET CARD ............................................. 30 
Appendix IV  Actionable Mutations for Sub-Protocol EAY131-E ............................. 31 
Appendix V  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................................... 32 
 

ECOG-ACRIN
EAY131-E
Cancer Research Group
Version Date: July 16, 2021
NCI Update Date: August 12, 2015
3
TREATMENT SUBPROTOCOL CHAIR
Lecia V. Sequist
Massachusetts General Hospital
55 Fruit Street, POB 212
Boston, MA  02114
Phone: 617-726-7812
Fax: 617-724-3166
Email: lvsequist@partners.org
TREATMENT SUBPROTOCOL CO-CHAIR 
Helena Yu
Memorial Sloan Kettering Cancer Center
300 East 66th Street 
New York, NY 10065
Phone: 646-888-4634
Fax: 646-227-7276
Email: YuH@mskcc.org
TRANSLATIONAL CHAIR
Christine Lovly MD PhD
Vanderbilt-Ingram Cancer Center
2220 Pierce Avenue South
777 PRB
Nashville, TN 37232
Phone: 615-936-3457
Fax: 615-343-7602
Email: christine.lovly@Vanderbilt.edu

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EAY131-E
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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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Schema
Long-Term Follow-Up
Osimertinib (AZD9291) 80 
mg orally daily continuously
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 35

ECOG-ACRIN
EAY131-E
Cancer Research Group
Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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1. Introduction
1.1
Osimertinib (AZ9291)
Osimertinib (AZD9291) is an irreversible, mutant specific EGFR tyrosine kinase 
inhibitor. It is effective in pre-clinical tumor models and clinical trials in patients 
with TKI sensitizing and T790M resistant tumors. It is generally well tolerated and 
its most common side effects are mild rash and diarrhea.
1.2
Supporting Preliminary Data
Activating mutations within the epidermal growth factor receptor (EGFR) 
mutations are present in approximately 20% of all lung adenocarcinomas.  
EGFR-mutant cancers are dependent on EGFR signaling for growth and survival, 
making inhibition of EGFR an attractive therapeutic target. EGFR tyrosine kinase 
inhibitors (TKIs) including erlotinib and afatinib are FDA approved for the 
treatment of EGFR-mutant lung cancers based on superior responses and 
progression free survival compared to cytotoxic chemotherapy.1,2 All patients that 
are treated with EGFR TKIs will eventually develop therapeutic resistance, on 
average after 10-12 months of therapy.1,2Tumor cells from more than half of 
patients with such “acquired resistance” contain a recurrent second-site mutation 
(T790M) in the EGFR kinase domain.3,4 EGFR T790M is often described as a 
gatekeeper mutation, and this substitution results in steric hindrance that 
prevents drug binding and also changes the receptor affinity for ATP.5 At present, 
there are no FDA approved therapies for patients with EGFR mutant lung cancer 
who develop acquired resistance mediated by the T790M mutation. 
The first- and second- generation EGFR TKIs (erlotinib and afatinib, respectively) 
were designed to inhibit wild-type EGFR. Recently, a new class of pyrimidine-
based EGFR TKIs has been developed which irreversibly inhibits classically 
sensitizing (EGFR L858R, EGFR exon 19 deletions [ex19del]) and resistant 
(EGFR T790M) forms of EGFR. The first drug in this class was WZ4002, and 
additional drugs include osimertinib (AZD9291), CO-1686, HM61713, EGF816 
and ASP8273. Osimertinib (AZD9291) has a greater than 200 times selectivity 
for EGFR L858R/T790M over wild-type EGFR (IC50s 480 nM to 1.8 μM across 
different cell lines).6 Treatment with osimertinib (AZD9291) in EGFR L858R, 
EGFR ex19del,  EGFR L858R/T790M and EGFR ex19del/T790M xenograft 
tumors also led to profound tumor growth regression. Osimertinib (AZD9291) 
Investigator’s Brochure 2014)
The phase 1 study of osimertinib (AZD9291) (NCT01802632) has shown 
extremely promising activity, specifically in patients with lung adenocarcinomas 
that harbor EGFR T790M.7 A total of 127 patients with centrally confirmed EGFR 
T790M who could be evaluated for response: the response rate was 61% (95% 
CI 52-70) and median PFS was 9.6 months (95% CI, 8.3 to not reached). 
Among all patients treated, no dose-limiting toxicities were seen at any of the 
doses evaluated. The most common (>10%) adverse events were diarrhea, 
rash/acne, nausea, decreased appetite, dry skin, pruritis, fatigue, paronychia, 
constipation, cough stomatitis, vomiting, anemia, dyspnea, upper respiratory tract 
infection, headache as presented in the Janne et al 2015 paper. Please refer to 
the Investigator’s Brochure for comprehensive safety data.

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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As of 9th February 2015, there were 25 (2.5%) ILD-like events reported out of 
more than 993 patients exposed to osimertinib (AZD9291). Of these, 12 were 
CTCAE Grade 1-2 events, 8 were Grade 3-4 events and 3 fatal (Grade 5) events 
(0.3%) as outlined above. Two events haven’t had a CTCAE grade reported yet.
11 patients experienced prolongation of the corrected QT (QTc) interval; none of 
these 11 events resulted in reduction or discontinuation of osimertinib 
(AZD9291). There were 7 fatal adverse events; 1/7 of these events was a 
pneumonia which was reported as being possibly drug-related.
The excellent responses of EGFR T790M harboring lung adenocarcinomas to 
osimertinib (AZD9291) provide the rationale to assess osimertinib (AZD9291) in 
other tumors with EGFR T790M. Osimertinib (AZD9291) is also active in pre-
clinical studies against other types of EGFR mutations which suggest that the 
compound may provide clinical benefit in tumors with other rare EGFR mutations 
as well.
Comprehensive mutation profiling allows us to identify rare, potentially actionable 
mutations in a wide array of cancer types. Figure 1 illustrates the frequency of 
EGFR mutations in various tumor types demonstrating that a broad array of 
cancers have a low frequency of these mutations of interest. EGFR T790M and 
other rare variants such as vIII, G719S, L861Q, exon 19 and 20 insertions 
represent a small minority of these EGFR mutations. In the COSMIC database, 
we identified listings of EGFR T790M mutations in cancers of the upper 
aerodigestive tract, the biliary tract, the large intestine, the central nervous 
system and the skin and we suspect these mutations will be more likely to be 
commonly identified as comprehensive molecular testing becomes routine for all 
tumors.
The phase 1 study of osimertinib (AZD9291) was conducted in patients with 
predominantly EGFR L858R or EGFR ex19del and concurrent EGFR T790M; 
there is no available clinical data to indicate whether osimertinib (AZD9291) has 
activity against tumors with other rare EGFR mutations or with T790M alone. 
There is preclinical data that demonstrates activity of osimertinib (AZD9291) in 
cells transfected with EGFR G719S, L861Q, exon 19 insertions, EGFR variant III,
and HER2 exon 20 insertions.6 We propose studying AZD9291 in patients with 
EGFR T790M in cancers other than lung adenocarcinomas. We also propose 
assessing the activity of AZD9291 in cancers with rare EGFR mutations among 
which osimertinib (AZD9291) was efficacious in pre-clinical studies (providing 
MATCH Level 3 evidence – see MATCH Master Protocol).
Rev.2/16

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EAY131-E
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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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Figure 1
Figure 1: Frequency of EGFR mutations in tumor types derived from the cBIO 
portal (http://www.cbioportal.org/public-portal/). The X-axis denotes the tumor 
type and the genomic study from which the data was derived. The Y-axis 
represents the frequency of the EGFR alterations in the studies represented on 
the X-axis.

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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2.
Selection of Patients
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, in order for a patient to be considered eligible for this 
study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. ____________________________
Patient’s Initials (L, F, M) _______________________
Physician Signature and Date ___________________
NOTE:
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu).
NOTE:
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.
NOTE:
All patients must have signed the relevant treatment consent form.
2.1
Eligibility Criteria
2.1.1
Patient must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7).
2.1.2
Patients must have either of the below, or another aberration, as 
determined via the MATCH Master Protocol and according to 
Appendix IV:
2.1.2.1
Any malignancy except NSCLC withEGFR T790M 
identified in their tumor, with or without an activating 
mutation
OR
2.1.2.2
Any malignancy harboring any of the following mutations:
EGFR G719A, G719C, G719D, G719S EGFR L861Q, 
S786I or an EGFR exon 19 in frame insertion mutation.
See Appendix IV for information on the targeted mutations and 
corresponding Levels of Evidence.
_____
_____
_____
_____
_____
Rev.2/16
Rev.2/16
Rev. Add13
Rev. Add25
Rev. Add29
Rev. Add29
Rev. Add29

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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2.1.3
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have no clinically important 
abnormalities in rhythm, conduction or morphology of resting ECG 
e.g. complete left bundle branch block, third degree heart block, and 
second-degree heart block.
Date of ECG:  _______________
2.1.4
Patients must have an ECHO or a nuclear study (MUGA or First 
Pass) within 4 weeks prior to registration and must not have a left 
ventricular ejection fraction (LVEF) < institutional lower limit of normal 
(LLN). If the LLN is not defined at a site, the LVEF must be > 50% for 
the patient to be eligible.
Date of ECHO/Nuclear Study:  _______________
2.1.5
Patients must not have known hypersensitivity to osimertinib 
(AZD9291) or compounds of similar chemical or biologic composition
or any of the inactive excipients of the tablets.
2.1.6
Patient must not have received osimertinib (AZD9291), WZ4002, CO-
1686, HM61713, EGF816 or ASP8273 previously.
2.1.7
Patients known to harbor germline EGFR T790M mutations are 
excluded from the study. Prospective testing for germline mutations is 
not required.
2.1.8
Patients must not have a history of interstitial lung disease, idiopathic 
pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, 
radiation pneumonitis requiring steroids, or evidence of active 
pneumonitis on screening chest computerized tomography (CT) scan. 
History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted.
2.1.9
Patients must not currently be receiving treatment with potent 
CYP3A4 inducters or medications “known to prolong” the QT interval 
as defined in Appendix II. Drugs that “may possibly prolong” the QT 
interval, as defined in Appendix II, are permitted if the patient has 
been stable on therapy for the period indicated for the specific 
medication.
2.1.10
Patients must agree to not donate sperm from the start of protocol 
treatment until at least 4 months after the last dose of protocol 
treatment.
Physician Signature
Date
OPTIONAL:
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation.
_____
_____
_____
_____
Rev. 2/16
_____
Rev. Add13
Rev. Add13
_____
Rev. Add13
Rev. Add13
_____
_____
Rev. Add13

ECOG-ACRIN
EAY131-E
Cancer Research Group
Version Date: July 16, 2021
NCI Update Date: August 12, 2015
10
3.
Osimertinib (AZD9291) Treatment Plan
3.1
Administration Schedule
Osimertinib (AZD9291) is given orally. The dose will be 80mg orally once daily 
continuously. A cycle is defined as 28 days.
Patients should be instructed that if they vomit after taking a dose, then they 
must not “make it up” with an extra dose, but instead, resume subsequent doses 
as prescribed.  Any missed dose should be skipped and dosing resumed with 
subsequent doses.
3.2
Adverse Event Reporting Requirements
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol. Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS). 
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met.
3.2.1
Additional instructions, requirements and exceptions for protocol 
EAY131-E
Additional Instructions
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497.  This will
need to be discussed on a case-by-case basis.
EAY131-E specific expedited reporting requirements:
x
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the female patient is on 
osimertinib (AZD9291), or within 28 days of the female 
patient’s last dose of osimertinib (AZD9291), are considered 
immediately reportable events. The pregnancy, suspected 
pregnancy, or positive/ inconclusive pregnancy test must be 
reported via CTEP-AERS within 24 hours of the Investigator’s 
knowledge.  Please refer to Appendix VIII in MATCH Master 
Protocol for detailed instructions on how to report the 
occurrence of a pregnancy as well as the outcome of all 
pregnancies.
EAY131-E specific expedited reporting exceptions:
For study Subprotocol E, the adverse events listed below do not
require expedited reporting via CTEP-AERS:
Rev. Add25
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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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x
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event.
3.2.2
Second Primary Cancer Reporting Requirements
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported as
follows.
x
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows:
1. Complete a Second Primary Form in Medidata Rave within 14 
days.
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis.
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN
via Medidata Rave.
x
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows:
1. Complete a Second Primary Form in Medidata Rave within 14 
days
2. Report the diagnosis on the Adverse Event Form or Late 
Adverse Event Form in the appropriate Treatment Cycle or 
Post Registration folder in Medidata Rave
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy
NOTE:
When reporting attribution on the AE Form, assess 
the relationship between the secondary malignancy 
and the current protocol treatment ONLY (and NOT 
relationship to any anti-cancer treatment received 
either before or after protocol treatment).
3. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis.
5. If the patient has been diagnosed with AML/MDS, upload a
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP.

ECOG-ACRIN
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NCI Update Date: August 12, 2015
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NOTE:
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease.
NOTE:
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial.
NOTE:
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form.

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.
2Interstitial lung disease includes the terms pneumonitis and interstitial lung disease. Dyspnea, cough and 
fever may be indicative of interstitial lung disease/pneumonitis.
3Nail changes may include the terms nail bed disorders, nail discoloration, nail disorder, nail loss, nail 
pigmentation, nail toxicity, nail dystrophy, nail ridging, onychoclasis, onycholysis, and onychomadesis.
Adverse events reported on AZD9291 (osimertinib) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that AZD9291 
(osimertinib) caused the adverse event:
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Myocardial 
infarction; Supraventricular tachycardia
EYE DISORDERS - Vision decreased
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Dyspepsia; Dysphagia; 
Gastritis; Gastrointestinal disorders - Other (intestinal ischemia); Pancreatitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; 
Fatigue; Fever2; Flu like symptoms; Generalized edema; Non-cardiac chest pain
INFECTIONS AND INFESTATIONS - Folliculitis; Lung infection; Nail infection; 
Papulopustular rash; Rash pustular; Shingles; Upper respiratory infection
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Other (drug eruption)
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase 
increased; CPK increased; 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 - Cough2; Dyspnea2;
Hypoxia; Pleural effusion; Respiratory failure
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (skin 
erosion)
VASCULAR DISORDERS - Hematoma; Thromboembolic event
NOTE:
AZD9291 (osimertinib) 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.

ECOG-ACRIN
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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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3.4
Dose Modifications 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov).
If there is a clinically-significant AE or unacceptable toxicity of any kind (grade 3 
of greater), the primary treatment strategy should be dose interruption and 
supportive care aimed at the AE. The patient may resume osimertinib (AZD9291)
dosing once the AE has resolved to grade 2 or less (see exceptions below). 
Dosing may resume at 80mg QD or 40mg QD at the discretion of the investigator 
provided the AE resolved to grade 2 or less within 21 days of dose interruption. If 
the toxicity does not resolve within 21 days to grade 2 or less, the patient should 
be removed from the protocol and followed until resolution.
Upon resolution of toxicity within 21 days and resumption of study drug:
x
If a further episode of the same AE subsequently requires dose interruption, 
osimertinib (AZD9291) must restart at 40mg QD.
x
If a different AE subsequently requires dose interruption, osimertinib 
(AZD9291) may restart at either 80mg QD or 40mg QD at the investigator’s 
discretion 
Adverse Events of Special Interest
1. Ophthalmic Events
Full ophthalmic assessment, including slit lamp examination, is required if a 
patient experiences any visual symptoms (including blurring of vision) (grade 
2 or greater), with additional tests if clinically indicated. Any clinically 
significant findings, including those confirmed by the ophthalmologist must be 
reported as an event on the eCRF in Medidata Rave. Ophthalmology 
examination results should be collected in the eCRF in Medidata Rave.
Patient will be advised to consult the clinic promptly if they have any 
concerns.
Keratitis
Keratitis was reported in 0.7% (n=6) of the 833 patients treated with 
osimertinib 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.
2. Interstitial lung disease
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological 
abnormality suggestive of interstitial lung disease is observed, an interruption 
in study treatment dosing is required as well as a full diagnostic workup to 
exclude alternative causes such as lymphangitic carcinomatosis, infection, 
allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of 
confirmatory High Resolution CT scans where other causes of respiratory 
symptoms have been excluded, a diagnosis of interstitial lung disease should 
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be considered and study treatment permanently discontinued. In the absence 
of a diagnosis of interstitial lung disease study treatment may be restarted 
following consultation with the study subprotocol PI’s.
3. Cardiovascular effects
Exclusion criteria for unstable cardiac conditions and risk factors for QT 
prolongations are included in the clinical study protocol. Concomitant use of 
regular medications that may prolong the QT interval will be restricted 
whenever feasible, but patients may receive any medication that is clinically 
indicated for the treatment of AEs. Electrolyte and vital sign assessments, 
including pulse rate and blood pressure, will be monitored regularly 
throughout the study. ECG will be performed at enrollment and prior to each 
treatment cycle. The investigator or designated physician will review each 
ECG prior to discharge from the clinic and may refer to a local cardiologist if 
appropriate for immediate management of the patient. 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.
QTc Prolongation
Patients with QTcF prolongation fulfilling the following criteria (i.e., confirmed 
QTcF prolongation to > 500 msec absolute or a > 60 msec increase from 
baseline) should have osimertinib (AZD9291) interrupted and regular ECGs 
performed until resolution to baseline. If the toxicity does not resolve to < 
grade 1 within 3 weeks the patient will be permanently withdrawn from
osimertinib (AZD9291) treatment.
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 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 has not been established. In patients with cardiac risk factors and 
those with conditions that can affect LVEF, cardiac monitoring, including an 
assessment of LVEF at baseline and during treatment, should be considered. 
In patients who develop relevant cardiac signs/symptoms during treatment, 
cardiac monitoring including LVEF assessment should be considered.
3.5
Supportive Care 
All supportive measures consistent with optimal patient care will be given 
throughout the study.
3.6
Duration of Agent-specific treatment
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies:
x
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet.
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x
Patient withdraws consent.
x
Patient experiences unacceptable toxicity.
x
Non-protocol therapies are administered.
x
Disease progression
3.7
Duration of Follow-Up
Refer to the MATCH Master Protocol for specifics on the duration of follow-up.

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4.
Study Parameters
4.1
Therapeutic Parameters for Osimertinib (AZD9291) Treatment
NOTE:
In addition to the study parameters listed in the MATCH Master Protocol, the below parameters must also be 
performed for patients on osimertinib (AZD9291) treatment.
NOTE:
All assessments required prior to registration to treatment should be done ≤4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG).
Test/Assessment
Prior to Registration 
to Treatment
Treatment
End of 
Treatment
Follow 
UpF
Every Cycle, prior 
to treatment
Every 2 
Cycles
H&P, Weight, Vital signsA
X
XJ
X
Performance status
X
XJ
X
CBC w/diff, pltsB
X
XJ
X
Serum chemistryB
X
XJ
X
Radiologic evaluationD
X
XD
XF
E-HCGC
X
Toxicity AssessmentG
X
X
XF
Pill Count/DiaryH
X
X
ECGK
X
XI
ECHO/Nuclear Study
X
Tumor biopsy and blood sample for MATCH Master ProtocolE
X
X
Eye evaluationL
X
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle).
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium,  SGOT[AST], SGPT[ALT], 
sodium, magnesium and serum tumor markers (including LDH, PSA if appropriate).  For eligibility purposes, participants with creatinine levels 
above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance.  CBC w/diff, platelets and serum chemistries should be 
performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of new cycle). CBC with 
differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to 
≤ grade 3. CBC and serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease.
C. Blood pregnancy test (patients of childbearing potential) required prior to beginning treatment.
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Rev.2/16
Rev. 5/16
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D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease.
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. Submit 
at the following time points, as applicable:
x
Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead. On-treatment kits for blood sample collections will be automatically shipped 
to sites upon registration to the treatment step.
x
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4).
x
At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up (with 
a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH Master 
Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of the
MATCH Master Protocol) and fax to 713-563-6506.
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred.
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle.
H. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle.
I.
An electrocardiogram must be done on C1D1 approximately 2 hours after receiving the first dose of osimertinib (AZD9291), on C1D8, and then on
D1 of each subsequent cycle.
J. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications.
K. Within 8 weeks of treatment assignment.
L. Patients should be asked about eye symptoms at baseline. Patients with unexplained eye symptoms should be referred to an ophthalmologist for
a full ophthalmic assessment.
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Rev. 2/16
Rev. 2/16
Rev. 3/17
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5.
Drug Formulation and Procurement
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees.
Availability
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB.
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information) 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.
Submit agent requests through the PMB Online Agent Order Processing (OAOP)
application (https://ctepcore.nci.nih.gov/OAOP). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status.
NCI Supplied Agent(s) – General Information
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov
anytime.
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov).
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov).  Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator.
Investigator Brochure Availability: 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 at IBCoordinator@mail.nih.gov.
Rev. 12/16
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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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5.1
Osimertinib (AZD9291) (NSC #781254)
5.1.1
Other Names 
Tagrisso™, AZD9291 mesylate
5.1.2
Classification
Epidermal growth factor (EGFR) inhibitor
5.1.3
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
5.1.4
Storage and Stability
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
5.1.5
Dose Specifics 
The dose will be 80mg orally once daily continuously.
5.1.6
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.
5.1.7
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.
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5.1.8
Incompatibilities
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.
5.1.9
Side Effects 
See Section 3.3 for side effects.
5.1.10
Patient Care Implications
Advise patients of reproductive potential to use effective methods of 
contraception. Patients of child-bearing potential must use an 
appropriate double barrier method of birth control (such as female use 
of a diaphragm, intrauterine device (IUD), sponge and spermicide, in 
addition to the male use of a condom) or involve female use of 
prescribed “birth control pills” or a prescribed birth control implant. 
Both double barrier contraception and birth control pill or implants 
must be used for at least one week prior to the start of the study and 
continuing for 16 weeks after the last dose of the study drugs.
Male patients must use barrier contraceptives (i.e., by use of 
condoms) from the start of study and continue for 16 weeks after the 
least dose of the study drugs.  Male patients should also refrain from 
donating sperm from the start of study treatment until 4 months after 
discontinuing study treatment
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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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6.
Translational Studies
Please refer to the MATCH Master Protocol for information on the Translational Studies.
7.
References
1. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as 
first-line treatment for European patients with advanced EGFR mutation-positive 
non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 
3 trial. The Lancet Oncology 2012;13:239-46.
2. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III 
Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung 
Adenocarcinoma With EGFR Mutations. Journal of Clinical Oncology  2013; 
31(27):3327-34.
3. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological 
evolution of lung cancers acquiring resistance to EGFR inhibitors. Science 
Translational Medicine 2011;3:75ra26.
4. Yu H, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of 
Mechanisms of Acquired Resistance to EGFR TKI therapy in 155 patients with 
EGFR-mutant Lung Cancers. Clinical Cancer Research 2013; 19(8):2240-7.
5. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase 
causes drug resistance by increasing the affinity for ATP. Proceedings of the 
National Academy of Sciences of the United States of America 2008;105:2070-5.
6. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. 
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to 
EGFR inhibitors in lung cancer. Cancer Discovery 2014; Sep;4(9):1046-61.
7. Janne PA et al N Engl J Med. 2015 Apr 30;372(18):1689-99.

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol E: Osimertinib (AZD9291)
Appendix I
Patient Pill Calendar
Pill Calendar Directions
1. Take your scheduled dose of each tablet.
2. If you forget, the missed tablets will not be taken later.
3. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit.
4. Take AZD9291 once daily by mouth, with or without food.
5. Swallow tablets whole. Do not crush or chew tablets.
6. Store tablets at room temperature.
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Patient Pill Calendar
This is a calendar on which you are to record the time and number of tablets you take 
each day. You should take your scheduled dose of each tablet. Note the times and the 
number of tablets that you take each day. If you develop any side effects, please 
record them and anything you would like to tell the doctor in the space provided. Bring 
any unused tablets and your completed pill calendar to your doctor’s visits.
AZD9291
DAY
Date
Time 
tablets
taken
Dose taken
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you think 
would be of interest.)
Month
Day
Year
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Patient Signature: __________________________________ Date: _____________

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol E: Osimertinib (AZD9291)
Appendix II
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 electronic case report form (eCRF).
1. Drugs Inducing CYP3A4 Metabolism That AstraZeneca Strongly Recommend Are Not 
Combined With Osimertinib
Osimertinib is metabolised by CYP3A4 and CYP3A5 enzymes.
A drug-drug interaction study of osimertinib evaluated in patients showed that there is 
potential for osimertinib being a victim when co-administered with strong inducers of 
CYP3A4 (osimertinib 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.
D1 Drugs Inducing CYP3A4
Contraindicated drugs
Withdrawal period prior to osimertinib 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.
2.
Medicines Whose Exposures May be Affected by Osimertinib That AstraZeneca 
Considers May be Allowed With Caution
Osimertinib may increase the concentration of sensitive breast cancer resistance protein 
(BCRP) substrates (concentration of the sensitive BCRP substrate, rosuvastatin, is 
increased).
D2 Exposure, Pharmacological Action and Toxicity May be Increased by Osimertinib
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.
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
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3.
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 on Therapeutics and The Critical Path Institute, Tucson, 
Arizona and Rockville, Maryland. Ref: http://www.arizonacert.org/medical-pros/drug-
lists/drug lists.htm.
3.1
Drugs known to prolong QT interval
The following drugs are known to prolong QT interval or induce Torsades de Pointes 
and should not be combined with osimertinib. Recommended withdrawal periods 
following cessation of treatment with these agents are provided in the table.
D3 Drugs Prolonging QT Interval
Contraindicated drug
Withdrawal period prior to osimertinib start
Clarithromycin, droperidol, erythromycin, 
procainamide
2 days
Cisapride, disopyramide, dofetilide, 
domperidone, ibutilide, quinidine, sotalol, 
sparfloxacin, thioridazine
7 days
Bepridil, chlorpromazine, halofantrine, 
haloperidol, mesoridazine
14 days
Levomethadyl, methadone, pimozide
4 weeks
Arsenic trioxide
6 weeks a
Pentamidine
8 weeks
Amiodarone, chloroquine
1 year
a Estimated value as pharmacokinetics of arsenic trioxide has not been studied
3.2
Drugs that may possibly prolong QT interval
The use of the following drugs is permitted (notwithstanding other exclusions and 
restrictions) provided the patient has been stable on therapy for the periods 
indicated.
D4 Drugs That May Prolong QT Interval
Drug
Minimum treatment period on 
medication prior to osimertinib start
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, 
foscarnet, galantamine, gemifloxacin, isridipine, 
ketoconazole, levofloxacin, mexiletine, nicardipine, 
octreotide, ofloxacin, ondansetron, quetiapine, 
ranolazine, telithromycin, tizanidine, vardenafil, 
venlafaxine, ziprasidone
2 days
Amantadine, amitriptyline, amoxapine, clozapine, 
doxepin, felbamate, flecainide, fluconazole, 
fosphenytoin, gatifloxacin, granisetron, imipramine, 
indapamide, lithium, moexipril/HCTZ, moxifloxacin, 
risperidone, roxithromycin, sertraline, trimethoprin-sulfa,
trimipramine, voriconazole
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Version Date: July 16, 2021
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Drug
Minimum treatment period on 
medication prior to osimertinib start
Azithromycin, citalopram, clomipramine, itraconazole, 
nortriptyline, paroxetine, solifenacin, tacrolimus
14 days
Fluoxetine 
5 weeks
Protriptyline
6 weeks
Tamoxifen
8 weeks

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Version Date: July 16, 2021
NCI Update Date: August 12, 2015
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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol E: Osimertinib (AZD9291)
Appendix IV
Actionable Mutations for Sub-Protocol EAY131-E
A function has been implemented in MATCHBOX to identify any in-frame insertions in exon 19 
of the EGFR gene at Level of Evidence code 3. Please refer to Section 1.4.2 of the MATCH 
Master Protocol for more information.
Gene Name
Variant ID
Variant 
Type
Level of 
Evidence Code
aMOI
EGFR
COSM6240
SNV
2
p.T790M
EGFR
COSM6252
SNV
3
p.G719S
EGFR
COSM6253
SNV
3
p.G719C
EGFR
COSM18425
SNV
3
p.G719D
EGFR
COSM6239
SNV
3
p.G719A
EGFR
COSM6213
SNV
3
p.L861Q
EGFR
COSM18441
MNV
3
p.G719C
EGFR
COSM6241
SNV
3
p.S768I
EGFR
COSM12423
Large Indel
3
p.V738_K739insKIPVaI
EGFR
COSM26443
Large Indel
3
p.V738_K739insKIPVaI
EGFR
COSM26444
Large Indel
3
p.I740_P741insPVaIKV
EGFR
COSM255152
Large Indel
3
p.I740_P741insPVaIKT
EGFR
COSM26720
Large Indel
3
p.A763_Y764insFQEA
EGFR
MVAR181
Large Indel
3
p. D770_N771insNPG
EGFR
COSM392166
Large Indel
3
p.V769_D770insASV
EGFR
COSM13428
Large Indel
3
p.D770_N771insSVD
EGFR
MVAR190
Large Indel
3
p.N771_P772insPGD
EGFR
COSM35508
SNV
3
p.R222C
EGFR
COSM13006
SNV
2
p.V774M
EGFR
EGFR-SEPT14.E24S10
Fusion
3
EGFR-SEPT14.E24S10
Rev. Add13
Rev. Add25
Rev. Add29

ECOG-ACRIN
EAY131-E
Cancer Research Group
Version Date: July 16, 2021
NCI Update Date: August 12, 2015
32
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol E: Osimertinib (AZD9291)
Appendix V
Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s Law
1. Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law. It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. Specific guidance on the managing liver abnormalities can 
be found in Section 3.4 of the protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with Sponsor clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) 
criteria are met.  HL criteria are met if there is no alternative explanation for the elevations in 
liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2. Definitions
2A.
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper 
Limit of Normal (ULN) together with total bilirubin (TBL) ≥ 2xULN at any point during 
the study following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP).
2B.
Hy’s Law (HL)
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than 
the IMP, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with 
(i.e. on the same day) the elevation in TBL, but there is no specified timeframe within 
which the elevations in transaminases and TBL must occur.
3. Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
x
ALT ≥ 3xULN
x
AST ≥ 3xULN
x
TBL ≥ 2xULN
Rev. Add13
Rev. Add29