MATCH Treatment Subprotocol A: Phase II Trial of Afatinib in Patients With Solid Tumors (Other Than Small Cell and Non-Small Cell Lung Cancer) or Lymphomas, That Have Activating Mutations of EGFR and Have Progressed After Standard Treatment
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid 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
September 15, 2020
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 #25 to EAY131-A, Phase II Trial of Afatinib in Patients with Solid 
Tumors (Other Than Small Cell and Non-Small Cell Lung Cancer) or Lymphomas, That Have 
Activating Mutations of EGFR and Have Progressed After Standard Treatment.
This addendum is in response to Dr. Jeffrey Moscow’s Request for Rapid Amendment for 
Afatinib July 29th, 2020, and also, Dr. Tali Johnson’s Amendment Request for updates to 
specific protocol language for Afatinib dated June 5, 2020.
Please replace your current copy of the protocol and Informed Consent document (if ICD 
changed) with this (these) updated version(s).  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.
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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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 #36 of Protocol #EAY131-A: “MATCH Treatment Subprotocol A: 
Phase II Trial of Afatinib in Patients with Solid Tumors (Other Than Small Cell and Non-Small 
Cell Lung Cancer) or Lymphomas, That Have Activating Mutations of EGFR and Have 
Progressed After Standard Treatment”. The following are ECOG-ACRIN’s responses to the 
CTEP review comments dated 8/27/2020. Please note that the Principal Investigator’s 
comments appear in bold below.
I.
Comments Requiring a Response – Major Issues:
# Section
Comments
1. 2.1.7 and 
2.1.8
CTEP review belatedly recognized a change in these two eligibility 
sections and reviewed them after the CIRB evaluation of this 
amendment.
The original wording of this section was:

ii 
# Section 
Comments 
"Patients with non-small cell lung cancer and small cell lung cancer will 
be excluded." 
The proposed section now reads:  
 "Patients with non-small cell lung cancer and small cell lung cancer with 
EGFR exon 19 or exon 21 L858R mutations will be excluded if no prior 
treatment with EGFR TKI has been given. Patients treated with prior 
osimertinib are eligible regardless of EGFR mutation." 
Please remove this new language.  MATCH is not designed to study 
mechanisms of resistance, and the inclusion of prior-osimertinib NSCLC 
patients is a fundamentally different research question that will dilute the 
exploration of the primary hypothesis of this arm. 
PI Response: Thank you, we have reverted back to the original 
language in Sections 2.1.7 and 2.1.8. 
Please see responses to the CIRB Early Phase Emphasis Review below. 
 
Re: CIRB Approval Pending Modification of Amendment Review 
Study ID, Study Title: EAY131, Molecular Analysis for Therapy Choice (MATCH) 
Protocol Version Date: 05/14/20 
 
Study Chair: Keith Flaherty, M.D., B.S. 
 
Dear NCI Adult CIRB - Early Phase Emphasis, 
Thank you for reviewing EAY131 (Protocol Version Date 05/14/20) protocol at the meeting of 
the NCI Adult CIRB - Early Phase Emphasis held on August 4, 2020. The CIRB determined that 
the regulatory and CIRB SOP requirements for approval are met, but the CIRB requests minor, 
directed modifications as described below.  
Stipulations(s): 
A response to the following is required: 
 
Section 
Change 
1. 
ICD Possible Side 
Effects of Afatinib 
 &  
Section 3.3  
As requested by CTEP, update the CAEPR & Risk List for SubProtocols 
affected by the Request for Rapid Amendment (RRA) for study drug 
Afatinib distributed July 29, 2020.   
PI Response: Updated the CAEPR and condensed risk list for 
Afatinib with Version 2.3, June 15, 2020. 
Additional Changes by Principal Investigator: 
The following revisions to EAY131-A protocol have been made in this addendum: 
 
Section 
Change 
2. 
Cover Page  
Updated Version date and addendum number. 
3. 
Cover Page  
Updated Dr. Karen L. Reckamp e-mail address. 
4. 
1.3 
Inserted section to provide rationale for addition of osimertinib resistant patients.  
5. 
1.4 
Inserted rationale for the exclusion of glioblastoma multiforme (GBM).  

iii 
 
Section 
Change 
6. 
2.1.2.3 
Revised to account for exon 20 in frame insertion.  
7. 
2.1.7 
Clarified eligibility criteria regarding prior treatment with EGFR Tyrosine Kinase 
Inhibitor.  
8. 
2.1.8 
Clarified eligibility criteria regarding the exclusion lung cancer patients.  
9. 
2.1.10 
Inserted exclusion criteria for patients with GBM.  
10. 3.2.1 
Revised language in the second box referencing “subject’ to “female patient” 
11. 3.3  
Updated Afatinib CAEPR with Version 2.3, June 15, 2020 
12. Appendix II 
Updated patient drug information template format.  
13. Appendix III  
Added exon 20 in frame insertions to aMOI list.  
The following revisions to EAY131-A Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
14. Page 1 
Updated Version Date. 
15. Possible Side 
Effects of Afatinib 
Updated Afatinib condensed risk list with Version 2.3, June 15, 2020. 
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900. 
We request review and approval of this addendum to EAY131-A so ECOG-ACRIN may activate 
it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
 
 

EAY131-A 
1 
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol A: Phase II Trial of 
Afatinib in Patients with Solid Tumors (Other Than Small 
Cell and Non-Small Cell Lung Cancer) or Lymphomas, 
That Have Activating Mutations of EGFR and Have 
Progressed After Standard Treatment
TREATMENT SUBPROTOCOL CHAIR:
Scott Gettinger, MD
TRANSLATIONAL CHAIR: Karen Reckamp, MD
Version Date: September 15, 2020
NCI Update Date:  August 12, 2015
NOTE: This subprotocol (EAY131-A) 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 #5 – 12/16
Addendum #7 – 3/17
Addendum #8 – 3/17
Addendum #13
Addendum #19
Addendum #21
Addendum #25
Agent
IND#
NSC#
Supply 
Afatinib
IND Sponsor: DCTD, NCI IND #: 
750691
NCI Supplied
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol A: Phase II Trial of Afatinib in Patients with Solid 
Tumors (Other Than Small Cell and Non-Small Cell Lung Cancer) or 
Lymphomas, That Have Activating Mutations of EGFR and Have Progressed 
After Standard Treatment .................................................................................. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 
Afatinib ...................................................................................................... 5 
1.2 
Supporting Preliminary Data ..................................................................... 5 
1.3 
Afatinib in osimertinib resistant EGFR mutant NSCLC .............................. 7 
1.4 
Exclusion of Glioblastoma Multiforme (GBM) .......................................... 7 
2. Selection of Patients ........................................................................................... 8 
2.1 
Eligibility Criteria ....................................................................................... 8 
3. Afatinib Treatment Plan .................................................................................... 11 
3.1 
Administration Schedule ......................................................................... 11 
3.2 
Adverse Event Reporting Requirements ................................................. 11 
3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Afatinib (NSC 750691) ............................................................................. 14 
3.4 
Dose Modifications ................................................................................. 18 
3.5 
Supportive Care ....................................................................................... 22 
3.6 
Duration of Agent-specific treatment ..................................................... 23 
3.7 
Duration of Follow-Up ............................................................................. 24 
4. Study Parameters .............................................................................................. 25 
4.1 
Therapeutic Parameters for Afatinib Treatment .................................... 25 
5. Drug Formulation and Procurement ................................................................. 27 
5.1 
Afatinib (NSC 750691) ............................................................................. 28 
6. Translational Studies ......................................................................................... 30 
7. References ........................................................................................................ 30 
Appendix I  Patient Pill Calendar ............................................................................. 32 
Appendix II  Patient Clinical Trial Wallet Card ......................................................... 34 
Appendix III  Actionable Mutations of Interest (aMOIs) ......................................... 35 
 
 
 
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TREATMENT SUBPROTOCOL CHAIR 
Scott Gettinger, MD 
333 Cedar Street 
Medical Oncology FMP 127, PO Box 208032 
New Haven, CT. 06520 
Phone: 203-737-5312   
Fax: 203-785-3788 
E-mail: scott.gettinger@yale.edu 
 
TRANSLATIONAL CHAIR 
Karen Lynn Reckamp, MD 
Cedars-Sinai Medical Center 
8700 Beverly Blvd, SCCT 1S27 
Los Angeles, California 90048 
Phone:310-423-5362 
Fax: 310-423-7182 
E-mail: karen.reckamp@cshs.org 
 
 
 
 
 
 

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Schema 
 
 
 
Long-Term Follow-Up
Afatinib 40 mg PO QD
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 35
 
 

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5 
1. Introduction 
1.1 
Afatinib 
Targeted treatments have proven to be clinically successful and represent the 
realization of precision medicine’s potential. In non-small cell lung cancer 
(NSCLC), molecularly targeted treatment with epidermal growth factor receptor 
(EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic responses in 
patients with activating mutations (Lynch, Bell et al 2004; Paez, Jänne et al 2004; 
Mok, Wu et al 2009).  
EGFR is a member of the human epidermal growth factor (HER) or ERBB family, 
a set of receptor tyrosine kinases that include EGFR (ERBB1), ERBB2, ERBB3, 
and ERBB4 (Pao and Chmielecki 2010). The receptors and their ligands regulate 
the proliferation of cancerous cells. EGFR mutations most frequently occur within 
exons 18-21, which constitute most of the tyrosine kinase binding domain of the 
receptor (Wu, Yu et al 2011). Exon 19 deletions (del19) and L858R within exon 
21 are the two most common EGFR mutations in non-small cell lung cancer 
(NSCLC). These mutations alter the receptor’s adenosine triphosphate (ATP) 
binding pocket by improving its affinity for ATP, resulting in constitutive activation 
(Herbst, Heymach et al 2008; Ohashi, Maruvka et al 2013). Reversible EGFR 
TKIs, erlotinib and gefitinib, preferentially bind to the receptor’s ATP binding 
pocket, blocking ATP binding and the dimerization needed for receptor activation 
(Pao and Chmielecki 2010).  In contrast, mutations such as exon 20 insertions 
and in-frame deletions or T790M alter the drug-receptor interaction and reduce 
ATP binding affinity to wild type receptor (Wu, Yu et al 2011). 
Afatinib is a potent, irreversible, orally available ErbB family blocker that displays 
antitumor efficacy both in vitro and in vivo. Afatinib displays more selective 
antitumor activity than classical cytotoxic drugs that have an indiscriminate effect 
on all proliferating cells and has the potential to provide significant benefit to 
patients with advanced malignancies by inducing tumor responses or slowing of 
tumor progression and metastasis (Li, Ambrogio et al 2008; Yap, Vidal et al 
2010). Afatinib is approved in the United States for the first-line treatment of 
patients with NSCLC whose tumors have non-resistant EGFR mutations as 
detected by an FDA-approved test. 
1.2 
Supporting Preliminary Data  
Two multinational randomized Phase III studies of afatinib in the first line 
treatment of mutation positive stage IIIB/IV NSCLC patients have been 
performed: the LUX-Lung 3 (Sequist, Yang et al 2013) and LUX-Lung 6 (Wu, 
Zhou et al 2014) studies.   
LUX-Lung 3 compared first line afatinib to cisplatin/pemetrexed and 
demonstrated afatinib’s superiority to chemotherapy in EGFR mutation positive 
NSCLC patients (Sequist, Yang et al 2013). 345 patients with performance status 
0-1 were randomized in a 2:1 ratio. In this trial patients treated with afatinib 
demonstrated significant and clinically meaningful improvements in progression 
free survival (PFS, median PFS afatinib vs. cisplatin/pemetrexed 11.1 vs. 6.9 
months, hazard ratio 0.58; 95% CI. 0.43 to 0.78; P=.001) and Objective 
Response Rate (ORR, afatinib vs cisplatin /pemetrexed 56% vs. 23%; P= .001).  
There were significant delays in time to deterioration of the cancer-related 
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symptoms of cough (afatinib /cisplatin pemetrexed, Hazard Ratio, HR, 0.60; 95% 
CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P =.01) 
in the afatinib treatment arm (Yang, Hirsch et al 2013). A pre-planned analysis of 
PFS in patients (n=308) with exon del 19 or L858R mutation was 13.6 months for 
afatinib and 6.9 months for chemotherapy (HR 0.47; 95% CI: 0.34 to 0.65; 
P=0.001). Higher response rates were observed in afatinib groups compared with 
chemotherapy 69% and 44%, respectively. 
LUX-Lung 6 compared first line afatinib to up to six cycles of 
cisplatin/gemcitabine and 364 NSCLC patients were treated with 2:1 
randomization (Wu, Zhou et al 2014). Patients treated with afatinib demonstrated 
significant improvements in progression free survival (median PFS afatinib vs. 
cisplatin/gemcitabine 11.0 months vs. 5.6 months, hazard ratio 0.28; 95% CI 0.20 
to 0.39; P< 0.0001) and ORR (afatinib vs. cisplatin/gemcitabine 66.9% vs. 23.0 
%, P < 0 .0001).  This study also demonstrated significant delays in time to 
deterioration of the cancer-related symptoms of cough (afatinib vs. 
cisplatin/gemcitabine HR 0.45, 95% CI, 0.30 to 0.68; P = .0001) and dyspnea 
(HR 0.54; 95% CI, 0.40 to 0.73; P< 0.0001) in the afatinib treatment arm. 
In a separate single arm study (LUX-Lung 2) in lung adenocarcinoma patients  
(stage IIIb with pleural effusion or stage IV)  with EGFR mutations, 129 patients 
were treated in  first-line or second-line with afatinib, 99 with a starting dose of 50 
mg and 30 with a starting dose of 40 mg (Yang, Shih et al 2012). Seventy-nine 
(61%) of 129 patients had an objective response (two complete responses, 77 
partial responses). 70 (66%) of the 106 patients with the two most common 
activating EGFR mutations (deletion 19 or L858R) had an objective response, as 
did nine (39%) of 23 patients with less common mutations. 
For NSCLC patients previously treated with a reversible EGFR TKI and clinically 
enriched for EGFR mutations, treatment with afatinib plus best supportive care 
resulted in a significant improvement in median PFS over patients treated with a 
placebo plus best supportive care in LUX-Lung 1 (Miller, Hirsch et al 2012). This 
improvement in PFS was accompanied by significant and meaningful 
improvements in cough, dyspnea, and pain, compared to the placebo group. 
Treatment with afatinib was also found to significantly delay the time to 
deterioration for Global health status/Quality of Life (QoL).  
A subsequent and larger study (LUX-Lung 5) enrolling a similar population of 
NSCLC patients resulted in a very similar median PFS as in LUX-Lung 1. In 
these studies, the PFS benefit of afatinib was consistent across all pre-planned 
subgroups with at least 50 patients, including gender, age, race, baseline 
Eastern Cooperative Oncology Group (ECOG) performance status, type of prior 
EGFR TKI, baseline tumor size, and lines of prior chemotherapy. In both of these 
studies (LUX-Lung 2 and 5) treatment with afatinib had the greatest PFS benefit 
for those patients who belonged to a subgroup  highly clinically enriched for 
EGFR mutations or who were positive for EGFR mutations by testing of tumor 
tissue. 
The significant benefit of afatinib in NSCLCs that have driver activating EGFR 
mutations argues for the evaluation of the effect of afatinib in other tumors with 
similar EGFR, and likely driver, mutations. The frequency of activating EGFR 
mutations is uncommon outside NSCLC, in tumors where EGFR mutations have 
been evaluated see Table below. The genomic alterations associated with 

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7 
deletions in exon 19 and substitutions in exon 21 (in addition to other variants) 
are highly sensitive to EGFR TKI inhibition (Lynch, Bell et al 2004; Shan, 
Eastwood et al 2012).  Therefore, it is reasonable to assess the objective 
response and progression free survival of patients with tumors other than 
NSCLC. 
Tumor site 
EGFR alteration (%) 
Breast 
0 
CNS 
3 
Colon 
0 
Head and neck 
2 
Prostate 
4 
Urinary tract  
1 
1.3 
Afatinib in osimertinib resistant EGFR mutant NSCLC 
Patients with activating EGFR mutations receive osimertinib as front line therapy 
as standard of care based on results of the FLUARA study.1 Resistance 
mechanisms, including novel mutations, have been identified, and many retain 
sensitivity to the second-generation EGFR inhibitor, afatinib. Multiple reports of 
EGFR G724S-mediated osimertinib resistance can be overcome by afatinib. 2,3 
Afatinib retained high kinase affinity, and was able to reduce colony formation 
and tumor growth in EGFR G724S cells.2 Additional studies confirmed that EGFR 
G724S cells were resistant to osimertinib, but demonstrated sensitivity to afatinib, 
but not erlotinib.3 In a case report and in vitro sensitivity assay EGFR L718V and 
C797S retained sensitivity to afatinib. 4 Another patient case showed an EGFR 
P794L mutation as a resistance mechanism to osimertinib. Protein modeling 
indicated that afatinib could bind the T790M/P794L ATP cleft, and therefore, the 
patient received afatinib with significant radiologic and clinical improvement.5 
Based on the growing literature, the afatinib Arm A of the MATCH trial is an ideal 
setting to understand this resistance and responses, in addition to increasing the 
potentially eligible patients for this arm. 
1.4 
Exclusion of Glioblastoma Multiforme (GBM) 
Due to recent findings that an excess of GBM patients have been accrued to the 
trial it is now necessary to limit their accrual to avoid overrepresentation of 
tumors of a particular subtype that would make the ‘tumor agnostic’ intent of the 
subprotocol unachievable. This has been modified under ‘eligibility criteria’. 
 
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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 
Patients 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 
Patient’s tumor must have either of the below, or another aberration, 
as determined via the MATCH Master Protocol and according to 
Appendix III: 
2.1.2.1 
Activating mutations of EGFR (del 19, L858R). 
OR 
2.1.2.2 
Any malignancy harboring any of the following mutations: 
EGFR G719A, G719C, G719D, G719S EGFR L861Q, 
EGFR S768I 
2.1.2.3 
Tumors with an exon 20 insertion alone without the above 
mutations will be excluded, with the exception of exon 20 
insertions approved as inclusion variants as part of the 
dynamic aMOI process. 
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See Appendix III for information on the targeted mutations and the 
corresponding Levels of Evidence (LOE). 
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). 
Date of ECG:  _______________ 
2.1.4 
Patients with known left ventricular dysfunction must have ECHO or a 
nuclear study (MUGA or First Pass) within 4 weeks prior to 
registration to treatment and must not have 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:  _______________ 
NOTE: 
Pre-treatment LVEF determination in patients without 
known left ventricular dysfunction is NOT otherwise 
required. 
2.1.5 
Patients must not have known hypersensitivity to Afatinib or 
compounds of similar chemical or biologic composition. 
2.1.6 
Patients must have  Grade 1 renal function as defined below: 
Creatinine  1.5 x normal institutional limits 
OR 
Measured Creatinine clearance  60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal or as calculated by the 
Cockcroft-Gault Equation. 
Creatinine clearance:  
 
The above renal eligibility criteria should be strictly followed and 
will override the MATCH Master Protocol requirements. 
2.1.7 
Patients must not have had prior treatment with an EGFR TKI (e.g. 
Afatinib, Erlotinib, Gefitinib, Neratinib, Dacomitinib, AZD9291, 
Cabertinib, CO-1686). 
2.1.8 
Patients with non-small cell lung cancer and small cell lung cancer will 
be excluded. 
2.1.9 
Patients with a history of interstitial lung disease will be excluded. 
2.1.10 
Patients with Glioblastoma Multiforme (GBM) will be excluded. 
2.1.11 
3DWLHQWVPXVWKDYH*UDGHGLDUUKHDDt baseline. 
 
 
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Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 

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NCI Update Date: August 12, 2015 
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3. 
Afatinib Treatment Plan 
3.1 
Administration Schedule 
Afatinib 40 mg PO QD, repeat cycles every 28 days until progression of disease, 
unacceptable toxicities or withdrawal of consent. 
NOTE: 
Afatinib tablets are taken once daily. Afatinib tablets should not be 
chewed nor crushed. 
NOTE: 
Do not take Afatinib with food. Afatinib should be taken at least one 
hour before food intake, or at least two hours after food intake. 
Missed doses should not be administered if within 12 hours of the next 
scheduled dose. If vomiting occurs after taking a dose of afatinib, the 
patient should not take an additional dose as a replacement. 
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 adverse event reporting instructions, requirements and 
exceptions for EAY131 – Subprotocol A 
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 – Subprotocol A 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 
Afatinib, or within 28 days of the female patient’s last dose of 
Afatinib, 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. 
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EAY131 – Subprotocol A specific expedited reporting 
exceptions: 
For Subprotocol A, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
x 
If an AE meets the reporting requirement 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 to 
ECOG-ACRIN using Medidata Rave 
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 via CTEP-AERS at http://ctep.cancer.gov  
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. 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. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 

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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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3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Afatinib 
(NSC 750691) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2596 patients. 
Below is the CAEPR for Afatinib. 
NOTE: 
If an AE meets the reporting requirement 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 in the SPEER. 
Version 2.3, June 15, 20201 
 
Adverse Events with Possible 
Relationship to Afatinib 
(CTCAE 5.0 Term) 
[n= 2596] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
EYE DISORDERS 
  
 
Eye disorders - Other 
(ocular event)2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Cheilitis 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal 
perforation3 
  
Mucositis oral4 
 
 
 Mucositis oral4 (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
Infections5 
 
 
 Infection5 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
Rev. 3/17 
Rev. Add21 
Rev. Add25 

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EAY131-A 
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NCI Update Date: August 12, 2015 
15 
 
Adverse Events with Possible 
Relationship to Afatinib 
(CTCAE 5.0 Term) 
[n= 2596] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Aspartate 
aminotransferase 
increased 
 
  
 
Creatinine increased6 
 
  
 
 
Ejection fraction 
decreased 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypokalemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
Renal and urinary 
disorders - Other (renal 
impairment)6 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Nasal congestion 
 
  
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(interstitial lung 
disease)7 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia  
syndrome 
 
Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
 
Pruritus 
 
  
 
Rash acneiform 
 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(nail effect)8 
 
 
Skin and subcutaneous tissue 
disorders - Other (nail effect)8 
(Gr 2) 
Skin and subcutaneous 
tissue disorders - Other 
(rash)9 
 
 
 Skin and subcutaneous tissue 
disorders - Other (rash)9 (Gr 2) 
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal 
necrolysis 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 

ECOG-ACRIN 
EAY131-A 
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Version Date: September 15, 2020 
 
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. 
2 Ocular disorders may include conjunctivitis, conjunctival irritation, conjunctival hyperemia, corneal 
abrasions, corneal erosion, dry eye, keratitis, ulcerative keratitis, keratopathy, and xerophthalmia. 
3 Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
4 Mucositis oral (stomatitis) may include stomatitis, aphthous stomatitis, mucosal inflammation, mouth 
ulceration, oral mucosa erosion, mucosal erosion, and mucosal ulceration. 
5 Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
6 Renal impairment may include acute kidney injury (acute renal failure), acute pre-renal failure, renal 
impairment, creatinine increased, blood urea increased, glomerular filtration rate increased, and 
glomerular filtration rate abnormal. 
7 Interstial lung disease may include acute interstitial pneumonitis, pneumonitis, acute respiratory distress 
syndrome, pulmonary infiltrates, and pulmonary fibrosis. 
8 Nail effect includes paronychia and nail disorder (e.g., nail ridging, nail loss, and nail discoloration). 
9 Rash may include rash, rash pustular, folliculitis, skin fissures, skin exfoliation, dermatitis, erythema, skin 
reaction, skin ulcer, skin toxicity, skin erosion, skin irritation, and skin swelling. 
Adverse events reported on afatinib trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that afatinib caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Bone marrow hypocellular  
EAR AND LABYRINTH DISORDERS - Vertigo 
GASTROINTESTINAL DISORDERS - Abdominal pain; Dry mouth; Dysphagia; Esophageal 
stenosis; Esophagitis; Gastritis; Gastroesophageal reflux disease; Oral pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Malaise; 
Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; 
GGT increased; INR increased; Lymphocyte count decreased; Neutrophil count decreased; 
Platelet count decreased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypoalbuminemia; Hypocalcemia; 
Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Myalgia; Pain 
in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Lethargy; Seizure 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system 
and breast disorders - Other (female genital tract fistula) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Oropharyngeal pain; Pleural effusion; Productive cough; Respiratory, thoracic and 
mediastinal disorders - Other (nasal dryness); Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (nasal inflammation)  

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia 
VASCULAR DISORDERS - Hypotension; Vasculitis 
NOTE: 
Afatinib 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. 

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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). 
Afatinib will be administered at the recommended dose of 40 mg orally once daily 
starting on the first day of administration and continue until disease progression 
or unacceptable toxicity. We chose the 40 mg daily dose since the Css still 
remains adequate at this dose. High Rates of dose modification were seen in 
previous studies with 50 mg daily dosing.
Afatinib will not be held for hematologic toxicity, unless it is determined to be a 
drug-related grade 3 or 4 hematologic event. 
Treatment may be delayed by 2 weeks due to toxicity. If treatment is delayed 
beyond 2 weeks the subject will come off study for unacceptable toxicity. 
Discontinuation of afatinib for any reason for more than 2 weeks will result 
in removal of the patient from this subprotocol.
The afatinib dose may be adjusted according to individual patient tolerance as 
outlined below.
Table 1. Dose Levels for Afatinib
Dose Level
Daily Dose/ 
Route
Dispensed 
As
Schedule
Starting dose 
level: 0
40 mg, PO
1 × 40-mg 
tablet
Daily during 
4- week cycle
–1 
30 mg, PO
1 × 30 mg 
tablet
Daily during 
4- week cycle
–2 
20 mg, PO
1 × 20-mg 
tablet
Daily during 
4- week cycle
3.4.1
Treatment compliance
Records of study medication usage and doses administered will be 
kept during the accountability will be noted. Patients will be asked to 
return all unused medication.
3.4.2
Toxicity monitoring & dose modification
Patients will have clinical and laboratory assessment while on study 
as per the Study Calendar. No dose escalations of afatinib will be 
permitted. 
In the event of any CTC, version 4.0 drug-related grade 3 or 4 non-
hematologic adverse event(s), drug should be held until the toxicity 
UHVROYHVWRgrade 1 and then the drug should be restarted at a one 
dose-level reduction with the exception noted in table 2. In addition, 
no dose modifications will be needed for low electrolytes (Na, K, 
Phos, Mg) unless the grade 3 or 4 adverse event were to last > 48 
Rev.2/16

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19 
hours despite optimal electrolyte repletion.  Please see supportive 
care guidelines for nausea, vomiting, diarrhea, fatigue, and rash. 
Patients should be carefully monitored for clinical signs and symptoms 
of CHF while receiving afatinib. In the presence of clinical 
manifestations of CHF, discontinuation of afatinib and assessment of 
LVEF is recommended. 
In the event of any CTC, version 4.0 drug-related grade 3 or 4 
hematologic adverse event(s), the drug should be held until the 
WR[LFLW\UHVROYHVWRJUDGHDQGWKHQWKHGUXJVKRXOGEHUHVWDUWHGDW
a one dose-level reduction. 
3.4.3 
Dose reduction for afatinib 
Intra-patient dose reduction by 1, and if needed 2, dose-levels will be 
allowed depending on the type and severity of toxicity encountered 
provided that criteria for patient withdrawal from study treatment have 
not been met. Intrapatient dose re-escalation is not allowed. 
All intra-patient dose reductions are relative to the lowest dose level of 
the current cycle. 
Recovery to acceptable levels of toxicity must occur within 2 weeks to 
allow continuation in the study. 
No more than 2 dose reductions are permitted for any patient. If 
further dose reduction is required, the patient must be removed from 
the study. 
The following table describes the recommended dose modifications 
for study treatment associated toxicity: 

ECOG-ACRIN 
EAY131-A 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
20 
Table 2. Dose Modification for Afatinib 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-hematologic 
Toxicity 
(except specific 
toxicities mentioned 
below)a,b,c 
Continue at 
the same 
dose level. 
Continue at the same dose level. 
Withhold dose until 
WR[LFLW\LVJUDGH 1 or 
has returned to baseline. 
Then reduce the dose by 
1 level and resume 
treatment. 
Withhold dose until toxicity is 
JUDGH 1 or has returned to 
baseline. Then reduce the dose 
by 1 level or discontinue 
treatment (discretion of the 
investigator). 
Cardiac Toxicity 
Continue at 
the same 
dose level. 
Continue at the same dose level except for 
asymptomatic decrease of LVEF by an absolute 
value of 20% (or more) and to < institutional LLN. 
:LWKKROGGRVHXQWLOWR[LFLW\LVJUDGH 1.  Then 
reduce dose by 1 level and resume treatment. 
Discontinue study 
treatment. 
Discontinue study treatment. 
Renal Toxicity 
Continue at 
the same 
dose level. 
:LWKKROGGRVHXQWLOWR[LFLW\LVJUDGH 1. Then 
reduce dose by 1 level and resume treatment. 
Withhold dose until 
WR[LFLW\LVJUDGH 1. 
Then reduce dose by 1 
level and resume 
treatment. 
Withhold dose until toxicity is 
JUDGH 1.  Then reduce dose by 
1 level and resume treatment or 
discontinue treatment 
(discretion of the investigator). 
Diarrhea 
Continue at 
the same 
dose level.b 
Continue at the same dose level unless diarrhea 
persists for 2 or more days despite adequate anti-
diarrheal medication or hydration. 
:LWKKROGGRVHXQWLOWR[LFLW\LVJUDGH 1. Then 
reduce dose by 1 level and resume treatment. 
Withhold dose until 
WR[LFLW\LVJUDGH 1. 
Then reduce dose by 1 
level and resume 
treatment. 
Withhold dose until toxicity is 
JUDGH 1 Then reduce dose by 
1 level and resume treatment. 
Rash  
(Papulopustular, 
pustular, acneiform, 
maculo-papular)d 
Continue at 
the same 
dose level. 
Continue at the same dose level unless rash 
persists and is intolerable or worsens over > 
7days. If this occurs: 
:LWKKROGGRVHXQWLOWR[LFLW\LVJUDGH 1. Then 
reduce dose by 1 level and resume treatment. 
Withhold dose until 
WR[LFLW\LVJUDGH
Then reduce dose by 1 
level and resume 
treatment. 
Discontinue study treatment 
Drug-induced 
hepatic impairment 
Continue at 
the same 
dose level. 
Continue at the same dose level. 
Withhold dose until 
WR[LFLW\LVJUDGHRU
has returned to baseline. 
Then reduce the dose by 
1 level and resume 
treatment. 
Discontinue study treatment 

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Cancer Research Group 
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Ulcerative keratitis 
Continue at 
the same 
dose level. 
Continue at the same dose level. 
Withhold dose until 
WR[LFLW\LVJUDGHRU
has returned to baseline. 
Then reduce the dose by 
1 level and resume 
treatment. 
Discontinue study treatment 
Interstitial lung 
disease 
If a patient develops respiratory problems consistent with possible interstitial lung disease (ILD), afatinib is to be withheld 
pending a diagnostic evaluation. Afatinib will be discontinued if a diagnosis of ILD is confirmed. 
a. No dose modifications will be needed for low electrolytes (Na, K, Phos, Mg) unless the grade 3 or 4 adverse event were to last > 48 hours 
despite optimal electrolyte repletion 
b. See supportive care for diarrhea in Section 3.5.1 
c. Nausea and vomiting should be graded after maximal medical management 
d. See supportive care for rash in Section 3.5.1 

ECOG-ACRIN 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
22 
Potential Drug Interactions: Afatinib is a substrate of P-glycoprotein 
(P-gp). Concomitant use of strong P-gp inhibitors and inducers should 
be used with caution. Strong P-gp inhibitors (e.g., ritonavir, 
cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, 
quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) may 
increase exposure to afatinib. Strong P-gp inducers (e.g. rifampicin, 
carbamazepine, phenytoin, phenobarbital or St. John’s Wort) may 
decrease exposure to afatinib. If strong P-gp inhibitors need to be 
concomitantly administered with afatinib, they should be administered 
simultaneously with or after afatinib administration.  
Because the lists of these agents are constantly changing, it is 
important to regularly consult a frequently-updated list such as Facts 
and Comparisons or Lexicomp; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information. The 
Principal Investigator should be alerted if the subject is taking any 
agents that are strong P-gp inhibitors or inducers. 
3.5 
Supportive Care  
3.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
After a treatment pause the dose of afatinib should be reduced 
according to the dose reduction scheme in Table 1. The occurrence of 
nausea and/or vomiting will be recorded in the AE section of the 
eCRF. 
Management of Diarrhea 
Close monitoring and proactive management of diarrhea is essential 
for successful treatment of patients with afatinib. Early and 
appropriate intervention can prevent the development of more severe 
diarrhea. In most cases, loperamide (Imodium) controls diarrhea 
caused by afatinib. 
The recommendations for management are as follows: 
If any diarrhea is experienced (CTCAE Grade 1), two 2 mg 
loperamide tablets (total dose 4 mg) should be taken immediately, 
followed by one 2 mg tablet with every loose bowel movement, up to a 
maximum daily dose of 8 tablets (16 mg).Other anti-diarrheal 
medications that could be uses include: Lomotil (5 mg, four times a 
day), or tincture of opium (15-20 drops orally every 4 hours) or 
octreotide (150 to 300 micrograms SQ twice a day). 
Oral hydration is important regardless of severity of diarrhea; 
appropriate rehydration (1.5L/m2/day plus equivalent of actual fluid 
loss) and electrolyte replacement should be recommended in the 
event of CTCAE Grade 2 and Grade 3 diarrhea. 
Management of Rash 
A proactive and early approach to management of rash is crucial. 
Rash can be managed by a variety of treatment options to relieve 
Rev.2/16 

ECOG-ACRIN 
EAY131-A 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
23 
symptoms and reduce the rash. The recommendations for 
management are as follows: 
General/Prevention: strict sun protection; use of a sunscreen of Sun 
Protection Factor 15 (SPF 15) or higher, preferably containing zinc 
oxide; use of a thick, alcohol-free emollient cream. 
CTCAE Grade 1 rash: mild rash may not need treatment. However, if 
treatment is considered necessary, topical hydrocortisone (1% or 
2.5%) cream and/or clindamycin 1% gel/lotion can be used. 
CTCAE Grade 2 rash: relief from major symptoms caused by CTCAE 
Grade 2 skin related adverse events should be achieved by a 
combination of local and systemic therapies including: 
1. Systemic antibiotics (e.g. doxycycline or minocycline etc.). 
2. Topical treatment (e.g. hydrocortisone 2.5% cream, clindamycin 
1% gel/lotion, pimecrolimus 1% cream). And / or 1) Antihistamines 
(e.g. diphenhydramine, etc.) 
3. Oral corticosteroid (low dose and short term i.e., < 10 days 
treatment) may be added at investigator’s discretion. 
Systemic and topical treatment should be initiated at the start of 
CTCAE Grade 2 rash and continued until improvement or resolution 
WR&7&$(*UDGH ,IJUDGHUDVKSHUVLVWVIRUGD\VGHVSLWH
treatment and is poorly tolerated by the patient, the investigator may 
choose to pause treatment for up to 14 days followed by a reduction 
in the dose of afatinib according to the dose reduction scheme in 
Table 2. 
Management of Fatigue 
)RULQWROHUDEOHIDWLJXHJUDGH 3), the next cycle of treatment may be 
delayed by up to two weeks. 
Management of Interstitial Lung Disease 
Although quite rare, interstitial lung disease (ILD) is a class effect of 
EGFR TKIs and can be life threatening. Therefore, patients should be 
monitored closely for symptoms consistent with ILD, such as new 
onset dyspnea without an obvious cause. Chest CT should be 
obtained to look for interstitial fibrotic changes if ILD is suspected. In 
the event that ILD is suspected, drug treatment should be 
discontinued and the patient should receive appropriate medical 
management and supportive care. Although there is no established 
treatment, systemic corticosteroids are often administered. Afatinib 
should not be restarted in those patients suspected of having drug-
related ILD and the subject should be removed from 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 

ECOG-ACRIN 
EAY131-A 
Cancer Research Group 
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NCI Update Date: August 12, 2015 
24 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
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. 

ECOG-ACRIN 
EAY131-A 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
25 
4. 
Study Parameters 
4.1 
Therapeutic Parameters for Afatinib Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol, the below parameters must also be 
performed for patients receiving afatinib 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 
Cycle 1, day 8 
and day 15G  
Every Cycle, prior 
to treatment 
Every 2 
Cycles 
H&P, Weight, Vital signsA 
X 
 
XJ 
 
 
X 
Performance status 
X 
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 
 
X 
 XF 
Pill Count/DiaryH 
 
 
X 
 
X 
 
ECGK 
X 
 
 XI 
 
 
 
Echocardiogram or Nuclear StudyK 
XI 
 
 XI 
 
 
 XI 
Tumor biopsy and  blood sample for MATCH Master ProtocolE 
 
 
 
X 
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 
GLIIHUHQWLDOZLOOEHSHUIRUPHGPRUHIUHTXHQWO\LQSDWLHQWVZLWKJUDGHQHXWURSHQLDRUWKURPERF\WRSHQLDXQWLOUHVROXWLRQWR 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 (women of childbearing potential) required prior to beginning treatment. 
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 
Rev.2/16 
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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. As clinically indicated 
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 (or within 4 weeks prior to registration to treatment for ECHO/nuclear study if clinically indicated, per 
Section 2.1.4) 
Rev.2/16 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
27 
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 the 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 
Rev.3/17 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
28 
5.1 
Afatinib (NSC 750691)  
5.1.1 
Other Names  
BIBW 2992; afatinib dimaleate, Gilotrif® 
5.1.2 
Classification  
Tyrosine Kinase Inhibitor 
5.1.3 
Mode of Action  
Afatinib is a potent and selective irreversible ErbB family blocker, 
binding to kinase domains of EGFR (ErbB1), HER2 (ErbB2), and 
HER4 (ErbB4). 
5.1.4 
Storage and Stability  
Storage: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-
86°F) [see USP Controlled Room Temperature].  
Stability: Commercial packaged bottles are labeled with the expiration 
date. Dispense medication in the original container to protect from 
exposure to high humidity and light. 
5.1.5 
Dose Specifics  
Afatinib 40 mg PO QD, repeat cycles every 28 days. Afatinib tablets 
should not be chewed nor crushed. 
5.1.6 
Preparation  
Afatinib is supplied by Boehringer Ingelheim and distributed by CTEP, 
DCTD, NCI as afatinib dimaleate film-coated tablets containing 40 mg, 
30 mg or 20 mg of afatinib in polypropylene bottles with desiccants 
and containing 30 tablets each. Tablet descriptions are as follows: 
40 mg: light blue, film-coated, round, biconvex, bevel-edged tablets, 
10 mm diameter, debossed with “T40” on one side and the Boehringer 
Ingelheim company symbol on the other side.  
30 mg: dark blue, film-coated, round, biconvex, bevel-edged tablets, 9 
mm diameter, debossed with “T30” on one side and the Boehringer 
Ingelheim company symbol on the other side.  
20 mg: white to slightly yellowish, film-coated, round, biconvex, bevel-
edged tablets, 8 mm diameter, debossed with “T20” on one side and 
the Boehringer Ingelheim company symbol on the other side. 
Inactive ingredients: 
Tablet Core: lactose monohydrate, microcrystalline cellulose, 
crospovidone, colloidal silicon dioxide, magnesium stearate.  
Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, 
polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only). 
5.1.7 
Route of Administration  
Oral. Administer afatinib on an empty stomach; at least 1 hour before 
or 2 hours after a meal. Missed doses should not be administered if 
within 12 hours of the next scheduled dose.   

ECOG-ACRIN 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
29 
5.1.8 
Incompatibilities  
Afatinib is a substrate of P-glycoprotein (P-gp). Concomitant use of 
strong P-gp inhibitors and inducers should be used with caution. 
Strong P-gp inhibitors (e.g., ritonavir, cyclosporine A, ketoconazole, 
itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, 
saquinavir, and amiodarone) may increase exposure to afatinib. 
Strong P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, 
phenobarbital or St. John’s Wort) may decrease exposure to afatinib. 
If strong P-gp inhibitors need to be concomitantly administered with 
afatinib, they should be administered simultaneously with or after 
afatinib administration. 
5.1.9 
Side Effects  
See Section 3.3 for side effects. 

ECOG-ACRIN 
EAY131-A 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
30 
6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
Herbst RS, Heymach J V, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-80. 
Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor 
highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702-4711. 
Lynch TJT, Bell DDW, Sordella R, et al. Activating Mutations in the Epidermal Growth 
Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to 
Gefitinib. N Engl J Med. 2004;350:2129-2139. 
Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, 
metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one 
or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet 
Oncol. 2012;13:528-538.  
Mok TTS, Wu Y-LY, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in 
pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 
Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine 
kinase inhibitor-resistant disease. J Clin Oncol. 2013;31:1070-80. 
Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with 
clinical response to gefitinib therapy. Science. 2004;304:1497-500. 
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-
cell lung cancer. Nat Rev Cancer. 2010;10:760-74. 
Schuler MH, Planchard D, Yang JCH, et al.  Interim analysis of afatinib monotherapy in 
patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib 
(E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy 
following progression on afatinib monotherapy. J Clin Oncol. 2012; 30: (suppl; abstr 
7557). 
Sequist L V, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J 
Clin Oncol. 2013;31:3327-34. 
Shan Y, Eastwood MP, Zhang X, et al. Oncogenic mutations counteract intrinsic disorder 
in the EGFR kinase and promote receptor dimerization.  Cell 2012; 149: 860-70. 
Wu J-Y, Yu C-J, Chang Y-C, Yang C-H, Shih J-Y, Yang P-C. Effectiveness of tyrosine 
kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown 
clinical significance in non-small cell lung cancer. Clin Cancer Res. 2011;17:3812-21. 
Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for first-line 
treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR 
mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 
2014;15:213-22.  
Yang JC-H, Shih J-Y, Su W-C, et al. Afatinib for patients with lung adenocarcinoma and 
epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 
2012;13:539-48. 

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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
31 
Yang JC-H, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: 
a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung 
adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3342-50.  
Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase 
inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 2010;28:3965-
72. 
 
 
 

ECOG-ACRIN 
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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
32 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol A: Afatinib 
Appendix I 
 
Patient Pill Calendar 
Storage: Store at Room Temperature 
Pill Calendar Directions 
1. Take your scheduled dose of each tablet. 
2. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit. 
3. Take afatinib on an empty stomach at least 1 hour before or 2 hours after a meal. 
4. Afatinib tablets are taken once daily. Afatinib tablets should not be chewed nor 
crushed. 
5. Missed doses should not be administered if within 12 hours of the next scheduled 
dose. 
6. Do not take an additional dose as a replacement if vomiting were to occur after 
taking a dose of Afatinib. 
7. Limit time in the sun, sun exposure can cause rash and severe sunburn. Apply 
sunscreen, wear hat and protective clothing for any sun exposure. 
 
 
Rev.12/16 
Rev.3/17 

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Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
33 
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. 
Afatinib 
DAY 
Date 
Time 
tablets 
taken 
Dose of 
tablets 
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: _____________ 
 

ECOG-ACRIN
EAY131-A 
Cancer Research Group
Version Date: September 15, 2020
NCI Update Date: August 12, 2015
34
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol A: Afatinib
Appendix II
Patient Clinical Trial Wallet Card
CLINICAL TRIAL WALLET CARD
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room.
Patient Name:       
Diagnosis:       
Study Doctor:      
Study Doctor Phone #:      
NCI Trial #:       
Study Drug(S):  
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov
Rev. Add25

ECOG-ACRIN 
EAY131-A 
Cancer Research Group 
Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
35 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol A: Afatinib 
Appendix III 
 
Actionable Mutations of Interest (aMOIs) 
A. Inclusion Variants: 
NOTE: 
A function has been implemented in MATCHBOX to identify any novel in-frame 
deletions in exon 19 of the EGFR gene at Level of Evidence code 1. This 
function also includes any activating mutation in the EGFR gene with Level of 
Evidence code 3 or higher not listed in the table below. 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 
Variant Description 
EGFR 
COSM6224 
SNV 
1 
p.L858R 
EGFR 
COSM6252 
SNV 
2 
p.G719S 
EGFR 
COSM6253 
SNV 
2 
p.G719C 
EGFR 
COSM18425 
SNV 
2 
p.G719D 
EGFR 
COSM6239 
SNV 
2 
p.G719A 
EGFR 
COSM6213 
SNV 
2 
p.L861Q 
EGFR 
COSM18441 
MNV 
2 
p.G719C 
EGFR 
COSM6241 
SNV 
2 
p.S768I 
EGFR 
COSM26038 
Large Indel 
1 
p.K745_E749del 
EGFR 
COSM1190791 
Large Indel 
1 
p.K745_A750delinsT 
EGFR 
COSM28517 
Large Indel 
1 
p.E746_E749del 
EGFR 
COSM18420 
Indel 
1 
p.E746del 
EGFR 
COSM24869 
Large Indel 
1 
p.E746_T751del 
EGFR 
COSM6223 
Large Indel 
1 
p. E746_A750del 
EGFR 
COSM13551 
Large Indel 
1 
p.E746_T751delinsI 
EGFR 
COSM13550 
Large Indel 
1 
p.E746_A750delinsIP 
EGFR 
COSM13552 
Large Indel 
1 
p.E746_T751delinsIP 
EGFR 
COSM13549 
Large Indel 
1 
p.E746_T751delinsA 
EGFR 
COSM133189 
Large Indel 
1 
p.E746_S752del 
EGFR 
COSM6225 
Large Indel 
1 
p.E746_A750del 
EGFR 
COSM6218 
Large Indel 
1 
p.E746_R748del 
EGFR 
COSM12728 
Large Indel 
1 
p.E746_T751del 
EGFR 
COSM26680 
Large Indel 
1 
p.E746_T751delinsI 
EGFR 
COSM51526 
Large Indel 
1 
p.E746_T751delinsIP 
Rev.2/16 
Rev. Add13 
Rev. Add19 
Rev. Add25 

ECOG-ACRIN 
EAY131-A 
Cancer Research Group 
Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
36 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence 
Code 
Variant Description 
EGFR 
COSM24970 
Large Indel 
1 
p.L747_K754del 
EGFR 
COSM12678 
Large Indel 
1 
p.E746_T751delinsA 
EGFR 
COSM12367 
Large Indel 
1 
p.E746_S752delinsA 
EGFR 
COSM12386 
Large Indel 
1 
p.E746_T751delinsV 
EGFR 
COSM133192 
Large Indel 
1 
p.E746_T751delinsV 
EGFR 
COSM18426 
Large Indel 
1 
p.E746_S752delinsV 
EGFR 
COSM18427 
Large Indel 
1 
p.E746_P753delinsVS 
EGFR 
COSM133193 
Large Indel 
1 
p.E746_T751delinsV 
EGFR 
COSM674057 
Large Indel 
1 
p.E746_S752delinsV 
EGFR 
COSM53205 
Large Indel 
1 
p.E746_T751delinsVa 
EGFR 
COSM12384 
Large Indel 
1 
p.E746_S752delinsV 
EGFR 
COSM12416 
Large Indel 
1 
p.E746_T751delinsVa 
EGFR 
COSM255211 
Large Indel 
1 
p.E746_P753delinsG 
EGFR 
COSM6254 
Large Indel 
1 
p.L747_T751del 
EGFR 
COSM6220 
Large Indel 
1 
p.E746_S752delinsG 
EGFR 
COSM12419 
Large Indel 
1 
p.L747_T751delinsQ 
EGFR 
COSM12422 
Large Indel 
1 
p.L747_A750delinsP 
EGFR 
COSM22944 
Large Indel 
1 
p.L747_T751delinsP 
EGFR 
COSM6255 
Large Indel 
1 
p.L747_S752del 
EGFR 
COSM51527 
Large Indel 
1 
p.L747_T751delinsQ 
EGFR 
COSM133195 
Large Indel 
1 
p.L747_A750delinsP 
EGFR 
COSM12387 
Large Indel 
1 
p.L747_P753delinsQ 
EGFR 
COSM12420 
Large Indel 
1 
p.L747_T751delinsQ 
EGFR 
COSM12382 
Large Indel 
1 
p.L747_A750delinsP 
EGFR 
COSM12383 
Large Indel 
1 
p.L747_T751delinsP 
EGFR 
COSM12370 
Large Indel 
1 
p.L747_P753delinsS 
EGFR 
COSM6210 
Large Indel 
1 
p.L747_T751delinsS 
EGFR 
COSM23634 
Large Indel 
1 
p.A750_E758delinsG 
EGFR 
COSM1667024 
Large Indel 
1 
p.T751_I759delinsN 
EGFR 
COSM96856 
Large Indel 
1 
p.T751_I759delinsN 
EGFR 
COSM24270 
Large Indel 
1 
p.T751_I759delinsN 
EGFR 
COSM13556 
Large Indel 
1 
p.T751_I759delinsN 
EGFR 
COSM6256 
Large Indel 
1 
p.S752_I759del 
EGFR 
COSM26720 
Large Indel 
3 
p.A763_Y764insFQEA 

ECOG-ACRIN 
EAY131-A 
Cancer Research Group 
Version Date: September 15, 2020 
 
NCI Update Date: August 12, 2015 
37 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence 
Code 
Variant Description 
EGFR 
MVAR116 
Large Indel 
3 
p.E746_A755delinsISERD 
EGFR 
COSM21683 
SNV 
3 
p.R108K 
EGFR 
COSM35508 
SNV 
3 
p.R222C 
EGFR 
COSM21686 
SNV 
3 
p.A289T 
EGFR 
COSM21685 
SNV 
3 
p.A289D 
EGFR 
COSM21687 
SNV 
3 
p.A289V 
EGFR 
COSM21689 
SNV 
3 
p.P596L 
EGFR 
COSM21690 
SNV 
3 
p.G598V 
EGFR 
EGFR-
SEPT14.E24S10 
Fusion 
3 
EGFR-SEPT14.E24S10 
B. Exclusion Variants: 
A function has been implemented in MATCHBOX to identify any novel in-frame insertions in 
exon 20 of the EGFR gene at Level of Evidence code 2, with the exception of exon 20 
insertions approved as inclusion variants as part of the dynamic aMOI process. 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence Code 
Variant Description 
EGFR 
COSM6240 
SNV 
2 
p.T790M