MATCH Treatment Subprotocol B: Phase II Study of Afatinib in Patients With Tumors With HER2 Activating Mutations
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 10, 2019 
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 #21 to EAY131-B, Phase II Study of Afatinib in Patients with Tumors 
with HER2 Activating Mutations.  
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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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.] 
This addendum is in response to Dr. Jeffrey Moscow’s June 19, 2019 Request for Rapid 
Amendment for Afatinib. 
The following revisions to EAY131-B protocol have been made in this addendum: 
Section 
Change 
1. 
Cover Page 
Updated Version date. 
2. 
3.3 
Updated the Afatinib CAEPR list with version 2.2, April 24, 2019. 
The following revisions to EAY131-B Informed Consent Document have been made in this 
addendum: 
Section 
Change 
1. 
Page 1 
Updated Version Date. 
2. 
What possible risks 
can I expect from 
taking part in this 
study? 
Updated the Afatinibpossible risks risk list with version 2.2 April 24, 2019. 

 
ii 
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-B so ECOG-ACRIN may activate 
it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
Enclosure 
CC: Phillpe Bedard MD  
Kari B. Wisinki, MD  
Eddy Yang, MD 
Alice Chen, MD 
Keith Thomas Flaherty, MD 
Lyndsay N. Harris. MD 
Peter O’Dwyer, MD 
Mickey Williams, PhD 
James V. Tricoli, PhD 
Stanley Hamilton, MD 
Lisa McShane, PhD  
Larry Rubinstein, PhD 
Robert Gray, PhD 
Shuli Li, PhD 
Lalitha Shankar, MD 
Susanna Lee, MD, PhD 
Constantine Gastonis, PhD 
Paolo Caimi, MD 
Shaji Kumar, MD 
Carlos Arteaga, MD 
Edith Mitchell, MD 
John J. Wright, MD, PhD 
Bruce Giantonio, MD 
Donna Marinucci 
Kerry Higgins 
Gayle Ipock 
Jean MacDonald 
Carol Chami, R.N. 
Juanita Andrews 
Melinda Flood 
Kelly Redmond 
Becky Fillingham 
Kevin Pollard 
Abuchi Agu 
Elanna Radomyshelsky 
Camilla Abreu  
Michael T. Balco 
Lauren Lambert 
Cayden Maican 
Margaret Cavenagh 
Ben Kim 
Alexandra Sachs 
 
 
 

EAY131-B 
1 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol B: Phase II Study of 
Afatinib in Patients with Tumors with HER2 Activating 
Mutations 
AFATINIB TREATMENT SUBPROTOCOL CHAIR: 
Philippe Bedard, MD 
AFATINIB TREATMENT SUBPROTOCOL CO-
CHAIR: 
Kari B. Wisinski, MD 
AFATINIB TRANSLATIONAL CHAIR: 
Eddy Yang, MD, PhD 
Version Date:  July 10, 2019 
NCI Update Date:  August 12, 2015 
NOTE: This subprotocol (EAY131-B) 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. Please 
reference the activation memo for the 
addendum activation date. 
Addendum #2 – 2/16 
Addendum #3 – 5/16 
Addendum #5 – 12/16 
Addendum #7 – 3/17 
Addendum #8 – 3/17 
Addendum #13 
Addendum #21 
Agent 
IND# 
NSC# 
Supply 
Afatinib 
NCI Supplied 
Rev. 5/16 
Rev. Add13 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol B: Phase II Study of Afatinib in Patients with 
Tumors with HER2 Activating Mutations ............................................................ 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 HER2 mutations are responsive to Afatinib dimaleate (BIBW 2992, 
Gilotrif®) .................................................................................................... 5 
2. Selection of Patients ......................................................................................... 17 
2.1 Eligibility Criteria ..................................................................................... 17 
3. Afatinib Treatment Plan .................................................................................... 19 
3.1 Administration Schedule ......................................................................... 19 
3.2 Adverse Event Reporting Requirements ................................................. 19 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Afatinib (BIBW 2992, NSC 750691) ......................................................... 22 
3.4 Dose Modifications ................................................................................. 26 
3.5 Supportive Care ....................................................................................... 30 
3.6 Duration of Agent-specific treatment ..................................................... 31 
3.7 Duration of Follow-Up ............................................................................. 31 
4. Study Parameters .............................................................................................. 32 
4.1 Therapeutic Parameters for Afatinib Treatment .................................... 32 
5. Drug Formulation and Procurement ................................................................. 34 
5.1 Afatinib (NSC 750691) ............................................................................. 35 
6. Translational Studies ......................................................................................... 37 
7. References ........................................................................................................ 37 
Appendix I  Patient Pill Calendar ............................................................................. 41 
Appendix II  Patient Drug Information Handout and Wallet Card .......................... 43 
Appendix III  Actionable Mutations of Interest (aMOIs) ......................................... 45 
 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
3 
 
TREATMENT SUBPROTOCOL CHAIR 
Philippe Bedard, MD 
University of Toronto 
Princess Margaret Cancer Centre 
OPG Building, 700 University Avenue 7th floor 
7-723 
Toronto, ON, Canada, M5G 1Z9 
Phone: (416) 946-4534 
Fax: (416) 946-6546 
Email: Philippe.Bedard@uhn.ca 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Kari B. Wisinski, MD  
Univ. of Wisconsin Carbone Cancer Center 
1111 Highland Ave, WIMR 6033 
Madison, WI 53705-2275 
Phone: 608- 262-2876 
Fax: 608- 265-6905 
Email: kbwisinski@medicine.wisc.edu 
 
TRANSLATIONAL CHAIR 
Eddy S. Yang, MD, PhD 
University of Alabama-Birmingham 
176F HSROC Rm 2232N 
1700 6th Avenue South 
Birmingham AL 35249-6832 
Phone: 205-934-2762  
Fax: 205-975-0784  
Email: eyang@uab.edu 
 
 
 
 
 
 
 
 
 
 
Rev. 5/16 
Rev. 3/17 
Rev. Add13 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
4 
Schema 
 
Long-Term Follow-Up
Afatinib 40mg PO once daily
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 70
 
 
Rev. 3/17 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
5 
1. 
Introduction 
1.1 
HER2 mutations are responsive to Afatinib dimaleate (BIBW 2992, Gilotrif®) 
The human epidermal growth factor receptor (HER) family pathway plays a 
critical role in multiple cellular functions.  There are four members in this family:  
HER1 (epidermal growth factor receptor [EGFR] or ErbB1), HER2 (ErbB2), 
HER3 (ErbB3) and HER4 (ErbB4).  Activation of the pathway via homo- or 
heterodimerization of these receptors can lead to cell proliferation, differentiation 
and survival.1  Agents targeting EGFR and HER2 have demonstrated activity in 
selected malignancies with HER2 overexpression/amplification or EGFR 
mutations.   
The human epidermal growth factor receptor-2 (ErbB2, HER2) is a 
transmembrane tyrosine kinase receptor which regulates cell growth and 
survival, as well as adhesion, migration, differentiation, and other cellular 
responses.2  The human epidermal growth factor receptor-2 (ErbB2, HER2) 
drives tumor proliferation with downstream signaling through the PI3K-AKT and 
MEK-ERK pathways.2,3  HER2 overexpression and amplification has been 
identified as a poor prognostic marker in a subset of patients diagnosed with 
breast, gastric or gastroesophageal junction cancer.2,4  However; agents 
targeting this pathway have significantly improved the survival of patients with 
HER2+ breast and gastric cancer.5-8  
Recently, mutations of the HER2 receptor tyrosine kinase have been identified in 
several different cancers. These mutations can reside in the kinase domain 
(D769Y, D769H, L755S, V777L, V842I, or in-frame exon 20 insertions), 
transmembrane domain (V659E/D, G660D), or the extracellular domain (G309A, 
G309E, S310F, S310Y or E321G) of HER29, 45. A novel splice variant of HER2 
resulting in deletion of exon 16 was also found to be a major oncogenic driver.46 
These mutations have been found in breast, lung, ovarian, and bladder cancers. 
Evidence supports that at least in some tumors, these mutations function as 
driver mutations. It is known that 2-4% of NSCLC harbor activating mutations10-13 
and that such mutations are also found in ovarian cancers14 as well as several 
other cancer subtypes.15  Recently, in a small study of 15 micropapillary 
urothelial carcinoma (MPUC), 40% harbored a HER2 mutations compared to the 
9.4% seen in 64 cases of non-MPUC cases.16 HER2 activating mutations lead to 
constitutive activation of the receptor and downstream AKT and MEK 
pathways.17 
Afatinib dimaleate (hereafter, referred to as afatinib) is a potent and selective, 
oral irreversible inhibitor of ErbB family members.  It is one of several dual 
EGFR/HER2 targeted agents in clinical development. Afatinib was more effective 
than erlotinib against EGFR mutant cancers in preclinical models.18 Afatinib has 
been reported to have efficacy against HER2 activating mutations. Preclinically, 
afatinib delayed tumor growth compared to placebo in mice harboring 
established tumors using the NSCLC cell line NCI-H1781, which has the HER2 
776insV mutation.17 Sensitivity to afatinib with tumor regressions measured by 
tumor volume was also noted in the transgenic lung cancer HER2 YVMA 
model.17 Similarly, afatinib was effective against Ba/F3 cells transformed with 
various activating HER2 mutations, including extracellular domain mutations.9 In 
Rev. 3/17 

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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
6 
these studies, the IC50 of afatinib was comparable to neratinib and more 
effective than lapatinib. 
In vitro efficacy of afatinib has also recently been observed in primary uterine 
cervical cancer cells harboring activating HER2 extracellular domain mutations 
(S280F and E375D). This was associated with blockade of cells in G1 phase of 
the cell cycle and reduced markers of activated HER2 pathway.19 
Afatinib has been shown to exert clinical activity against tumors harboring ErbB2 
(HER2) mutations.   In one exploratory phase II study, three patients with lung 
adenocarcinoma exhibiting activating mutations of HER2 in exon 20 were treated 
with 50mg/day afatinib.20  In all three patients, an objective partial response was 
observed, and time to progression ranged between 3-4 months. 
In another study, 65 patients with HER2 mutated (exon 20 insertion) lung cancer 
were retrospectively identified.11  In this cohort, 22 evaluable patients who 
received HER2-directed therapies were analyzed.  Interestingly, the disease 
control rate observed in patients who received afatinib as monotherapy (n=4) 
was 100%.  In contrast, no responses were observed with lapatinib, a 
EGFR/HER2 reversible inhibitor (n=2), or masatinib (n=1) monotherapy.  The 
remaining 15 patients received trastuzumab in combination with chemotherapy 
and achieved a disease control rate of 96%. 
A rapid and durable complete response following afatinib therapy was also 
observed in a patient with Li-Fraumeni Syndrome and metastatic 
adenocarcinoma of the lung harboring synchronous EGFR L858R and HER2 
S310F mutations.21 A separate case report also reported response to lapatinib in 
combination with chemotherapy in a Li Fraumeni patient with lung cancer 
possessing a HER2 kinase activating mutation.22 
A phase II study of trastuzumab pre-treated HER2 positive (amplification or over 
expression) advanced breast cancer patients (N=41) with afatinib 50mg 
demonstrated 10% partial response and 37% stable disease.  Mean duration of 
objective response was 153 days.23 
Recently, 3 of 4 lung adenocarcinoma patients with mutations in the HER2 
transmembrane domain (V659 and G660) also had durable clinical responses to 
Afatinib.46 
The most up-to-date preclinical and clinical study information for afatinib can be 
found in the Investigator's Brochure (2014).25 
1.1.1 
Mechanisms of Action and Preclinical Data with Afatinib 
Afatinib is a highly potent, irreversible ErbB family blocker.  The 
activity of EGFR, HER2 and HER4 kinases are inhibited with IC50 
values of 0.5nM, 14nM and 1nM, respectively (Investigator’s 
Brochure, 2014).25  Afatinib did not demonstrate significant inhibitory 
activity in a larger panel of protein kinases and in receptor-ligand 
binding assays, supporting the selectivity of this compound for the 
ErbB receptor family.  Afatinib was designed to allow covalent binding 
to specific cysteine residues within the catalytic cleft of the targeted 
enzymes (Cys 797 in EGFR, Cys 805 in HER2 and Cys 803 in 
HER4), thus resulting in prolonged duration of action in cellular 
washout experiments.25,26   

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NCI Update Date: August 12, 2015 
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In preclinical in vitro models, afatinib effectively inhibits ligand-induced 
EGFR and constitutive HER2 phosphorylation, leading to tumor 
growth inhibition and regression. When afatinib was evaluated in 
NSCLC cell lines harboring EGFR kinase activating and resistance 
mutations, afatinib inhibited receptor activation and proliferation.27-29  
Afatinib also inhibits the proliferation of H1781 NSCLC cells displaying 
wild type EGFR and mutated HER2 receptors (G776VinsC).25   
Xenograft and transgenic mouse models have been used to evaluate 
the anti-tumor activity of afatinib.  In mice, afatinib is bioavailable after 
oral administration and reaches efficacious plasma exposure with 
once daily dosing.25  Afatinib induced tumor regression in tumor 
xenograft models derived from four human cell lines known to co-
express ErbB receptors (A431 vulvar carcinoma  NCI-N87 gastric 
carcinoma, SKOV-3 ovarian carcinoma, MDA-MB-453 breast 
carcinoma) with tumor to control (T/C) ratios of 2-4% at doses 20-
30mg/kg/d.25 Afatinib has also demonstrated activity in the 
trastuzumab-resistant HER2 positive cell line, SUM-190.  In EGFR 
double mutant (EGFRL858R/T790M) NSCLC xenograft models as 
well as inducible EGFRL858R/T790M transgenic mice, the 
tumor/control (T/C) values in the afatinib treated groups ranged from 
12-18%.18,30 Other preclinical studies supporting the use of afatinib in 
tumors with activating HER2 mutations are mentioned in section 1.1. 
Preclinical data also support combinations of afatinib with rapamycin, 
cetuximab, nintedanib (BBF 1120), multiple chemotherapy agents 
(vinorelbine, docetaxel) and radiation.17,30-33 In the bladder cancer cell 
line 5637, which harbors the S310F mutation, afatinib synergized with 
the MEK inhibitor PD184352 to inhibit cell survival.9   
Preclinical pharmacokinetics from xenograft models showed that the 
plasma concentration of afatinib associated with anti-tumor activity 
ranged from 80-285nM with corresponding AUC 0-24h from 589-
3198nMh.25 
Preclinical toxicity from GLP studies in animals showed no effect on 
body temperature, general behavior, locomotor activity, respiratory 
function and no major effects on heart rate and ECG.  Non- GLP 
studies in animals were devoid of CNS and pulmonary effects.  The 
only effect seen on the cardiovascular system was reduced 
contractility at higher intravenous doses.  An effect on renal and liver 
function was seen with the oral dose of 300mg/kg in rats.  
Furthermore, a dose-dependent effect on gastrointestinal function was 
seen, including soft feces, loose stool. 
In oral repeat-dose studies in rats and minipigs the main target organs 
were the skin (mice and rats), the gastrointestinal tract (mice, rats and 
minipigs) and the kidneys (rat). In the gastrointestinal tract, a dose 
dependent atrophy of the epithelium and concomitant focal 
erosions/ulcerations in the stomach of rats and minipigs were 
observed. Clinically, this was characterized by diarrhea in both 
species and fecal occult blood in individual minipigs. Whereas atrophy 
was predominant in the intestinal epithelia of rats and minipigs, in the 
mouse, hypertrophy and hyperplasia were noted, at plasma levels >2x 

ECOG-ACRIN 
EAY131-B 
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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
8 
that observed in humans. Other organs with epithelial atrophy were 
the skin, prostate, uterus, and vagina in rats and the upper respiratory 
tract, the prostate, the seminal vesicles and the cornea of the eyes in 
minipigs and mice. In addition, the mucinous glands in the 
gastrointestinal and respiratory tract were atrophic. All these changes 
were generally minimal to moderate and reversible and are most likely 
related to the inhibition of the ErbB-signaling by afatinib.  In mice, no 
renal papillary necrosis was observed despite reaching life-
threatening toxicity and markedly higher systemic drug exposure 
compared with rats. The observed reactive neutrophilia was 
considered secondary to the inflammatory processes in the skin 
(mice, rats) and the gastrointestinal tract (minipigs).  
No indication for cardiotoxicity was observed in the chronic oral 
repeat-dose toxicity studies up to 26 weeks in rats or 52 weeks in 
minipigs. However, because a negative inotropic effect (reduced 
contractility) was observed in pigs given intravenous doses of 6.65 
mg/kg afatinib or more, appropriate monitoring of contractility is to be 
considered in clinical trials.  
1.1.2 
Clinical Pharmacokinetics (PK) and Activity of Afatinib 
1.1.2.1 
Clinical Pharmacokinetics 
Clinical pharmacokinetic data of afatinib were derived from 
PK data from Phase I/II and III studies with monotherapy or 
combinations. 
Absorption and distribution:  Afatinib plasma concentration-
time profiles were comparable for the individual dose 
groups tested (10 to 100 mg), exhibiting at least 
biexponential disposition kinetics and increased with 
increasing doses. A moderate to high variability was 
observed for the plasma concentrations e.g., for the 40 mg 
dose group with geometric Coefficient of Variations (gCVs) 
ranging from 50.8 to 221 %. A similar variability range was 
observed in the other dose groups ranging from 10 to 100 
mg.  Maximum plasma concentrations mainly occurred at 2 
to 5 hours after drug administration.  Afatinib exhibited 
similar disposition characteristics after oral administration 
at all dose levels after single dose and at steady state, 
which could be described by at least biexponential 
disposition kinetics. In cancer patients, afatinib showed a 
high apparent volume of distribution during the terminal 
phase both after single dose and at steady state (Vz/F and 
Vz/F,ss) which might indicate a high tissue distribution of 
the drug.  However, the respective values should be 
interpreted with caution as the absolute bioavailability (F) 
of afatinib in humans is not known.  Plasma protein-binding 
of afatinib in humans was non-saturable up to 500nM.  
Binding of afatinib to human serum albumin (45mg/L) was 
moderate (79.6%).  Protein binding was not changed in 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
9 
mild and moderately liver impaired subjects compared to 
matched healthy controls. 
Food Effect:  A food effect study comparing the 
pharmacokinetics of afatinib (40 mg) administered as 
tablets to cancer patients revealed that absorption was 
decreased with a reduction of afatinib gMean Cmax and 
AUC0-∞ values by around 50% and 39%, respectively 
under fed conditions compared to fasted conditions. Since 
a statistically significant food effect was observed, afatinib 
should be taken without food (i.e. food should not be 
consumed for at least 3 hours before and at least 1 hour 
after taking afatinib). 
Metabolism, excretion, and accumulation:  Metabolism is of 
subordinate role for afatinib in vivo.  Apparent total body 
clearance (CL/F and CL/F,ss) in cancer patients was 
moderate to high. However, the absolute bioavailability (F) 
of afatinib in humans is unknown.  The contribution of renal 
excretion to the total body clearance of afatinib was low. 
The major route of elimination was via feces.  
Accumulation ratios based on AUC ranged from 2.53 to 
3.40 and were higher than the ratios based on Cmax 
(range of gMean values: 2.00 to 2.67). Using the overall 
gMean accumulation ratio of AUC (2.77), the accumulation 
(or effective) half-life can be calculated according to the 
following formula t1/2=τ·ln2/ln(RA,AUC/(RA,AUC-1)).34 
The respective accumulation half-life value of afatinib is 37 
h. This is in line with the overall gMean apparent terminal 
half-life at steady state in cancer patients, which was 37.2 
h). Statistical analysis confirmed that steady state was 
attained within 8 days of afatinib treatment. Afatinib trough 
values were stable over the observed treatment period (of 
6 months and longer) and their intra-individual variability 
determined per dose group was moderate (gCVs ranging 
from 22.19% to 67.50%).  See Table 1.    
Dose Proportionality:  Afatinib displays non-linear 
pharmacokinetics in the therapeutic dose range as AUC 
and Cmax values increased slightly more than proportional 
in the range of 20 to 50 mg (after single dose and multiple 
dose administration.  
PK in Hepatic and Renal Insufficiency:  Hepatically mild 
(Child Pugh A, score of 5 or 6 points) and moderate (Child 
Pugh B, score of 7 to 9 points) impaired patients received 
a single oral dose of afatinib 50 mg and were compared to 
healthy subjects.  Overall, exposure of afatinib was similar 
in patients with mild and moderate liver impairment and in 
healthy controls. The results are in line with the population 
PK analysis, which demonstrated no significant impact on 
afatinib exposure based on clinically laboratory tests 
indicative of an impaired hepatic function.   

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
10 
Less than 5% of a single dose afatinib is excreted via the 
kidneys. The safety, pharmacokinetics and efficacy of 
afatinib have not been studied in patients with renal 
impairment. In the PopPK analysis, exposure to afatinib 
slightly increased with lowering the creatinine clearance 
(CrCL), i.e. for a patient with a CrCL of 60 or 30 mL/min 
exposure (AUCτ,ss) to afatinib increased by 13% and 
42%, respectively, and decreased by 6% and 20% in 
patients with a CrCL of 90 or 120 mL/min, respectively, 
compared to a patient with the CrCL of 79 mL/min (median 
within analyzed population). As the effect sizes were within 
the observed inter-patient variability of exposure, no dose 
adjustment is considered necessary in patients with mild or 
moderate renal impairment. 
Population PK:  No statistically significant effect was seen 
based on smoking status, ethnic origin, age, liver 
metastases or liver function parameters.   Predicted 
individual effects are considered to be mild to moderate for 
creatinine clearance, gender, body weight, ECOG 
performance status, alkaline phosphatase, lactate 
dehydrogenase and total plasma protein levels. 
Although several phase II studies used 50 mg daily, the 
phase I data confirms that Css at 40 mg exceeds IC50 for 
HER2, thus this will be the starting dose for this 
subprotocol.44 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
11 
Table 1: 
Comparison of gMean pharmacokinetic parameters of afatinib in cancer patients for the 20mg, 30mg, 40 mg and 50mg 
dose group and for the whole dose range (10-100mg) from 5 monotherapy trials23. 
Afatnib BS 
20mg 
30mg 
40mg 
50mg 
Overall (10 – 100mg) 
N 
gMean (gCV%) 
N 
gMean (gCV%) 
N 
gMean (gCV%) 
N 
gMean (gCV%) 
N 
gMean 
AUC 0-24 [ng·h/mL] 
12 
119 (56.6) 
10 
189 (95.9) 
30 
324 (68.9) 
69 
459 (68.0) 
 
 
AUC t,ss [ng·h/mL] 
15 
380 (77.2) 
8 
660 (92.4) 
26 
631 (85.9) 
51 
1130 (59.6) 
 
 
Cmax [ng/mL] 
13 
11.6 (85.1) 
10 
16.3 (139) 
30 
25.2 (73.3) 
73 
40.8 (76.6) 
 
 
Cmax,ss [ng/mL] 
15 
24.5 (88.5) 
8 
46.5 (120) 
27 
38.0 (105) 
51 
77.0 (63.6) 
 
 
tmax [h] a 
13 3.00 (0.500 - 24.0) 10 2.00 (0.567 - 692) 
30 3.98 (0.583 - 9.10) 
73 3.13 (0900 - 9.05) 189 
3.02 (0.467 - 24.0) 
tmax,ss [h] a 
15 4.98 (0.500 - 9.08) 
8 
2.01 (0.517 - 4.00) 27 2.98 (0.467 - 23.8) 
51 3.82 (1.00 - 7.05) 149 
3.00 (0.467 - 23.8) 
t1/2 [h] 
11 
22.3 (80.3) 
10 
21.3 (82.1) 
30 
26.9 (61.1) 
13 
21.9 (54.8) 
127 
21.4 (56.5) 
t1/2,ss [h] 
15 
47.1 (51.6) 
7 
33.4 (56.8) 
23 
36.3 (57.1) 
7 
22.3 (25.4) 
100 
37.2 (45.5) 
CL/F [mL/min] 
11 
1430 (64.7) 
10 
1370 (72.9) 
30 
952 (86.2) 
13 
1090 (94.0) 
127 
1050 (76.3) 
CL/F,ss [mL/min] 
15 
877 (77.2) 
8 
758 (92.4) 
25 
1070 (87.9) 
7 
1390 (47.3) 
104 
898 (89.2) 
Vz/F [L] 
11 
2770 (61.8) 
10 
2520 (109) 
30 
2220 (101) 
13 
2080 (123) 
127 
1940 (87.7) 
Vz/F,ss [L] 
15 
3570 (107) 
7 
2000 (67.8) 
23 
2870 (101) 
7 
2690 (47.8) 
99 
2770 (99.3) 
RA,AUC 
11 
3.14 (27.6) 
8 
3.40 (83.1) 
9 
2.53 (48.0) 
49 
2.61 (59.1) 
120 
2.77 (63.1) 
RA,Cmax 
12 
2.23 (26.5 
8 
2.67 (98.8) 
9 
2.08 (57.7) 
51 
2.00 (69.2) 
123 
2.11 (70.2) 
a Median range 
 

ECOG-ACRIN 
EAY131-B 
Cancer Research Group 
Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
12 
Potential for Drug-Drug Interactions:  Afatinib at 
concentrations up to 100 μM did not show potent inhibition 
of the cytochrome P450 isoenzymes that are most relevant 
for drug metabolism in human (1A1/2, 2A6, 2B6,2C8, 2C9, 
2C19, 2D6, 2E1, 3A4, 4A11). Therefore, drug-drug 
interactions based on inhibition of P450 enzymes by 
afatinib are unlikely to occur.25 Induction of in vitro enzyme 
activity was not found for any of the P450 enzymes tested 
(1A2, 2B6, 2C8, 2C9, 2C19, 3A4) following treatment with 
up to 5 μM of afatinib for 48 h. No relevant induction of 
mRNA levels was observed for the respective enzymes 
upon treatment with afatinib. Based on the results from this 
study, metabolic drug-drug interactions of afatinib resulting 
from induction of cytochrome P450 enzymes are not 
expected.  The co-administration of the potent P-gp 
inhibitor ritonavir did not relevantly change the exposure to 
40 mg afatinib when taken simultaneously with or 6 h after 
afatinib but increased the exposure to 20 mg afatinib by 
48% (AUC0-∞) and 39 % (Cmax) when administered 1h 
before afatinib. Pretreatment with the potent P-gp inducer 
rifampicin decreased the plasma exposure of 40 mg 
afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), 
respectively. Therefore, caution should be exercised when 
combining afatinib with potent P-gp modulators. However, 
changes in afatinib bioavailability by this kind of drugs are 
considered mild to moderate and do not require any 
adjustment to the starting dose. 
1.1.2.2 
Clinical Activity  
Monotherapy studies in advanced NSCLC:  
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. 
Previously, on July 12, 2013, the U.S. Food and Drug 
Administration (FDA) approved afatinib for the treatment of 
patients with metastatic non-small cell lung cancer 
(NSCLC) whose tumors have EGFR exon 19 deletions or 
exon 21 (L858R) substitution mutations detected by an 
FDA-approved test (U.S. Food and Drug Administration, 
2013).24 
Two open-label phase III trials have evaluated afatinib 
40mg vs standard platinum-based doublet chemotherapy 
in first-line treatment of EGFR mutation positive advanced 
NSCLC patients.35,36  In both studies, afatinib significantly 
prolonged PFS compared to chemotherapy (11.1 vs 6.9 
mo, HR 0.58; 95% CI 0.43-0.78; p=0.004 and 11.0 vs. 
5.6mo HR 0.28; 95%CI 0.2-0.39; p< 0.0001.  In those with 
common EGFR mutations, the PFS improved to a greater 
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extent (13.6mo vs 6.9mo; HR 0.47; p< 0.0001 and 11.1 vs 
5.6mo, HR 0.25; p< 0.0001). A separate randomized, 
double-blind, placebo- controlled phase IIb/III trial, 
compared afatinib 50mg po qd to placebo in EGFR 
tyrosine kinase inhibitor (TKI) pre-treated patients with 
advanced NSCLC.37 Although no difference in OS was 
noted (10.8 vs 12mo) comparing afatinib to placebo, 
secondary endpoints favored afatinib including 
progression-free survival, ORR and HRQoL.37,38  
Afatinib has been shown to exert clinical activity against 
tumors harboring ErbB2 (HER2) mutations. In one 
exploratory phase II study, three patients with lung 
adenocarcinoma exhibiting activating mutations of HER2 in 
exon 20 were treated with 50mg/day afatinib.20  In all three 
patients, an objective partial response was observed, and 
time to progression ranged between 3-4 months. In 
another study, 65 patients with HER2 mutated (exon 20 
insertion) lung cancer were retrospectively identified.11  In 
this cohort, 22 evaluable patients who received HER2-
directed therapies were analyzed. Interestingly, the 
disease control rate observed in patients who received 
afatinib as monotherapy (n=4) was 100%. In contrast, no 
responses were observed with lapatinib, a EGFR/HER2 
reversible inhibitor (n=2), or masatinib (n=1) monotherapy. 
The remaining 15 patients received trastuzumab in 
combination with chemotherapy and achieved a disease 
control rate of 96%. 
Monotherapy studies in solid tumor malignancies other 
than NSCLC:  
Kwak et al studied afatinib in patients with solid tumors 
(gastric, gastroespophageal, esophageal, biliary, or 
gallbladder, transitional cell urothelial or gynecological) 
and either EGFR or HER2 amplification, or EGFR 
activating mutation in archival tumor tissue (NSCLC was 
excluded). Of 38 FISH positive tumors, 29 had HER2 
amplification. Of the 388 patients, 20 received afatinib.  Of 
these, 13 had HER2 amplification (10high-level, 2 low 
level). The response rate was 5% (one CR) in this group - 
a woman with high HER2 amplification in endometrial 
carcinoma. The trial was terminated early because of 
recruitment challenges. Eight patients (40%) of HER2 
amplified patients had stable disease as best response.39 
In a phase II open-label trial in patients (N=124) with 
advanced squamous head and neck cancer not pre-
screened for target, patients were randomized (1:1) to 
afatinib 50mg daily vs. cetuximab (250mg/m2/week).  The 
primary endpoint was maximum tumor shrinkage from 
baseline before crossover. Mean tumor shrinkage by 
independent central review was 16.6% and 10.1% for 

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afatinib and cetuximab, respectively (p=0.30) and disease 
control rate was also similar in the two groups.40  In a 
phase III trial in patients with recurrent/metastatic HNSCC,  
after progression on/after platinum-based therapy patients 
were randomized 2:1 to oral treatment with afatinib 40mg 
daily (322 patients) or intravenous methotrexate 40mg/m2 
weekly (161 patients).41 There was significant improvement 
in the primary endpoint of PFS with afatinib (median 2.6 vs 
1.7 months; p = 0.03), the disease control rate was higher 
with afatinib (49.1% vs 38.5%; p=0.035) and afatinib 
showed delay in deterioration of global health status, pain 
and swallowing (all p ≤ 0.03), and provided improvement in 
pain. The most frequent grade 3/4 drug-related adverse 
events were rash/acne (9.7%) and diarrhea (9.4%) with 
afatinib.  
In metastatic HER2 negative breast cancer, no objective 
responses were observed in 50 patients treated with 
afatinib, although 3 patients with triple negative breast 
cancer showed disease stabilization for 4 months and 
longer.42   
In patients with glioblastoma multiforme, the phase II 
portion of a phase I/II study randomized 119 patients to 
afatinib monotherapy vs afatinib with temozolomide vs 
temozolomide alone. PFS at 6 months by investigator 
assessment was 3%, 10% and 23%, respectively.  One 
patient (2.4%) in the afatinib arm had a PR.43 
Afatinib has been shown to exert clinical activity against 
tumors harboring ErbB2 (HER2) mutations 
1.1.3 
Afatinib Safety Profile  
A Comprehensive Adverse Events and Potential Risks (CAEPR) 
list using NCI Common Terminology Criteria for Adverse Events 
(CTCAE) terms is included in Section 3.3 of the protocol. 
Based on phase I studies, the MTD for continuous administration of 
single agent oral afatinib was 50mg or 40mg daily. The data from the 
monotherapy trials indicate that the safety profile of afatinib is 
characterized by significant incidence of dose-dependent 
gastrointestinal and skin toxicities.  The most common toxicities seen 
are:  diarrhea, rash/acne and stomatitis.  The majority of these are low 
grade (grade 1-2).   
AEs of special interest 
Diarrhea, rash, stomatitis and ILD are considered AEs of special 
interest because they are either known class effects (i.e., have been 
observed with other EGFR inhibitors) or are potentially life-threatening 
(Investigator’s Brochure, 2014).  The following sections provide 
integrated summaries for these AEs across different clinical trials, with 
emphasis on trials using afatinib as monotherapy, especially at the 
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Section 3.4 of the protocol has dose modification guidelines for 
toxicities.   
Diarrhea 
Diarrhea is the most common AE observed across afatinib 
monotherapy trials, typically affecting > 80% of patients. Grade 3 
diarrhea with the 40mg po qd dose was 15.3% vs 17.2% with the 
50mg po qd dose. The majority of patients (> 70%) experienced 
diarrhea within 14 days of starting afatinib. Grade 3 diarrhea most 
frequently occurred within the first 6 weeks of treatment. Risk factors 
for grade 3 diarrhea included:  low body weight (< 50kg), females, and 
low baseline renal function (CrCl < 80mL/min). SAE of diarrhea were 
reported in 4-7% of patients and grade 5 diarrhea has been reported.  
Dehydration and renal impairment have both been reported related to 
diarrhea. Proactive management of diarrhea including adequate 
hydration and antidiarrheal agents (i.e. loperamide) is important and 
should be started at first signs of diarrhea.   
Rash/Acne 
Rash/acne is one of the most common AE reported in patients on 
afatinib trials with the total incidence reaching 90% in the pivotal 
NSCLC trial using afatinib monotherapy at 40mg po qd. Grade 3 
rash/acne was similar at 40mg and 50mg (14 and 16.2%, 
respectively). In general, rash manifests as a mild or moderate 
erythematous and acneiform rash, which may occur or worsen in 
areas exposed to sun. The majority of patients experienced onset of 
rash/acne within the first 4 weeks of treatment (79.7% at 40mg and 
65.1% at 50mg).  Risk factors for grade 3 events included low body 
weight (< 50kg) and low baseline renal function(<80mL/min).  
Protective clothing, and/or use of sun screen is advisable. Early 
intervention (e.g. emollients, antibiotics) of dermatologic reaction is 
also recommended.  Dose reduction allowed successful management 
of rash in the majority of cases.  Rare cases of bullous, blistering and 
exfoliative skin conditions have been reported including cases 
suggestive of Stevens-Johnson syndrome.  Afatinib should be 
interrupted or discontinued if these occur. 
Palmar-plantar erythrodysaesthesia syndrome was also reported as a 
dermatologic AE with afatinib at rates of 6.6-7.7%. The majority were 
grade 1-2, but grade 3 events have been reported. 
Interstitial Lung disease (ILD)  
ILD or ILD-like events are a well-described, infrequent risk of EGFR 
inhibitors.  There have been reports of ILD or ILD-like events in 1.5% 
of afatinib treated patients. The rate of these events is similar to that 
observed with other EGFR inhibitors. Careful assessment of all 
patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnea, cough, fever) should be performed to 
exclude ILD. Treatment should be interrupted pending investigation of 
these symptoms. If ILD is diagnosed, afatinib should be permanently 
discontinued and appropriate treatment instituted as necessary. 

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Hepatic Adverse Events 
Hepatic AEs include elevated hepatic enzymes, which are primarily 
grade 1-2 and did not lead to treatment discontinuation.  In the entire 
afatinib exposed population, 10.8% (95% CI 10.1-11.7%) were 
reported with AEs indicative of hepatic impairment with 8 pts with 
hepatic AEs leading to death. These were considered not related to 
afatinib in 5 patients (related to progressive disease or sepsis). Drug-
related fatal case of acute hepatic failure has been reported.   Periodic 
liver function testing is recommended in patients treated with afatinib.   
Keratitis 
Keratitis and ulcerative keratitis have been reported with the EGFR 
inhibitors. In 6,002 afatinib treated patients, 39 (0.6%) cases were 
identified.   
Effect on QTc 
A phase II study in patients with advanced solid tumors investigated 
the effect of afatinib on the QTc interval.  Afatinib at doses of 50mg 
daily did not prolong the QT interval or the heart rate corrected QT 
interval (QTcF). It did not affect heart rate.  No other clinically 
meaningful changes in QTcF or ECG endpoints were observed. 
Events of cardiac dysfunction/LVEF decrease 
Left ventricular ejection fraction (LVEF) decrease has been reported 
with agents targeting HER2, in particular with the monoclonal 
antibody, trastuzumab.  In the phase IIb/III trial in advanced NSCLC 
using afatinib 50mg, 4 (1.0%) afatinib treated patients vs 1 (0.5%) 
placebo patients experienced an AE of cardiac failure, 
cardiopulmonary failure, hepatic congestion or left heart failure. This 
was a non-significant difference (HR 1.32, 0.14-12.50).37  In study 
1200.32, with 40mg of afatinib, the frequency of these AEs was 2.6% 
in the afatinib arm vs 0.9% in the chemotherapy arm.  This was not 
significantly increased when corrected for time at risk (HR 1.18, 0.12-
11.39). Furthermore, the heart failure or LVEF decrease events were 
all grade 2 or lower.35 
 

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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 activating HER2 mutation, as determined 
via the MATCH Master Protocol and according to Appendix III. 
Additionally, any in-frame insertions in exon 20 will be considered an 
activating mutation. 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 
Rev.2/16 
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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 diarrhea at baseline. 
2.1.7 
Patients with a history of interstitial lung disease will be excluded. 
2.1.8 
Patients must not have had prior treatment with any of the following 
TKIs, which have known activity against HER2 kinase: 
• Neratinib 
• Afatinib 
• AC-480 (BMS-599626) 
• AEE 788 
• AST 1306 
• AZD8931 
• Canertinib (CI 1033) 
• CP-724714 
• CUDC-101 
• Dacomitinib 
• Lapatinib 
• Perlitinib 
• TAK285  
2.1.9 
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. 
2.1.10 
Patients with non-small cell lung cancer will be excluded. 
 
 
 
 
 
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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3. 
Afatinib Treatment Plan 
3.1 
Administration Schedule 
Patients will be instructed to take afatinib 40mg PO daily at the same time each 
day continuously for each 28 day cycle until tumor progression or unless patient 
experiences unacceptable toxicities. 
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. 
3.1.1 
Potential Drug-drug interaction 
Afatinib is a substrate of P-glycoprotein (P-gp). Thus, in patients 
taking P-gp inhibitors (including but not limited to ritonavir, 
cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, 
quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone), or 
strong P-gp inducers (including but not limited to rifampicin, 
carbamazepine, phenytoin, phenobarbital or St. John’s Wort), which 
may alter exposure to afatinib, afatinib should be administered 
simultaneously with or before drugs that affect P-gp.  
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. 
3.2 
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. 

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3.2.1 
Additional instructions, requirements and exceptions for EAY131 – 
Subprotocol B 
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 B specific expedited reporting 
requirements: 
• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the subject is on Afatinib, or 
within 28 days of the subject’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. 
 
EAY131 - Subprotocol B specific expedited reporting 
exceptions: 
For Subprotocol B, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
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 to 
ECOG-ACRIN using Medidata Rave 
• 
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. 

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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. 
• 
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. 
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 
(BIBW 2992, 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 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 in the SPEER.  
Version 2.2, April 24, 20191 
 
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 (eye 
disorders)2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Cheilitis 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Mucositis oral3 
 
 
 Mucositis oral3 (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 
  
Infection4 
 
 
 Infection4 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
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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 increased5 
 
  
 
 
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)5 
 
  
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)6 
  
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)7 
 
 
Skin and subcutaneous tissue 
disorders - Other (nail effect)7 (Gr 
2) 
Skin and subcutaneous 
tissue disorders - Other 
(rash)8 
 
 
 Skin and subcutaneous tissue 
disorders - Other (rash)8 (Gr 2) 
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal 
necrolysis 
  

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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 
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 Mucositis oral (stomatitis) may include stomatitis, aphthous stomatitis, mucosal inflammation, mouth 
ulceration, oral mucosa erosion, mucosal erosion, and mucosal ulceration. 
4 Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
5 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. 
6 Interstial lung disease may include acute interstitial pneumonitis, pneumonitis, acute respiratory distress 
syndrome, pulmonary infiltrates, and pulmonary fibrosis. 
7 Nail effect includes paronychia and nail disorder (e.g., nail ridging, nail loss, and nail discoloration). 
8 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 failure; 
Respiratory, thoracic and mediastinal disorders - Other (nasal dryness); Respiratory, thoracic 
and mediastinal disorders - Other (nasal inflammation)  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia 

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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. With the 50 mg dose used in previous trials of 
afatinib in HER2+, patients showed poor tolerability data. 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 longer 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 
resolves to ≤ 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 
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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 
toxicity resolves to ≤ grade 1 and then the drug should be restarted at 
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: 

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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 
toxicity is grade ≤ 1 or 
has returned to 
baseline. Then reduce 
the dose by 1 level 
and resume treatment. 
Withhold dose until toxicity is 
grade ≤ 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. 
Withhold dose until toxicity is grade ≤ 1. Then 
reduce dose by 1 level and resume treatment. 
Discontinue study 
treatment. 
Discontinue study treatment. 
Renal Toxicity 
Continue 
at the 
same dose 
level. 
Withhold dose until toxicity is grade  
≤ 1. Then reduce dose by 1 level and resume 
treatment. 
Withhold dose until 
toxicity is grade ≤1. 
Then reduce dose by 1 
level and resume 
treatment. 
Withhold dose until toxicity is 
grade ≤ 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. 
Withhold dose until toxicity is grade  
≤ 1. Then reduce dose by 1 level and resume 
treatment. 
Withhold dose until 
toxicity is grade ≤ 1. 
Then reduce dose by 1 
level and resume 
treatment. 
Withhold dose until toxicity is 
grade ≤ 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 > 7 days. 
If this occurs: 
Withhold dose until toxicity is grade ≤1. Then 
reduce dose by 1 level and resume treatment. 
Withhold dose until 
toxicity is grade ≤ 1.  
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 
toxicity is grade ≤ 1 or 
has returned to 
baseline. Then reduce 
the dose by 1 level 
and resume treatment. 
Discontinue study treatment 

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Ulcerative keratitis 
Continue 
at the 
same dose 
level. 
Continue at the same dose level. 
Withhold dose until 
toxicity is grade ≤ 1 or 
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 

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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 used 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 
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 
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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 
to CTCAE Grade ≤ 1. If grade 2 rash persists for ≥ 7 days despite 
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 
For intolerable fatigue (grade ≥ 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: 
• 
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. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered.  
• 
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 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 15 G 
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 
-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 
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 (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 
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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: 
• 
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. 
• 
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• 
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 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) 
 
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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 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 
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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:  40 mg po once daily 
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.   

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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. 

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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
1. Olayioye MA, Neve RM, Lane HA, et al: The ErbB signaling network: receptor 
heterodimerization in development and cancer. The EMBO journal 19:3159-67, 2000 
2. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse 
and survival with amplification of the HER-2/neu oncogene. Science 235:177-82, 
1987 
3. Spector NL, Blackwell KL: Understanding the mechanisms behind trastuzumab 
therapy for human epidermal growth factor receptor 2-positive breast cancer. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 
27:5838-47, 2009 
4. Begnami MD, Fukuda E, Fregnani JH, et al: Prognostic implications of altered human 
epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 
are predictors of poor outcome. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 29:3030-6, 2011 
5. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced 
gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, 
randomised controlled trial. Lancet 376:687-97, 2010 
6. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for 
operable HER2-positive breast cancer. The New England journal of medicine 
353:1673-84, 2005 
7. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. The 
New England journal of medicine 344:783-92, 2001 
8. Swain SM, Kim SB, Cortes J, et al: Pertuzumab, trastuzumab, and docetaxel for 
HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results 
from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 
14:461-71, 2013 
9. Greulich H, Kaplan B, Mertins P, et al: Functional analysis of receptor tyrosine kinase 
mutations in lung cancer identifies oncogenic extracellular domain mutations of 
ERBB2. Proceedings of the National Academy of Sciences of the United States of 
America 109:14476-81, 2012 
10. Arcila ME, Chaft JE, Nafa K, et al: Prevalence, clinicopathologic associations, and 
molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung 
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41 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol B: 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. 
 
 
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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. 
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: _____________ 

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NCI Update Date: August 12, 2015 
43 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol B: Afatinib 
Appendix II 
 
Patient Drug Information Handout and Wallet Card 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent Afatinib.  This clinical trial is sponsored by the National Cancer Institute.  
This form is addressed to the patient, but includes important information for others who care for 
this patient.  
Afatinib interacts with other drugs.  Because of this, it is very important to tell your study doctors 
about all of your medicine before you start this study.  It is also very important to tell them if you 
stop taking any regular medicine, or if you start taking a new medicine while you take part in this 
study.  When you talk about your medicine with your study doctor, include medicine you buy 
without a prescription at the drug store (over-the-counter remedy), or herbal supplements such 
as St. John’s wort.  
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These 
are the things that you and they need to know:  
Afatinib interacts with other drugs that effect P-glycoprotein, a protein on the surface of cells in 
our body that helps move drugs and other substances in and out of cells.  
• 
Afatinib must be used very carefully with other medicines that increase the activity of P-
glycoprotein (inducers) or decrease the activity of P-glycoprotein (inhibitors).   
o Substances that increase the activity of P-glycoprotein (“inducers”) could reduce the 
effectiveness of afatinib, while substances that decrease the activity of P-glycoprotein 
(“inhibitors”) could result in high levels of afatinib, increasing the chance of harmful side 
effects. 
• 
You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• 
Before you start the study, your study doctor will work with your regular prescriber to switch 
any medicines that are considered “strong inducers/inhibitors P-glycoprotein.”  
• 
Your prescribers should consult a medical reference to see if any medicine they want to 
prescribe is on a list of drugs to avoid.   
• 
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the generic 
name and determine, with the pharmacist’s help, whether there could be an adverse 
interaction.   
Other medicines can be a problem with your study drugs.  
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
• 
Your regular prescriber should check a medical reference or call your study doctor before 

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prescribing any new medicine for you.   
Your study doctor’s name is:  
_____________________________________  
and he or she can be contacted at:  
_____________________________________. 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
___Afatinib_____.  This clinical trial is sponsored by the NCI.  
__Afatinib___ interacts with drugs that effect P-glycoprotein.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
__Afatinib____ interacts with drugs that effect P-glycoprotein and 
must be used very carefully with other medicines that interact with P-
glycoprotein.  
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors of P-glycoprotein.” 
➢ Before prescribing new medicines, your regular prescribers should 
go to medical reference for a list of drugs to avoid, or contact your 
study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
 

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Version Date: July 10, 2019 
 
NCI Update Date: August 12, 2015 
45 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol B: Afatinib 
Appendix III 
 
Actionable Mutations of Interest (aMOIs) 
Inclusion Variants 
A function has been implemented in MATCHBOX to identify any novel in-frame insertions in 
exon 20 of the ERBB2 gene at Level of Evidence code 2. This function also includes any 
putative activating mutations in exon 20 of the ERBB2 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
aMOI 
ERBB2 
COSM1251412 
SNV 
2 
p.D769Y 
ERBB2 
COSM12556 
Large Indel 
2 
p.V777_G778insGSP 
ERBB2 
COSM13170 
SNV 
2 
p.D769H 
ERBB2 
COSM14060 
SNV 
2 
p.L755S 
ERBB2 
COSM14062 
SNV 
2 
p.V777L 
ERBB2 
COSM14065 
SNV 
2 
p.V842I 
ERBB2 
COSM20959 
Large Indel 
2 
p.A775_G776insYVMA 
ERBB2 
COSM35764 
SNV 
3 
p.E321G 
ERBB2 
COSM436496 
SNV 
3 
p.G309A 
ERBB2 
COSM48358 
SNV 
3 
p.S310F 
ERBB2 
COSM94224 
SNV 
3 
p.G309E 
ERBB2 
COSM94225 
SNV 
3 
p.S310Y 
ERBB2 
COSM682 
Large Indel 
2 
p.E770_A771insAYVM 
ERBB2 
COSM12558 
Large Indel 
2 
p.A771_Y772insYVMA 
ERBB2 
OMINDEL569 
Indel 
2 
p.G776delinsVC 
ERBB2 
COSM85995 
Indel 
2 
p.G776delinsVC 
ERBB2 
COSM12553 
Indel 
2 
p.G776delinsVC 
ERBB2 
COSM12552 
Indel 
2 
p.G776delinsVC 
ERBB2 
COSM12555 
Large Indel 
2 
p.V777_G778insGSP 
ERBB2 
COSM303948 
Large Indel 
2 
p.V777_G778insGSP 
ERBB2 
COSM303939 
Large Indel 
2 
p.V777_G778insCG 
ERBB2 
COSM26681 
Indel 
2 
p.G778_S779insG 
ERBB2 
COSM681 
Large Indel 
2 
p.S779_P780insVGS 
ERBB2 
COSM51317 
SNV 
3 
p.I767M 
ERBB2 
COSM3724566 
SNV 
3 
p.V659E 
ERBB2 
COSM4681497 
SNV 
3 
p.G660D 
ERBB2 
COSM4849559 
SNV 
3 
p.G660R 
ERBB2 
COSM436500 
SNV 
3 
p.V777L 
ERBB2 
COSM436498 
SNV 
3 
p.678Q 
 
Rev.2/16, 3/17 
Rev. 5/16 
Rev.12/16 
Rev.Add13