Trial Outcomes & Findings for Testing Afatinib in Combination With Pembrolizumab in Patients With Squamous Cell Carcinoma of the Lung (NCT NCT03157089)

Last Updated: 2021-02-23

Results Overview

Objective response rate is defined as percentage of participants with the best overall response of complete response (CR, disappearance of all target lesions) or confirmed partial response (PR, at least a 30% decrease in sum of diameter (SoD, longest diameter (LD) measured for all lesions except lymph nodes, where shortest diameter (ShD) was used) of target lesions, reference is baseline SoD). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

24 participants

Primary outcome timeframe

Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.

Results posted on

2021-02-23

Participant Flow

This trial is an open-label, single arm phase II study assessing the tolerability and anti-tumour activity of afatinib when given in combination with a fixed dose of pembrolizumab in patients with locally advanced or metastatic squamous non-small-cell lung cancer (NSCLC), who progressed during or after first line platinum-based standard therapy and had no prior treatment with an immune checkpoint inhibitor or Epidermal Growth Factor Receptor (EGFR) targeted therapy.

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group, if any of the entry criteria were violated. The trial consisted of 2 parts: A safety run-in and the main part. After the safety run-in, a safety-monitoring committee (SMC) decided not to proceed with the main part.

Participant milestones

Participant milestones
Measure	Afatinib 40 mg + Pembrolizumab 200 mg 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Overall Study STARTED	12	12
Overall Study Treated	12	12
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	12	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib 40 mg + Pembrolizumab 200 mg 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Overall Study Treated only with pembrolizumab	1	0
Overall Study Adverse Event	5	4
Overall Study Progressive disease	6	8

Baseline Characteristics

Testing Afatinib in Combination With Pembrolizumab in Patients With Squamous Cell Carcinoma of the Lung

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Total n=24 Participants Total of all reporting groups
Age, Continuous	62.8 Years STANDARD_DEVIATION 10.0 • n=5 Participants	63.3 Years STANDARD_DEVIATION 7.3 • n=7 Participants	63.1 Years STANDARD_DEVIATION 8.6 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.

Population: The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Objective Response Rate (ORR)	16.7 Percentage of Participants	8.3 Percentage of Participants

SECONDARY outcome

Timeframe: 21 days (1 treatment cycle) from study treatment (afatinib and pembrolizumab) administration.

Population: The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab. Because the Safety Monitoring Committee (SMC) decided that the benefit-risk ratio of afatinib in combination with pembrolizumab was not favorable, the trial was stopped according to a protocol-defined option and the decision on RP2D was not performed.

Recommended Phase II Dose (RP2D) was to be calculated through a Bayesian logistic regression model (BLRM) with overdose control that was to be fitted to binary toxicity outcomes. After 12 patients had completed at least one cycle (one cycle equals 21 days and consists of one time infusion of pembrolizumab at Day 1 + daily intake of afatinib) of treatment, the prior distributions were to be updated through Gibbs sampling procedures with the accumulated dose limiting toxicity (DLT) data from the first treatment cycle. The estimate of parameters was to be updated as data were accumulated using the BLRM. At the end of the dose confirmation, the toxicity probability at each dose level was to be calculated to determine an estimate of the RP2D. Posterior probabilities for the rate of DLT were to be summarised from BLRM. Confirmation of the RP2D by the Safety Monitoring Committee (SMC) was to be based on these probabilities as well as on the review of other safety and laboratory data.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=24 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Recommended Phase II Dose (RP2D)	NA Milligramm (mg) Because the Safety Monitoring Committee (SMC) decided that the benefit-risk ratio of afatinib in combination with pembrolizumab was not favorable, the trial was ended according to a protocol-defined option and the decision on RP2D was not performed.	—

SECONDARY outcome

Timeframe: Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.

Population: The treated set (TS) included all participants who received at least one dose of afatinib or pembrolizumab.

Disease control rate was calculated as percentage of participants with CR, PR, or stable disease (SD, neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum of diameters (SoD), nor sufficient increase to qualify for progressive disease (PD, at least a 20% increase in the SoD of target lesions, taking as reference the smallest SoD recorded on study (including baseline), together with an absolute increase in the SoD of at least 5 millimeter (mm ) or the appearance of one or more new lesions). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Disease Control Rate (DCR)	50 Percentage of participants	58.3 Percentage of participants

SECONDARY outcome

Timeframe: Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 436 days.

Population: All participants who received at least one dose of afatinib or pembrolizumab and showed objective response.

For participants who showed objective response, duration of objective response (DoR), was defined as the time from first documented complete response (CR) or partial response (PR) until the earliest of disease progression (PD) or death. Tumour response was assessed based on local radiological image (CT or MRI) evaluation by the investigators according to RECIST version 1.1. The number of participants with objective response who experienced the event "disease progression or death (whichever came first)" is reported instead of a metric summarizing the time-to-event data with unit of time, as the number analyzed was too small to perform a Kaplan-Meier-analysis.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=2 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=1 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Duration of Objective Response (DOR)	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.

Population: The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.

Progression-free survival was defined as the time (weeks) from the date of the first afatinib or pembrolizumab administration to the date of disease progression (at least a 20% increase in the sum of diameter (SoD, longest diameter (LD) measured for all lesions except lymph nodes, where shortest diameter (ShD) was used) of target lesions, taking as reference the smallest SoD recorded on study (including baseline), together with an absolute increase in the SoD of at least 5 mm or the appearance of one or more new lesions) or death (if the patient died without progression). The date of progression for the primary analyses was determined based on investigator assessment. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to RECIST version 1.1. Median and 95% Confidence Interval were calculated using Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Progression-free Survival (PFS)	9.0 weeks Interval 4.6 to 27.1	14.4 weeks Interval 5.0 to 26.1

SECONDARY outcome

Timeframe: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days.

Population: The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.

Overall survival is defined as the time from the date of treatment start to the date of death from any cause. Participants without event were censored. Median and 95% Confidence Interval were calculated using Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Overall Survival (OS)	37.9 weeks Interval 15.0 to 59.3	26.6 weeks Interval 8.6 to 53.6

SECONDARY outcome

Timeframe: Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.

Population: The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.

Tumour shrinkage (in millimeters) is defined as the difference between the minimum post-baseline sum of diameters of target lesions (SoD, longest for non-nodal lesions, short axis for nodal lesions) and the baseline sum of diameters of the same set of target lesions. Tumour shrinkage is reported as percentage change from baseline and represents the maximum decrease or the minimum increase from baseline in SoD in percentage of the baseline SoD. Negative values indicate a reduction in the SoD; positive values indicate an increase in the SoD. Tumour response was assessed based on local radiological image (CT or MRI) evaluation by the investigators according to RECIST 1.1.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 Participants 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 Participants 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Tumour Shrinkage	-7.7 Percentage change Standard Deviation 29.83	22.0 Percentage change Standard Deviation 71.84

Adverse Events

Afatinib 40 mg + Pembrolizumab 200 mg

Serious events: 4 serious events

Other events: 12 other events

Deaths: 10 deaths

Afatinib 30 mg + Pembrolizumab 200 mg

Serious events: 9 serious events

Other events: 12 other events

Deaths: 10 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Afatinib 40 mg + Pembrolizumab 200 mg n=12 participants at risk 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.	Afatinib 30 mg + Pembrolizumab 200 mg n=12 participants at risk 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
Cardiac disorders Acute coronary syndrome	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Cardiac disorders Pericardial effusion	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Cardiac disorders Sinus bradycardia	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Gastrointestinal disorders Diarrhoea	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Gastrointestinal disorders Vomiting	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
General disorders Multiple organ dysfunction syndrome	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Hepatobiliary disorders Immune-mediated hepatitis	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Infections and infestations Bronchitis	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	25.0% 3/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Infections and infestations Pneumonia	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Investigations Blood bilirubin increased	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	16.7% 2/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Respiratory, thoracic and mediastinal disorders Immune-mediated pneumonitis	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Respiratory, thoracic and mediastinal disorders Pneumonitis	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Skin and subcutaneous tissue disorders Pruritus	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
Vascular disorders Extremity necrosis	0.00% 0/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.	8.3% 1/12 • [Timeframe for All-Cause Mortality]: From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days. [Timeframe for Serious and Other Adverse Events]: From the time of first drug administration till the end of treatment + 30 days residual effect period (REP), up to 558 days. The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.