Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: A Phase 1b/2, Open-Label, Dose-Finding Study to Evaluate Safety, Efficacy,
Pharmacokinetics and Pharmacodynamics of Avelumab (MSB0010718C) in Combination
With Either Crizotinib or PF-06463922 in Patients With Advanced or Metastatic Non-Small
Cell Lung Cancer
Study Number: B9991005 (Javelin Lung 101)
Regulatory Agency or Public Disclosure Identifier Number:
US IND Number: 126,111
NCT ID: NCT02584634
EudraCT Number: 2015-001879-43
Study Phase: Phase 1b/2
Name of Study Intervention: Avelumab, Crizotinib, Lorlatinib
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: Final CSR (Last Participant Last Visit date) Version 1.0,
15 December 2022
Number of Study Center(s) and Investigator(s):A total of 43 participants were enrolled at 16 sites in 6 countries (2 of the sites in France did
not screen any participants). A list of study centers and investigators involved in this study isprovided in Appendix 16.1.4.1.
Publications:
Shaw AT, Lee S-H, Ramalingam SS, et al. Avelumab (anti-PD-L1) in combination withcrizotinib or lorlatinib in patients with previously treated advanced NSCLC: Phase 1b resultsfrom JAVELIN Lung 101. Journal of Clinical Oncology. 2018;36(15_suppl):9008-08.

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Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Study Period:
Study Initiation Date (First Participant First Visit): 18 December 2015.
Primary Completion Date: 02 February 2021.
Study Completion Date (Last Participant Last Visit): 13 July 2022.
On 05 June 2018, a Dear Investigator Letter was issued to notify the investigational sites thatno new participants could be screened or randomized.
Rationale:
The purpose of the study was to assess efficacy, safety, pharmacokinetics (PK) andpharmacodynamics (PD) of avelumab + crizotinib combination and avelumab + lorlatinib
combination in cohorts of adult participants with locally advanced or metastatic non-small
cell lung cancer (NSCLC).
Enrollment in the study was terminated early based on the changing landscape in treatment
options for treatment-naïve Anaplastic Lymphoma Kinase (ALK)-positive NSCLC. Thisdecision was not due to any safety concerns or regulatory interactions. All participants on
active treatment at the time of the early enrollment termination could continue treatment andfollow-up per the protocol. Participants could opt to be transitioned to the B9991046
continuation study if meeting the eligibility criteria.
Objectives, Endpoints, and Statistical Methods:
The study objectives and endpoints are presented in Table S1. Only Dose Level 0 (DL0) was
studied in both Group A and Group B, and no other doses were explored. The pre-specified
criterion to proceed to Phase 2 was not met for Group A. Given the small number ofparticipants in Group B (N=3) who received study intervention in Phase 2, applicablesummaries for Phase 1b and Phase 2 were combined.
Efficacy: The full analysis set was used for all efficacy analyses. Summaries were presented
separately for Group A and Group B. Best overall response (BOR) was summarized, andobjective response rate (ORR) and disease control rate (DCR) were calculated along with thecorresponding exact 2-sided 95% confidence intervals (CIs). Progression-free survival (PFS),
overall survival (OS), and duration of response (DR) were analyzed by the Kaplan-Meiermethod while time to tumor response (TTR) was summarized with descriptive statistics.
Safety: Summaries and analyses of the primary safety endpoint were based on thedose-limiting toxicity (DLT)-evaluable analysis set. All other summaries and analyses ofsafety parameters were based on the safety analysis set by treatment group. Safety data weresummarized using appropriate tabulations and descriptive statistics (pooling together
participants treated at the maximum tolerated dose [MTD] from both phases of the study).

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Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Pharmacokinetic: Standard plasma PK parameters for crizotinib and lorlatinib were estimatedusing non-compartmental analysis. Dose-normalized parameters were reported as
appropriate. Descriptive statistics for the PK parameters for crizotinib and PF-06260182 andlorlatinib were provided by dose, cycle, and day of assessment in tabular form.
Crizotinib, PF-06260182, and lorlatinib plasma concentrations were summarized
descriptively (n, mean, standard deviation [SD], coefficient of variation [CV], median,minimum, maximum, geometric mean, its associated CV, and 95% CI) by cycle, day andnominal time. Median profiles of crizotinib, PF-06260182, and lorlatinib concentration-timedata were plotted by cycle and day using nominal times.
Trough concentration (Ctrough) and maximum concentration (Cmax) for avelumab weresummarized descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean,
its associated CV, and 95% CI) by cycle and day. The trough concentrations for avelumab
were plotted for each dose using a box-whisker plot by cycle and day in order to assess theattainment of steady-state.
Immunogenicity: The analyses of immunogenicity data were based on the immunogenicity
analysis set by treatment group. Participants were characterized into different anti-drug
antibodies (ADA) categories based on the pre-defined criteria.
Biomarker: The biomarker analyses were based on the relevant biomarker analysis sets bytreatment group. For each biomarker or set of biomarkers, participants may be classified as
positive, negative, or some other category according to scoring algorithms and cut-offs
established from external sources. BOR was summarized for each biomarker category if
appropriate. The number of responders (participants with BOR of complete response [CR] or
partial response [PR]) was tabulated relative to biomarker classifications using a contingency
table and a Fisher’s exact test may be performed.

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Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints
Type
Primary
Safety (Phase 1b)

ObjectiveEfficacy (Phase 2)Secondary
Safety (Phases 1band 2)
Efficacy(Phases 1b and 2)
PK (Phases 1b and
2)





Endpoints

Group A (ALK-negative): To determine MTD and theRP2D of the combination of avelumab with crizotinib
Group B (ALK-positive): To determine the MTD and theRP2D of the combination of avelumab with lorlatinib
Group A: To assess ORR per RECIST v1.1 in previously
treated locally advanced or metastatic ALK-negative
NSCLC participants treated with the combination of
avelumab and crizotinib at the RP2DGroup B: To assess ORR and CR rate per RECIST v1.1
in previously untreated locally advanced or metastatic
ALK-positive NSCLC participants treated with the
combination of avelumab and lorlatinib at the RP2D

First 2 cycles DLTs for Group A and Group B

Confirmed OR per RECIST v.1.1 for Group A
Confirmed OR and CR per RECIST v.1.1 for Group B

To evaluate the safety and tolerability of avelumab in
combination with crizotinib (Group A) or withlorlatinib (Group B)
To assess antitumor activity of avelumab in combination
with crizotinib (Group A) or with lorlatinib (Group B)
To characterize the PK of avelumab in combination withcrizotinib (Group A) or with lorlatinib (Group B)AEs and laboratory test abnormalities as graded by NCI
CTCAE v4.03; vital signs (blood pressure, pulse rate)DC, DR, TTR, PFS per RECIST v1.1, and OS.

PK parameters of crizotinib, its metabolite PF-06260182,
avelumab and lorlatinib were determined as data permitted:
 Cmax, Tmax, AUCtau, AUClast, CL/F, Vz/F for crizotinib
following multiple dosing in the presence of avelumab Cmax, Tmax, AUCtau, MRAUCtau, and MRCmax for
PF-06260182 following multiple dosing in the presenceof avelumab Single and multiple dose PK (Cmax and Ctrough, plasma
concentration at the end of dosing interval) of avelumabin the presence of crizotinib and lorlatinib
 Cmax, Tmax, AUCtau, AUClast, CL/F, and Vz/F for lorlatinib
following multiple dosing in the presence of avelumab, if
data permitted

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Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints
Type
Immunogenicity(Phases 1b and 2)
Biomarker(Phases 1b and 2)



Objective
To assess the immunogenicity of avelumab

To evaluate candidate predictive biomarkers of sensitivity
or resistance to combination therapy in pretreatment
tumor tissue
Exploratory (Not Reported)
Efficacy
 To explore the antitumor effect of avelumab in
combination with crizotinib (Group A) or withlorlatinib (Group B) by irRECIST
Biomarker
 To explore the predictive and PD characteristics ofperipheral blood and additional tumor tissue biomarkers







Endpoints
Avelumab (ADA; nAb):
 ADA/nAb titers for avelumab given in combination withcrizotinib or lorlatinib
Tumor tissue biomarkers, including but not limited to, PD-L1
expression and tumor infiltrating CD8+ T cells by IHC

irOR per irRECISTPeripheral blood and additional tumor tissue biomarkers
consisting of the levels of cells, DNA, RNA or proteins that
may be related to anti-tumor immune response and/or
response to or disease progression on avelumab in
combination with either crizotinib or lorlatinib, such as
TNF-α, IFNγ and/or tissue FoxP3, PD-1, PD-L2
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; ALK = Anaplastic Lymphoma Kinase; AUClast = area under the concentration time
curve from time of dosing to the last collection time point; AUCtau = area under the plasma concentration time curve during the dosing interval time (tau);
CD8= cluster of differentiation 8; CL/F = apparent plasma clearance; Cmax = maximum concentration; CR = complete response; CTCAE = Common
Terminology Criteria for Adverse Events; Ctrough = trough concentration; DC = disease control; DLT = dose-limiting toxicity; DR = duration of response;
FoxP3 = forkhead box P3; IFN = interferon-gamma; IHC = immunohistochemistry; irOR = immune-related objective response; irRECIST = immunerelated RECIST; MRAUCtau = metabolite to parent ratio for AUCtau; MRCmax = metabolite to parent ratio for Cmax; MTD = maximum tolerated dose;
nAb = neutralizing antibody; NCI = National Cancer Institute; NSCLC = non-small cell lung cancer; OR = objective response; ORR = objective response
rate; OS = overall survival; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand-1; PD-L2 = programmed death ligand-2;
PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended Phase 2 dose;
Tmax = time for Cmax; TNF- = Tumor Necrosis Factor alpha; TTR = time to tumor response; Vz/F = apparent volume of distribution.
Summaries for Phase 2 alone were not performed due to the small number of participants receiving study intervention in Phase 2. Summaries wereinstead based on Phase 1b and Phase 2 combined, if applicable.
Exploratory endpoint analyses were not conducted for this study as enrollment was terminated.

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Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Methodology:
This was a Phase 1b/2, open-label, multi-center, multiple-dose, safety, PK and PD study ofGroup A (avelumab + crizotinib combination) and Group B (avelumab + lorlatinib
combination) in cohorts of adult participants with locally advanced or metastatic NSCLC(Figure S1). The study included Screening, Treatment Period, safety follow-up, and longterm Follow-Up. Safety follow-up period was up to 90 days after the last study treatment.
Additional long-term follow-up was collected until death, lost to follow up, study terminationby sponsor, or withdrawal by subject.
This is the final clinical study report (CSR) synopsis, reporting data as of last participant lastvisit (LPLV, ie, 13 July 2022).
Figure S1. Study Schema

Abbreviations: ALK = Anaplastic Lymphoma Kinase; MTD = maximum tolerated dose; ORR = objective
response rate; PD = pharmacodynamic(s); PD-1 = programmed death receptor 1; PK = pharmacokinetic(s);RP2D = recommended Phase 2 dose.
Group A (avelumab + crizotinib combination) included the participants with previously treated locallyadvanced or metastatic ALK-negative NSCLC.
Group B (avelumab + lorlatinib combination) included the participants with locally advanced or metastatic
ALK-positive NSCLC. Group B Phase 2 was limited to participants who were treatment-naïve for locallyadvanced or metastatic disease.

Number of Participants (planned and analyzed):
On 05 June 2018, a Dear Investigator Letter was issued to notify the investigational sites thatno new participants could be screened or randomized. Enrollment in the study wasterminated early based on the changing landscape in treatment options for treatment-naïve
ALK-positive NSCLC. This decision was not due to any safety concerns or regulatoryinteractions. All participants on active treatment at the time of the early enrollment
termination could continue treatment and follow-up per the protocol. A total of
43 participants were enrolled and treated in the study (12 participants in Group A and
31 participants in Group B). The analysis data sets are presented in Table S2.
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Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS

Table S2. Analysis Data Sets - All Screened Participants (Protocol B9991005)

Screened
Full analysis set [1]Safety analysis set [2]DLT-evaluable analysis set [3]Avelumab PK concentration
analysis set [4]Crizotinib PK concentration
analysis set [4]Lorlatinib PK concentration
analysis set [4]Crizotinib PK parameter
analysis set [5]Lorlatinib PK parameter
analysis set [5]Immunogenicity analysis set [6]PD-L1 Biomarker analysis set[7]
CD8 Biomarker analysis set [7]Avelumab 10mg/kg IV Q2W +Crizotinib 250mg PO BIDn (%)

Avelumab 10mg/kg IV Q2W +Lorlatinib 100mg PO QD
n (%)

Total
n (%)

12
12 (100.0)
12 (100.0)
12 (100.0)31
31 (100.0)
28 ( 90.3)
31 (100.0)

66
43
43 (100.0)
40 ( 93.0)
43 (100.0)

12 (100.0)0

12 ( 27.9)

031 (100.0)

31 ( 72.1)

10 ( 83.3)

0

10 ( 23.3)

026 ( 83.9)

26 ( 60.5)

12 (100.0)
9 ( 75.0)

31 (100.0)
24 ( 77.4)

43 (100.0)
33 ( 76.7)

10 ( 83.3)

22 ( 71.0)

32 ( 74.4)

The denominator to calculate percentages is the number of participants in the full analysis set within each treatment group.
[1] Full analysis set: participants who received at least one dose of study drug.
[2] Safety analysis set: participants who received at least one dose of study drug.
[3] DLT-evaluable analysis set: participants enrolled in phase 1b who are in the safety analysis set, and either experience
DLT during the first 2 cycles (28 days), or complete the observation period for the first 2 cycles of treatment.
[4] PK concentration analysis set: participants in the safety analysis set who have at least one post-dose concentration
measurement above the lower limit of quantitation (LLQ) for avelumab, crizotinib or lorlatinib respectively.
[5] PK parameter analysis set: participants in the safety analysis set who have at least one of the PK parameters of interestfor crizotinib or lorlatinib respectively.
[6] Immunogenicity analysis set: participants in the safety analysis set who have at least one ADA/nAb sample result.
[7] Biomarker analysis set: participants in the safety analysis set who have at least one screening biomarker assessment for
PD-L1 or CD8 respectively.
PFIZER CONFIDENTIAL SDTM Creation: 10AUG2022 (07:03) Source Data: adsl Table Generation: 02SEP2022(04:41)(Cutoff date : 13JUL2022 Snapshot date : 09AUG2022) Output File: ./B9991005/B9991005_CSR/adsl_s002
Table 14.1.1.1 is for Pfizer internal use.

Diagnosis and Main Criteria for Inclusion and Exclusion:
Enrolled in this study were participants with locally advanced or metastatic NSCLC;
previously treated locally advanced or metastatic ALK-negative-NSCLC for Group A, andlocally advanced or metastatic ALK-positive NSCLC for Group B. Group B Phase 2 waslimited to participants who were treatment-naïve.
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Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Study Interventions, Dose, Mode of Administration, and Batch Number(s):The study interventions used in this study were avelumab, crizotinib and lorlatinib, suppliedby Pfizer. The avelumab + crizotinib combination was administered for Group A, and theavelumab + lorlatinib combination for Group B. A cycle was defined as 14 days, regardlessof missed doses or dose delays.
Avelumab was formulated as a 20 mg/mL solution, and intended for intravenous (IV)administration. The starting dose of avelumab was 10 mg/kg IV every 2 weeks(Q2W) for both Group A and Group B.

Crizotinib was supplied for oral administration as 200 mg or 250 mg capsules. The
starting dose of crizotinib in Group A was 250 mg twice daily (BID).



Lorlatinib was supplied for oral administration as 25 mg tablets. The starting dose oflorlatinib in Group B was 100 mg once daily (QD).

The manufacturing lot numbers for the study interventions dispensed in this study areprovided in Table S3.

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Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Table S3. Study Interventions Administered
Investigational Product Description
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
MSB0010718C Solution for Infusion,
20 mg/mL (10 mL/vial)
PF-06463922 25 mg Round White
Film-Coated Tablet
PF-06463922 25 mg Round White
Film-Coated Tablet
PF-06463922 25 mg Round White
Film-Coated Tablet
PF-06463922 25 mg Round White
Film-Coated Tablet
PF-06463922 25 mg Round White
Film-Coated Tablet
PF-06463922 25 mg Round White
Film-Coated Tablet

Vendor Lot
Number

Pfizer Lot
NumberStrength/
Potency

Dosage Form

AU018962

18-000772

200 mgSolution

PD1E002

15-002315

200 mgSolution

PD1F004

15-006068

200 mgSolution

PD1F01116-000913

200 mgSolution

PD1G005

16-004671

200 mgSolution

PD1J001

18-002394

200 mgSolution

PD1J008

19-000790

200 mgSolution

20-DP-00118

20-000099

25 mg

TabletN/A

15-002606

25 mg

TabletN/A

15-004169

25 mg

TabletN/A

15-007544

25 mg

TabletN/A

16-004078

25 mg

TabletN/A

18-002755

25 mg

TabletDuration of Study Intervention:
Avelumab, crizotinib and lorlatinib were administered in 14-day cycles. MTD and RP2D
were planned to be identified for both Group A and Group B, and a dose expansion was alsoplanned for Group B in Phase 1b. Participants meeting pre-specified criterion were enrolled
in Phase 2. Planned duration of study interventions were not defined.
Summary of Results:
Demographic and Other Baseline Characteristics:
The majority of the participants were Asian (58.1% of participants) or White (39.5% ofparticipants). The mean (SD) body weight was 66.3 (17.89) kg. The mean (SD) body massindex (BMI) was 24.2 (5.08) kg/m2. Most of the histology treated was adenocarcinoma(90.7% of participants). Most participants (40 out of 43) had a baseline Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0 or 1.

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CLINICAL STUDY REPORT SYNOPSIS
Exposure:
The median duration of exposure was 15.0 weeks for avelumab and 6.1 weeks for crizotinib
in Group A. The median duration of exposure was 42.0 weeks for avelumab and 45.9 weeks
for lorlatinib in Group B.
Efficacy Results:
Primary endpoint:Of the 12 participants in Group A, no participant had a BOR of confirmed CR and
3 participants had a BOR of confirmed PR. Of the 31 participants in Group B,
1 participant had a BOR of confirmed CR and 15 participants had a BOR of confirmed
PR. The confirmed ORR was 25.0% (95% CI: 5.5%, 57.2%) for Group A and 51.6%(95% CI: 33.1%, 69.8%) for Group B.

Secondary endpoints:


The DCR was 58.3% in Group A, and 71.0% in Group B.

Of the 12 participants in Group A, 10 (83.3%) participants were reported with a death.
The Kaplan-Meier estimate of median OS was 16.4 months (95% CI: 5.4, 27.6). Of the
31 participants in Group B, 15 (48.4%) participants were reported with a death. The
Kaplan-Meier estimate of median OS was 32.9 months (95% CI: 10.7, not evaluable[NE]).

All 12 participants in Group A had a subsequent PFS event (all had progressive disease).
The Kaplan-Meier estimate of median PFS was 3.7 months (95% CI: 1.5, 5.5). Of the
31 participants in Group B, 23 (74.2%) had subsequent PFS events (22 had progressive
disease and 1 died). The Kaplan-Meier estimate of median PFS was 6.4 months (95% CI:
3.7, 9.2).

The median TTR was 1.4 months (range: 1.4, 6.9) among 3 responders in Group A and
1.8 months (range: 1.3, 3.7) among 16 responders in Group B.

All the 3 participants with confirmed CR or PR in Group A had progressive disease. The
Kaplan-Meier estimate of median DR was 3.7 months (95% CI: 3.7, 4.6). Of the 16
participants with confirmed CR or PR in Group B, 10 had progressive disease, and none
had reported death. The Kaplan-Meier estimate of median DR was 14.7 months (95% CI:
3.7, NE).

Safety Results:
Dose-Limiting Toxicities: Of the 12 DLT-evaluable participants in Group A, 5 (41.7%)
participants were reported to have at least 1 DLT. Of the 28 DLT-evaluable participants inGroup B, 2 (7.1%) participants were reported to have a DLT. The MTD was exceeded at
avelumab 10 mg/kg IV Q2W + crizotinib 250 mg BID orally for Group A, and no dose
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Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
de-escalation was suggested as per the mTPI method. MTD/RP2D was determined as
avelumab 10 mg/kg IV Q2W + lorlatinib 100 mg QD orally for Group B. The RP2D wasused in Phase 2 for Group B. The pre-specified criterion to proceed to Phase 2 was not met
for Group A.
Adverse Events: An overview of the treatment-emergent adverse events (TEAEs) ispresented in Table S4.

Table S4. Summary of Adverse Events During the On-Treatment Period - Safety
Analysis Set (Protocol B9991005)

Number (%) of ParticipantsParticipants with TEAEs
Participants with grade ≥ 3 TEAEs
Participants with treatment-related TEAEs
Participants with grade ≥ 3 treatment-related
TEAEs
Participants with serious TEAEs
Participants with serious treatment-related
TEAEs
Participants with TEAEs leading todiscontinuation of avelumab
Participants with TEAEs leading todiscontinuation of crizotinib
Participants with TEAEs leading todiscontinuation of lorlatinib
Participants with TEAEs leading todiscontinuation of any study drug
Participants with TEAEs leading todiscontinuation of all study drugs
Participants with treatment-related TEAEs
leading to discontinuation of avelumab
Participants with treatment-related TEAEs
leading to discontinuation of crizotinib
Participants with treatment-related TEAEs
leading to discontinuation of lorlatinib
Participants with TEAEs leading to death
Participants with treatment-related TEAEs
leading to death
Participants with infusion-related reactions(IRRs)Avelumab 10 mg/kg IV Q2W +Crizotinib 250 mg PO BID(N=12)n (%)

Avelumab 10 mg/kg IV Q2W +Lorlatinib 100 mg PO QD(N=31)n (%)

12 (100.0)
7 (58.3)
12 (100.0)
6 (50.0)30 (96.8)
23 (74.2)
28 (90.3)
16 (51.6)

5 (41.7)
2 (16.7)

21 (67.7)
6 (19.4)

3 (25.0)

10 (32.3)

6 (50.0)00

2 (6.5)6 (50.0)

10 (32.3)

3 (25.0)

1 (3.2)2 (16.7)

9 (29.0)

5 (41.7)

002 (6.5)1 (8.3)0

4 (12.9)
1 (3.2)5 (41.7)

9 (29.0)

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CLINICAL STUDY REPORT SYNOPSIS
Table S4. Summary of Adverse Events During the On-Treatment Period - Safety
Analysis Set (Protocol B9991005)

Number (%) of Participants

Avelumab 10 mg/kg IV Q2W +Crizotinib 250 mg PO BID(N=12)n (%)

Avelumab 10 mg/kg IV Q2W +Lorlatinib 100 mg PO QD(N=31)n (%)

The denominator to calculate percentages is N, the number of participants in the safety analysis set within each treatmentgroup.
Treatment-related AEs include AEs related to at least one study drug in the combination.
Any study drug = at least one study drug in the combination. All study drugs = all study drugs in the combination.
MedDRA (v25.0) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 10AUG2022 (07:25) Source Data: adae Table Generation: 26SEP2022(11:48)(Cutoff date : 13JUL2022 Snapshot date : 09AUG2022) Output File: ./B9991005/B9991005_CSR/adae_s020
Table 14.3.1.2.1 is for Pfizer internal use.

In Group A, the most frequent all-causality TEAE of any grade was Nausea (7 [58.3%]
participants), which was considered to be treatment related in all participants. The mostfrequent all-causality TEAE of Grade ≥3 was Alanine aminotransferase increased(2 [16.7%] participants), which was considered to be treatment related for both participants.
In Group B, the most frequent all-causality TEAE of any grade was Blood cholesterol
increased (19 [61.3%] participants), which was considered to be treatment related in allparticipants. The most frequent all-causality TEAEs of Grade ≥3 were Lipase increased andHypertriglyceridaemia (4 [12.9%] participants each). The most frequent treatment-related
TEAE of Grade ≥3 was Hypertriglyceridaemia (4 [12.9%] participants).
Ten (83.3%) participants in Group A and 15 (48.4%) participants in Group B died. The
primary cause of death was disease progression (6 [50.0%] participants in Group A and13 [41.9%] participants in Group B). Most deaths (9 out of 10 deaths in Group A and 12 out
of 15 deaths in Group B) occurred more than 30 days following the last dose of study
intervention. During the on-treatment period, 1 (8.3%) participant in Group A had a TEAE
leading to death, which was not considered to be treatment related. Four (12.9%) participantsin Group B had TEAEs leading to death, with Dyspnoea for 1 participant consideredtreatment related.
In Group A, 5 (41.7%) participants experienced all-causality serious adverse events (SAEs).
Each SAE was reported in 1 (8.3%) participant. Treatment-related SAEs were reported in
2 (16.7%) participants. In Group B, 21 (67.7%) participants experienced all-causality SAEs.
Treatment-related SAEs were reported in 6 (19.4%) participants.
A total of 6 (50.0%) participants in Group A and 10 (32.3%) participants in Group B
experienced all-causality TEAEs leading to permanent discontinuation of any study drug.
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Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Infusion-related reaction (IRRs) of any grade were reported in 5 (41.7%) participants inGroup A and 9 (29.0%) participants in Group B. No Grade ≥3 IRRs were reported inGroup A, and 1 (3.2%) participant in Group B had Grade ≥3 IRR.
Pharmacokinetic Results:
Avelumab PK: Serum maximum concentrations of avelumab were similar between Cycle 1
Day 1 and Cycle 2 Day 1. Serum trough concentrations of avelumab appeared to reach steadystate which were above 10 µg/mL at Cycle 2. The serum concentrations of avelumab tended
to be comparable across participants in each treatment group (Group A and Group B).
Crizotinib and Metabolite PF-06260182 PK: Crizotinib and its metabolite PF-06260182
exposures as measured by AUCtau and Cmax values following co-administration of avelumab
were reported. Crizotinib exposure in combination with avelumab was in the range of that
following administration of crizotinib alone (historical data). The variability of crizotinib
CL/F (based on %CV) was high due to the small sample size.
Lorlatinib PK: Lorlatinib exposures as measured by AUCtau, AUClast and Cmax values
following co-administration of avelumab were reported. Lorlatinib steady-state plasma PK in
combination with avelumab was similar to those following administration of lorlatinib alone(historical data).
Other Results:
Biomarker: In Group A, a total of 9 participants were evaluable for programmed deathligand-1 (PD-L1) biomarker analysis; 7 participants were PD-L1 positive and 2 participants
were PD-L1 negative. None of the participants evaluable for PD-L1 biomarker analysis inGroup A were responders (BOR of CR or PR), regardless of PD-L1 status. The DCR was
similar between the PD-L1 positive and negative subgroups (42.9% and 50.0%,
respectively).
In Group B, a total of 24 participants were evaluable for PD-L1 biomarker analysis;
20 participants were PD-L1 positive and 4 participants were PD-L1 negative. The ORR wasnumerically lower in the PD-L1 positive subgroup (50.0%) compared with the PD-L1
negative subgroup (75.0%). The DCR was numerically lower in PD-L1 positive subgroup(65.0%) compared with the PD-L1 negative subgroup (75.0%).
In Group A, a total of 10 participants were evaluable for cluster of differentiation 8 (CD8)biomarker analysis; 6 participants were CD8 positive and 4 participants were CD8 negative.
None of the CD8 positive participants evaluable for CD8 biomarker analysis in Group A
were responders (BOR of CR or PR). The ORR was 25.0% for the CD8 negative subgroup.
The DCR was identical between the CD8 positive and negative subgroups (50.0% for both).
In Group B, a total of 22 participants were evaluable for CD8 biomarker analysis;
4 participants were CD8 positive and 18 participants were CD8 negative. The ORR was
higher in the CD8 positive subgroup (50.0%) compared with the CD8 negative subgroup
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Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS(44.4%). The DCR was higher in CD8 positive subgroup (75.0%) compared with the CD8
negative subgroup (61.1%).
Immunogenicity: Among 12 participants with at least one valid post-baseline ADA result andwithout positive baseline ADA result in Group A, 3 (25.0%) participants developed
treatment-induced ADA by avelumab, and of these, 2 participants had persistent ADA
response.
Among 30 participants with at least one valid post-baseline ADA result and without positive
baseline ADA result in Group B, 6 (20.0%) participants developed treatment-induced ADA
by avelumab, and of these, 3 participants had persistent ADA response.
Due to the low observed immunogenicity rate, nAb analysis was not conducted.
Conclusions:
Efficacy

For Group A (avelumab + crizotinib), minimal anti-tumor activity was observed inparticipants with locally advanced or metastatic ALK-negative NSCLC.

For Group B (avelumab + lorlatinib), anti-tumor activity was observed in participants
with locally advanced or metastatic ALK-positive NSCLC; however, there were notsufficient data to determine whether this anti-tumor activity was clinically significant
when compared to historical lorlatinib monotherapy in participants with treatment-naïve
ALK-positive NSCLC.

Safety

The MTD was exceeded at avelumab 10 mg/kg IV Q2W + crizotinib 250 mg BID orally
for Group A, and no dose de-escalation was suggested as per the mTPI method. The
MTD/RP2D was determined as avelumab 10 mg/kg IV Q2W + lorlatinib 100 mg QD
orally for Group B. The RP2D was used in Phase 2 for Group B. The pre-specified
criterion to proceed to Phase 2 was not met for Group A.



Safety profiles of the combination regimens tested were characterized by manageable
toxicities and were generally consistent with the known safety profile of each agent in the
combination. No new safety concerns for avelumab, crizotinib or lorlatinib wereidentified in the treatment combinations on study.

PKCo-administration of IV doses of avelumab with multiple oral doses of crizotinib or
lorlatinib had no clinically meaningful effect on the exposure of crizotinib or lorlatinib.

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Page 14Final Abbreviated Clinical Study Report
Protocol B9991005 (Javelin Lung 101)

CLINICAL STUDY REPORT SYNOPSIS
Immunogenicity


The observed incidence of treatment-induced ADA response to avelumab was 25.0% for
avelumab + crizotinib combination and 20.0% for avelumab + lorlatinib combination,
which tended to be comparable across other studies.

Biomarker
There appeared to be no meaningful differences in the proportion of participants inGroup A and Group B achieving an objective response whose tumors were PD-L1
positive versus those whose tumors were PD-L1 negative. Similarly, there appeared to be
no meaningful differences in the proportion of participants in Group A and Group B with
CD8 positive versus CD8 negative cells achieving an objective response. However, due
to the small number of participants, a valid conclusion cannot be determined.

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