Study to Evaluate Safety, Efficacy, Pharmacokinetics And Pharmacodynamics Of Avelumab In Combination With Either Crizotinib Or PF-06463922 In Patients With NSCLC. (Javelin Lung 101)

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02584634
• Collaborator: (none)
• Enrollment: 43
• Locations: 21
• Arms: 2
• Anticipated Duration (Months): 77.1
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of avelumab when combined with either crizotinib or PF-06463922.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer	Drug: Avelumab; Drug: PF-06463922; Drug: Crizotinib	Phase 1/Phase 2

Detailed Description

This is a Phase 1b/2, open label, multi center, multiple dose, safety, pharmacokinetic and pharmacodynamic study of Group A and Group B in cohorts of adult patients with locally advanced or metastatic NSCLC.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Non-Randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Dec 18, 2015
• Actual Primary Completion Date: Feb 2, 2021
• Anticipated Study Completion Date: May 22, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A ALK negative Non-Small Cell Lung Cancer	Drug: Avelumab; Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg; Other Names: MSB0010718C ; Drug: Crizotinib; Capsules. Taken orally once or twice every day in doses of either 200mg or 250mg.; Other Names: PF-02341066
Experimental: Group B ALK positive Non-Small Cell Lung Cancer	Drug: Avelumab; Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg; Other Names: MSB0010718C ; Drug: PF-06463922; Tablets taken orally once every day in doses of either 100mg, 75mg, or 50mg.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-limiting Toxicities (DLTs): Phase 1b [First 2 cycles (1 cycle = 14 days)]

   Any of the following adverse events (AEs) occurring during the primary DLT observation period that are attributable to one, the other, or both study drugs were classified as DLTs: Grade 4 (life-threatening) neutropenia if >7 days in duration; febrile neutropenia; Grade >=3 (severe or life threatening) neutropenic infection; Grade >=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia >7 days; Grade 4 anemia; any Grade >=3 toxicity, except for any of the following: transient (<=6 hours) Grade 3 (severe) flu like symptoms or fever; transient (<=24 hours) Grade 3 fatigue, local reactions, or headache that resolved to Grade <=1 (no AE or mild AE); Grade 3 nausea and/or vomiting, diarrhea or skin toxicity that resolved to Grade <=1 within 7 days; any Grade >=3 amylase or lipase abnormality; tumor flare phenomenon; single laboratory values out of normal range that were not related to treatment, did not have any clinical correlate, and resolve to Grade <=1 within 7 days.

2. Percentage of Participants With Objective Response (OR): Phase 2 [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   OR is defined as complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 from start date (the date of first dose of study treatment) until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm and all lymph nodes must be non-pathological in size (<10 mm short axis). PR is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

3. Percentage of Participants With CR for Group B: Phase 2 [Baseline up to 60 months]

   Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm and all lymph nodes must be non-pathological in size (<10 mm short axis).

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Baseline up to 30 days after last dose of study treatment or the day before start day of new anti-cancer therapy (maximum of 5 years)]

   TEAEs are those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period. Treatment-related AEs was any untoward medical occurrence attributed to study drug in a participant who received study drug. Per NCI CTCAE v4.03: Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment; Grade 4 (Life-threatening) events caused participant to be in imminent danger of death; Grade 5 (Death) events=death related to an AE. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in participant hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

2. Number of Participants With Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 Per NCI CTCAE v4.03 [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   The laboratory results were graded according to the NCI CTCAE v4.03 severity grade. Grade 1=mild AE. Grade 2=moderate AE. Grade 3=severe AE. Grade 4=life-threatening consequences; urgent intervention indicated. Shift tables were provided to examine the distribution of laboratory toxicities. The following parameters had met the criteria of CTCAE grade shift change from Grade <=2 at baseline to Grade 3 or 4 post baseline: anemia, lymphocyte count decreased, lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, Creatine phosphokinase (CPK) increased, Gamma glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hypermagnesemia, hypertriglyceridemia, hypoalbuminemia, hyponatremia, lipase increased, serum amylase increased. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment.

3. Number of Participants With Vital Signs Meeting Pre-defined Criteria [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   Pre-defined criteria in vital signs: pulse rate >120 beats per minute (bpm), sitting diastolic blood pressure (DBP) increase and decrease in change from baseline of >= 20 millimeter of mercury (mmHg), sitting systolic blood pressure(SBP) < 90 mmHg, increase and decrease in change from baseline of >= 30mmHg. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment.

4. Disease Control Rate (DCR) [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   DC is defined as objective response (CR or PR) or stable disease (SD) per RECIST v.1.1 from the date of first dose of study treatment until disease progression or death due to any cause. The DCR is the proportion of patients with DC. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm. PR is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions.

5. Duration of Response (DR) [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   DR: time from first documented occurrence of response (PR or CR) until date of first documented PD or death due to underlying cancer. Per RECIST 1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions; any pathological lymph nodes assigned as target lesions/non-target lesions have a reduction in short axis to <10 mm. PR: at least a >=30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. PD: at least a >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of new lesions. Participants with no PD and were still alive by 02 Feb 2020, were censored at last adequate tumor assessment. Kaplan-Meier method was used for DR analysis.

6. Time to Tumor Response (TTR) [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   TTR is defined, for participants with an objective response (CR or PR), as the time from the start date (the date of first dose of treatment) to the first documentation of objective response (CR or PR) which is subsequently confirmed. Per RECIST v1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters.

7. Progression-free Survival (PFS) [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   PFS is defined as the time from start date (the date of first dose of treatment) to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurs first. Per RECIST v1.1: PD: a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

8. Kaplan-Meier Estimates of Overall Survival (OS) [Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)]

   OS is defined as the time from start date (the date of first dose of treatment) to the date of death due to any cause.

9. Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

   Cmax of crizotinib in the presence of avelumab was observed directly from data.

10. Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    Tmax of crizotinib in the presence of avelumab was observed directly from data as time of first occurrence.

11. Area Under The Plasma Concentration-Time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    AUCtau of crizotinib in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval is defined as after single dose from time zero to the next dose (after single dose and at steady state).

12. Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

13. Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    Cmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data.

14. Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    Tmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data as time of first occurrence.

15. AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    AUCtau of crizotinib metabolite PF-06260182 in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state).

16. Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    MRAUCtau of metabolite PF-06260182 in the presence of avelumab was caculated (MRAUCtau=Metabolite AUCtau/parent AUCtau). Parent=crizotinib, metabolite=PF-06260182

17. Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2]

    MRCmax of metabolite PF-06260182 in the presence of avelumab was caculated (MRCmax=Metabolite Cmax/parent Cmax). Parent=crizotinib, metabolite=PF-06260182

18. Cmax of Lorlatinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2]

    Cmax of lorlatinib in the presence of avelumab was observed directly from data.

19. Tmax of Lorlatinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2]

    Tmax of lorlatinib in the presence of avelumab was observed directly from data.

20. AUCtau of Lorlatinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2]

    AUCtau of lorlatinib in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state).

21. Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2]

    AUClast of lorlatinib in the presence of avelumab.

22. CL/F of Lorlatinib in The Presence of Avelumab [Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2]

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

23. Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab [Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 1 Day 1.]

    Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B.

24. Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab [Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 2 Day 1]

    Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B.

25. Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab [Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, and 47.]

    Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of crizotinib was observed directly from the data in Group A.

26. Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab [Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, 41, and 47.]

    Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of lorlatinib was observed directly from the data in Group B.

27. Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status [Day 1 of Cycles 1-5, then every 12 weeks thereafter, end of treatment/withdrawal, and 30 days after last avelumab dose (up to a maximum of 5 years)]

    ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Baseline is defined as the last assessment on or prior to the date/time of the first dose of avelumab.

28. Number of Participants With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression [Baseline]

    PD-L1 protein expression is determined by using Combined Positive Score (CPS), which is the percentage of viable tumor and tumor-infiltrated immune cells (restricted to lymphocytes and macrophages) within or directly associated with tumor cell strands showing partial or complete membrane staining using the SP263 antibody. Positive is defined as CPS>=1% and negative is defined as CPS <1%.

29. Number of Participants With Positive Tumor Infiltrating CD8+ Lymphocytes [Baseline]

    Tumor infiltrating CD8+ lymphocytes is defined as the number of CD8+ cells per unit area and the percent of counted cells. Positive is defined as >=1% and negative is defined as <1%.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• Inclusion Criteria

• Diagnosis of advanced or metastatic NSCLC. Group A must be ALK negative NSCLC and Group B must be ALK positive NSCLC

• Group A at least one prior regimen of therapy

• Group B any number of prior regimens.

• Mandatory tumor tissue available

• At least one measurable lesion

• ECOG Performance status 0 or 1

• Adequate bone marrow, renal, liver and pancreatic function

• Negative pregnancy test for females of childbearing potential

• Group B Phase 2: No prior systemic treatment for advanced or metastatic disease (adjuvant and/or neoadjuvant therapies are allowed if completed at least 6 months prior to study entry. No prior tyrosine kinase inhibitor therapy is allowed at any time prior to study entry)

Exclusion Criteria:

• No prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody.

• No Severe or Chronic medical conditions including gastrointestinal abnormalities or significant cardiac history

• No active infection requiring systemic therapy

• Prior organ transplantation including allogenic stem cell transplantation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
2	Emory University Hospital	Atlanta	Georgia	United States	30322
3	The Emory Clinic	Atlanta	Georgia	United States	30322
4	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114-2696
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Ophthalmic Consultants of Boston Inc (OCB)	Boston	Massachusetts	United States	02114
8	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
9	Chris O'Brien Lifehouse	Camperdown	New South Wales	Australia	2050
10	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
11	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
12	Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
13	Aichi cancer center central hospital	Nagoya	Aichi	Japan	464-8681
14	National Hospital Organization Kyushu Cancer Center	Fukuoka		Japan	811-1395
15	The Cancer Institute Hospital of JFCR	Koto-ku, Tokyo		Japan	135-8550
16	National Cancer Center	Goyang-Si	Gyeonggi-do	Korea, Republic of	10408
17	Asan Medical Center	Seoul		Korea, Republic of	05505
18	Samsung Medical Center	Seoul		Korea, Republic of	06351
19	Institut Catala d'Oncologia de Badalona	Badalona	Barcelona	Spain	08916
20	Hospital Quiron Barcelona	Barcelona		Spain	08023
21	Hospital Universitari de la Vall d'Hebron	Barcelona		Spain	08035

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Jun 30, 2017
• Statistical Analysis Plan - Jul 12, 2019

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02584634
• Other Study ID Numbers: B9991005; 2015-001879-43; JAVELIN LUNG 101
• First Posted: Oct 22, 2015
• Last Update Posted: Feb 9, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pfizer: Non-Small Cell Lung Cancer; NSCLC; ALK; avelumab; crizotinib; PF-06463922
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Avelumab; Crizotinib

Study Results

Participant Flow

Pre-assignment Detail	Forty-three participants were assigned to the treatment, of which 12 participants in Group A and 31 participants in Group B. The results are reported based on data available on primary completion date (02 Feb 2021).

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Period Title: Overall Study
STARTED	12	31
COMPLETED	0	0
NOT COMPLETED	12	31

Baseline Characteristics

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib	Total
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.	Total of all reporting groups
Overall Participants	12	31	43
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.67 (10.43)	53.32 (11.59)	54.81 (11.41)
Age, Customized (Number) [Number]
<65 years	9 75%	25 80.6%	7 16.3%
65-<75 years	2 16.7%	5 16.1%	2 4.7%
75-<85 years	1 8.3%	1 3.2%	2 4.7%
Sex: Female, Male (Count of Participants)
Female	6 50%	19 61.3%	25 58.1%
Male	6 50%	12 38.7%	18 41.9%
Race/Ethnicity, Customized (Number) [Number]
American Indian or Alaska Native	0 0%	1 3.2%	1 2.3%
Asian	8 66.7%	17 54.8%	25 58.1%
White	4 33.3%	13 41.9%	17 39.5%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	0 0%	1 3.2%	1 2.3%
Not Hispanic or Latino	11 91.7%	30 96.8%	41 95.3%
Not Reported	1 8.3%	0 0%	1 2.3%
Age Range (Years) [Median (Full Range) ]
Median (Full Range) [Years]	59.5	54	55

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-limiting Toxicities (DLTs): Phase 1b
Description	Any of the following adverse events (AEs) occurring during the primary DLT observation period that are attributable to one, the other, or both study drugs were classified as DLTs: Grade 4 (life-threatening) neutropenia if >7 days in duration; febrile neutropenia; Grade >=3 (severe or life threatening) neutropenic infection; Grade >=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia >7 days; Grade 4 anemia; any Grade >=3 toxicity, except for any of the following: transient (<=6 hours) Grade 3 (severe) flu like symptoms or fever; transient (<=24 hours) Grade 3 fatigue, local reactions, or headache that resolved to Grade <=1 (no AE or mild AE); Grade 3 nausea and/or vomiting, diarrhea or skin toxicity that resolved to Grade <=1 within 7 days; any Grade >=3 amylase or lipase abnormality; tumor flare phenomenon; single laboratory values out of normal range that were not related to treatment, did not have any clinical correlate, and resolve to Grade <=1 within 7 days.
Time Frame	First 2 cycles (1 cycle = 14 days)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants enrolled in Phase 1b who were in the safety analysis set (all participants who received at least one dose of study drug), and either experienced DLT during the first 2 cycles (1 cycle = 14 days), or completed the observation period for the first 2 cycles of treatment.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	28
Count of Participants [Participants]	5 41.7%	2 6.5%

2. Primary Outcome

Title	Percentage of Participants With Objective Response (OR): Phase 2
Description	OR is defined as complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 from start date (the date of first dose of study treatment) until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm and all lymph nodes must be non-pathological in size (<10 mm short axis). PR is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Number (95% Confidence Interval) [Percentage of participants]	25.0 208.3%	51.6 166.5%

3. Primary Outcome

Title	Percentage of Participants With CR for Group B: Phase 2
Description	Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm and all lymph nodes must be non-pathological in size (<10 mm short axis).
Time Frame	Baseline up to 60 months

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug in Group B. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received. Results for Group A are not reported for this outcome measure according to the protocol.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants (treatment naive) with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	31
Number [Percentage of participants]	3.2 26.7%

4. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	TEAEs are those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period. Treatment-related AEs was any untoward medical occurrence attributed to study drug in a participant who received study drug. Per NCI CTCAE v4.03: Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment; Grade 4 (Life-threatening) events caused participant to be in imminent danger of death; Grade 5 (Death) events=death related to an AE. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in participant hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame	Baseline up to 30 days after last dose of study treatment or the day before start day of new anti-cancer therapy (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one study treatment, the participant were classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Participants with TEAEs	12 100%	30 96.8%
Participants with Grade >= 3 TEAEs	7 58.3%	22 71%
Participants with treatment-related TEAEs	12 100%	28 90.3%
Participants with Grade >= 3 treatment-related TEAEs	6 50%	16 51.6%
Participants with SAEs	5 41.7%	19 61.3%
Participants with treatment-related SAEs	2 16.7%	6 19.4%
Participants with TEAEs leading to discontinuation of avelumab	3 25%	9 29%
Participants with TEAEs leading to discontinuation of crizotinib	6 50%
Participants with TEAEs leading to discontinuation of lorlatinib	2 16.7%
Participants with TEAEs leading to discontinuation of any study drug	6 50%	9 29%
Participants with TEAEs leading to discontinuation of all study drugs	3 25%	1 3.2%
Participants with treatment-related TEAEs leading to discontinuation of avelumab	2 16.7%	8 25.8%
Participants with treatment-related TEAEs leading to discontinuation of crizotinib	5 41.7%
Participants with treatment-related TEAEs leading to discontinuation of lorlatinib	2 16.7%
Participants with TEAEs leading to death	1 8.3%	3 9.7%
Participants with treatment-related TEAEs leading to death	0 0%	1 3.2%

5. Secondary Outcome

Title	Number of Participants With Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 Per NCI CTCAE v4.03
Description	The laboratory results were graded according to the NCI CTCAE v4.03 severity grade. Grade 1=mild AE. Grade 2=moderate AE. Grade 3=severe AE. Grade 4=life-threatening consequences; urgent intervention indicated. Shift tables were provided to examine the distribution of laboratory toxicities. The following parameters had met the criteria of CTCAE grade shift change from Grade <=2 at baseline to Grade 3 or 4 post baseline: anemia, lymphocyte count decreased, lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, Creatine phosphokinase (CPK) increased, Gamma glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hypermagnesemia, hypertriglyceridemia, hypoalbuminemia, hyponatremia, lipase increased, serum amylase increased. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug and who could be evaluated for CTCAE criteria for each parameter in each treatment group. Participants were classified according to the study treatment actually received. If a participant received more than one study treatment, the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Anemia	0 0%	3 9.7%
Lymphocyte count decreased	1 8.3%	2 6.5%
Lymphocyte count increased	0 0%	2 6.5%
Neutrophil count decreased	1 8.3%	0 0%
White blood cell decreased	1 8.3%	0 0%
Alanine aminotransferase increased	3 25%	0 0%
Aspartate aminotransferase increased	2 16.7%	1 3.2%
Blood bilirubin increased	0 0%	1 3.2%
Cholesterol high	0 0%	5 16.1%
CPK increased	0 0%	2 6.5%
GGT increased	1 8.3%	5 16.1%
Hypercalcemia	0 0%	2 6.5%
Hyperglycemia	1 8.3%	1 3.2%
Hypermagnesemia	0 0%	1 3.2%
Hypertriglyceridemia	0 0%	7 22.6%
Hypoalbuminemia	0 0%	1 3.2%
Hyponatremia	1 8.3%	3 9.7%
Lipase increased	1 8.3%	5 16.1%
Serum amylase increased	0 0%	1 3.2%
Hemoglobin increased	0 0%	0 0%
Platelet count decreased	0 0%	0 0%
Alkaline phosphatase increased	0 0%	0 0%
Creatinine increased	0 0%	0 0%
Hyperkalemia	0 0%	0 0%
Hypernatremia	0 0%	0 0%
Hypocalcemia	0 0%	0 0%
Hypoglycemia	0 0%	0 0%
Hypokalemia	0 0%	0 0%
Hypomagnesemia	0 0%	0 0%
Hypophosphatemia	0 0%	0 0%

6. Secondary Outcome

Title	Number of Participants With Vital Signs Meeting Pre-defined Criteria
Description	Pre-defined criteria in vital signs: pulse rate >120 beats per minute (bpm), sitting diastolic blood pressure (DBP) increase and decrease in change from baseline of >= 20 millimeter of mercury (mmHg), sitting systolic blood pressure(SBP) < 90 mmHg, increase and decrease in change from baseline of >= 30mmHg. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one study treatment, the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Pulse rate >120 bpm	0 0%	4 12.9%
Sitting DBP change >= 20 mmHg increase	2 16.7%	12 38.7%
Sitting DBP change >= 20 mmHg decrease	5 41.7%	8 25.8%
Sitting SBP <90 mmHg	1 8.3%	4 12.9%
Sitting SBP change >= 30 mmHg increase	1 8.3%	11 35.5%
Sitting SBP change >= 30 mmHg decrease	3 25%	2 6.5%

7. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DC is defined as objective response (CR or PR) or stable disease (SD) per RECIST v.1.1 from the date of first dose of study treatment until disease progression or death due to any cause. The DCR is the proportion of patients with DC. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm. PR is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Number (95% Confidence Interval) [Percentage of participants]	58.3 485.8%	71.0 229%

8. Secondary Outcome

Title	Duration of Response (DR)
Description	DR: time from first documented occurrence of response (PR or CR) until date of first documented PD or death due to underlying cancer. Per RECIST 1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions; any pathological lymph nodes assigned as target lesions/non-target lesions have a reduction in short axis to <10 mm. PR: at least a >=30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. PD: at least a >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of new lesions. Participants with no PD and were still alive by 02 Feb 2020, were censored at last adequate tumor assessment. Kaplan-Meier method was used for DR analysis.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug and who had confirmed complete response or partial response. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	3	16
Median (95% Confidence Interval) [Month]	3.7	14.7

9. Secondary Outcome

Title	Time to Tumor Response (TTR)
Description	TTR is defined, for participants with an objective response (CR or PR), as the time from the start date (the date of first dose of treatment) to the first documentation of objective response (CR or PR) which is subsequently confirmed. Per RECIST v1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug and who had confirmed complete response or partial response. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	3	16
Median (Full Range) [Months]	1.4	1.8

10. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined as the time from start date (the date of first dose of treatment) to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurs first. Per RECIST v1.1: PD: a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Median (95% Confidence Interval) [Months]	3.7	6.4

11. Secondary Outcome

Title	Kaplan-Meier Estimates of Overall Survival (OS)
Description	OS is defined as the time from start date (the date of first dose of treatment) to the date of death due to any cause.
Time Frame	Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	12	31
Median (95% Confidence Interval) [Months]	16.4	32.9

12. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab
Description	Cmax of crizotinib in the presence of avelumab was observed directly from data.
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the pharmacokinetic (PK) parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [nanograms per millilitre (ng/mL)]	281 (74)

13. Secondary Outcome

Title	Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab
Description	Tmax of crizotinib in the presence of avelumab was observed directly from data as time of first occurrence.
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Median (Full Range) [Hours]	2.03

14. Secondary Outcome

Title	Area Under The Plasma Concentration-Time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab
Description	AUCtau of crizotinib in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval is defined as after single dose from time zero to the next dose (after single dose and at steady state).
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [nanograms*hours per millilitre (ng*h/mL)]	2755 (82)

15. Secondary Outcome

Title	Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [Liter per hour (L/h)]	90.76 (82)

16. Secondary Outcome

Title	Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab
Description	Cmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data.
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	84.11 (91)

17. Secondary Outcome

Title	Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab
Description	Tmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data as time of first occurrence.
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Median (Full Range) [Hours]	3.02

18. Secondary Outcome

Title	AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab
Description	AUCtau of crizotinib metabolite PF-06260182 in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state).
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	789.1 (116)

19. Secondary Outcome

Title	Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab
Description	MRAUCtau of metabolite PF-06260182 in the presence of avelumab was caculated (MRAUCtau=Metabolite AUCtau/parent AUCtau). Parent=crizotinib, metabolite=PF-06260182
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	0.2779 (33)

20. Secondary Outcome

Title	Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab
Description	MRCmax of metabolite PF-06260182 in the presence of avelumab was caculated (MRCmax=Metabolite Cmax/parent Cmax). Parent=crizotinib, metabolite=PF-06260182
Time Frame	Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	0.2902 (25)

21. Secondary Outcome

Title	Cmax of Lorlatinib in The Presence of Avelumab
Description	Cmax of lorlatinib in the presence of avelumab was observed directly from data.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this outcome measure.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	596.9 (33)

22. Secondary Outcome

Title	Tmax of Lorlatinib in The Presence of Avelumab
Description	Tmax of lorlatinib in the presence of avelumab was observed directly from data.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this outcome measure.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	26
Median (Full Range) [Hours]	1.23

23. Secondary Outcome

Title	AUCtau of Lorlatinib in The Presence of Avelumab
Description	AUCtau of lorlatinib in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this outcome measure.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	19
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	5807 (42)

24. Secondary Outcome

Title	Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab
Description	AUClast of lorlatinib in the presence of avelumab.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this outcome measure.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	4872 (52)

25. Secondary Outcome

Title	CL/F of Lorlatinib in The Presence of Avelumab
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this outcome measure.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	19
Geometric Mean (Geometric Coefficient of Variation) [L/h]	16.97 (44)

26. Secondary Outcome

Title	Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab
Description	Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B.
Time Frame	Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 1 Day 1.

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one post-dose concentration measurement above the lower limit of quantification for avelumab.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	8	16
Geometric Mean (Geometric Coefficient of Variation) [micrograms/milliliter (ug/mL)]	193.2 (14)	195.7 (28)

27. Secondary Outcome

Title	Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab
Description	Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B.
Time Frame	Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had at least one post-dose concentration measurement above the lower limit of quantification for avelumab.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	8	17
Geometric Mean (Geometric Coefficient of Variation) [ug/mL]	174.5 (35)	169.4 (68)

28. Secondary Outcome

Title	Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab
Description	Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of crizotinib was observed directly from the data in Group A.
Time Frame	Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, and 47.

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had least one observation. Number of Participants Analyzed represents the total number of participants in the analysis population for this outcome measure. Number Analyzed represents the number of participants with concentration measurement above lower limit of quantification at each visit. Group B was not evaluable for this outcome measure.

Arm/Group Title	Group A: Avelumab + Crizotinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.
Measure Participants	12
Cycle 2 Day 1	11.76 (68)
Cycle 3 Day 1	16.26 (53)
Cycle 4 Day 1	16.71 (34)
Cycle 5 Day 1	14.21 (46)
Cycle 11 Day 1	26.64 (4)
Cycle 17 Day 1	30.59 (9)
Cycle 23 Day 1	30.63 (15)
Cycle 29 Day 1	30.72 (55)
Cycle 35 Day 1	37.31 (27)
Cycle 47 Day 1	40.91 (15)

29. Secondary Outcome

Title	Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab
Description	Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of lorlatinib was observed directly from the data in Group B.
Time Frame	Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, 41, and 47.

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received at least one dose of study drug and who had least one observation. Number of Participants Analyzed represents the total number of participants in the analysis population for this outcome measure. Number Analyzed represents the number of participants with concentration measurement above lower limit of quantification at each visit. Group A was not evaluable for this outcome measure.

Arm/Group Title	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	25
Cycle 2 Day 1	16.86 (88)
Cycle 3 Day 1	16.99 (116)
Cycle 4 Day 1	23.71 (80)
Cycle 5 Day 1	26.74 (68)
Cycle 11 Day 1	31.31 (71)
Cycle 17 Day 1	32.69 (60)
Cycle 23 Day 1	33.20 (56)
Cycle 29 Day 1	25.77 (66)
Cycle 35 Day 1	31.27 (47)
Cycle 41 Day 1	30.81 (59)
Cycle 47 Day 1	39.63 (64)

30. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status
Description	ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Baseline is defined as the last assessment on or prior to the date/time of the first dose of avelumab.
Time Frame	Day 1 of Cycles 1-5, then every 12 weeks thereafter, end of treatment/withdrawal, and 30 days after last avelumab dose (up to a maximum of 5 years)

Outcome Measure Data

Analysis Population Description

The analysis population was a subset of the safety analysis set (all participants who received at least one dose of study drug) and included participants who had at least one ADA sample collected for avelumab.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib	All Participants
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.	Including all the participants from Group A and Group B.
Measure Participants	12	31	43
ADA never-positive	9 75%	25 80.6%	34 79.1%
ADA ever-positive	3 25%	6 19.4%	9 20.9%

31. Secondary Outcome

Title	Number of Participants With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression
Description	PD-L1 protein expression is determined by using Combined Positive Score (CPS), which is the percentage of viable tumor and tumor-infiltrated immune cells (restricted to lymphocytes and macrophages) within or directly associated with tumor cell strands showing partial or complete membrane staining using the SP263 antibody. Positive is defined as CPS>=1% and negative is defined as CPS <1%.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The analysis population was a subset of the safety analysis set (all participants who received at least one dose of study drug) and included participants who had at least one biomarker parameter of PD-L1 from the corresponding assay sample with at least one baseline biomarker measurement.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	9	24
Positive	7 58.3%	20 64.5%
Negative	2 16.7%	4 12.9%

32. Secondary Outcome

Title	Number of Participants With Positive Tumor Infiltrating CD8+ Lymphocytes
Description	Tumor infiltrating CD8+ lymphocytes is defined as the number of CD8+ cells per unit area and the percent of counted cells. Positive is defined as >=1% and negative is defined as <1%.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The analysis population was a subset of the safety analysis set (all participants who received at least one dose of study drug) and included participants who had at least one biomarker parameter of tumor infiltrating CD8+ lymphocytes from the corresponding assay sample with at least one baseline biomarker measurement.

Arm/Group Title	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.	Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
Measure Participants	10	22
Positive	6 50%	4 12.9%
Negative	4 33.3%	18 58.1%

Adverse Events

Time Frame	Baseline up to 30 days post lost dose of study treatment with a maximum of 5 years)
Adverse Event Reporting Description	Participants were only counted once per treatment for each category.
Arm/Group Title	Group A: Avelumab + Crizotinib		Group B: Avelumab + Lorlatinib
Arm/Group Description	Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.		Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.
All Cause Mortality
	Group A: Avelumab + Crizotinib		Group B: Avelumab + Lorlatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)		15/31 (48.4%)
Serious Adverse Events
	Group A: Avelumab + Crizotinib		Group B: Avelumab + Lorlatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/12 (41.7%)		19/31 (61.3%)
Blood and lymphatic system disorders
Febrile neutropenia	1/12 (8.3%)		0/31 (0%)
Cardiac disorders
Cardiac tamponade	0/12 (0%)		1/31 (3.2%)
Pericardial effusion	0/12 (0%)		1/31 (3.2%)
Gastrointestinal disorders
Abdominal pain	0/12 (0%)		1/31 (3.2%)
General disorders
Chest pain	0/12 (0%)		1/31 (3.2%)
Disease progression	1/12 (8.3%)		0/31 (0%)
Pyrexia	0/12 (0%)		1/31 (3.2%)
Hepatobiliary disorders
Hepatitis	1/12 (8.3%)		0/31 (0%)
Infections and infestations
Cellulitis	0/12 (0%)		1/31 (3.2%)
Clostridium difficile infection	0/12 (0%)		1/31 (3.2%)
Pneumonia	0/12 (0%)		2/31 (6.5%)
Postoperative wound infection	0/12 (0%)		1/31 (3.2%)
Sepsis	0/12 (0%)		1/31 (3.2%)
Tonsillitis	0/12 (0%)		1/31 (3.2%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/12 (0%)		1/31 (3.2%)
Femur fracture	0/12 (0%)		1/31 (3.2%)
Road traffic accident	0/12 (0%)		1/31 (3.2%)
Investigations
Aspartate aminotransferase increased	0/12 (0%)		1/31 (3.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer	0/12 (0%)		1/31 (3.2%)
Nervous system disorders
Central nervous system vasculitis	0/12 (0%)		1/31 (3.2%)
Cerebral haemorrhage	0/12 (0%)		1/31 (3.2%)
Cerebral infarction	0/12 (0%)		1/31 (3.2%)
Seizure	0/12 (0%)		1/31 (3.2%)
Psychiatric disorders
Confusional state	0/12 (0%)		2/31 (6.5%)
Delirium	0/12 (0%)		1/31 (3.2%)
Renal and urinary disorders
Nephrolithiasis	0/12 (0%)		1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/12 (0%)		1/31 (3.2%)
Pneumonitis	1/12 (8.3%)		2/31 (6.5%)
Pneumothorax	1/12 (8.3%)		0/31 (0%)
Pulmonary embolism	0/12 (0%)		2/31 (6.5%)
Skin and subcutaneous tissue disorders
Rash	1/12 (8.3%)		0/31 (0%)
Vascular disorders
Deep vein thrombosis	0/12 (0%)		1/31 (3.2%)
Superior vena cava occlusion	0/12 (0%)		1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Group A: Avelumab + Crizotinib		Group B: Avelumab + Lorlatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		28/31 (90.3%)
Blood and lymphatic system disorders
Anaemia	3/12 (25%)		6/31 (19.4%)
Thrombocytopenia	1/12 (8.3%)		0/31 (0%)
Cardiac disorders
Atrioventricular block first degree	0/12 (0%)		2/31 (6.5%)
Pericardial effusion	1/12 (8.3%)		1/31 (3.2%)
Ear and labyrinth disorders
Tinnitus	1/12 (8.3%)		1/31 (3.2%)
Endocrine disorders
Hypothyroidism	0/12 (0%)		8/31 (25.8%)
Eye disorders
Dry eye	1/12 (8.3%)		1/31 (3.2%)
Keratitis	1/12 (8.3%)		0/31 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/12 (8.3%)		2/31 (6.5%)
Abdominal pain	1/12 (8.3%)		5/31 (16.1%)
Constipation	2/12 (16.7%)		7/31 (22.6%)
Diarrhoea	3/12 (25%)		7/31 (22.6%)
Dry mouth	1/12 (8.3%)		0/31 (0%)
Gastrooesophageal reflux disease	0/12 (0%)		2/31 (6.5%)
Nausea	7/12 (58.3%)		4/31 (12.9%)
Oesophageal pain	1/12 (8.3%)		0/31 (0%)
Stomatitis	1/12 (8.3%)		2/31 (6.5%)
Vomiting	6/12 (50%)		5/31 (16.1%)
General disorders
Asthenia	2/12 (16.7%)		3/31 (9.7%)
Chest pain	0/12 (0%)		4/31 (12.9%)
Chills	3/12 (25%)		2/31 (6.5%)
Fatigue	1/12 (8.3%)		4/31 (12.9%)
Hypothermia	1/12 (8.3%)		0/31 (0%)
Localised oedema	0/12 (0%)		2/31 (6.5%)
Mucosal inflammation	2/12 (16.7%)		0/31 (0%)
Oedema	1/12 (8.3%)		1/31 (3.2%)
Oedema peripheral	1/12 (8.3%)		12/31 (38.7%)
Peripheral swelling	0/12 (0%)		2/31 (6.5%)
Pyrexia	3/12 (25%)		5/31 (16.1%)
Swelling face	1/12 (8.3%)		1/31 (3.2%)
Hepatobiliary disorders
Hepatitis	1/12 (8.3%)		0/31 (0%)
Infections and infestations
Cellulitis	1/12 (8.3%)		3/31 (9.7%)
Conjunctivitis	0/12 (0%)		2/31 (6.5%)
Cystitis	0/12 (0%)		2/31 (6.5%)
Gastroenteritis	1/12 (8.3%)		1/31 (3.2%)
Lower respiratory tract infection	0/12 (0%)		2/31 (6.5%)
Nasopharyngitis	0/12 (0%)		3/31 (9.7%)
Rhinitis	0/12 (0%)		2/31 (6.5%)
Tooth abscess	0/12 (0%)		2/31 (6.5%)
Upper respiratory tract infection	1/12 (8.3%)		5/31 (16.1%)
Urinary tract infection	0/12 (0%)		3/31 (9.7%)
Injury, poisoning and procedural complications
Infusion related reaction	2/12 (16.7%)		6/31 (19.4%)
Procedural pain	1/12 (8.3%)		1/31 (3.2%)
Investigations
Alanine aminotransferase increased	4/12 (33.3%)		9/31 (29%)
Amylase increased	1/12 (8.3%)		3/31 (9.7%)
Aspartate aminotransferase increased	3/12 (25%)		7/31 (22.6%)
Blood alkaline phosphatase increased	1/12 (8.3%)		2/31 (6.5%)
Blood cholesterol increased	0/12 (0%)		18/31 (58.1%)
Blood creatine phosphokinase increased	1/12 (8.3%)		4/31 (12.9%)
Blood creatinine increased	2/12 (16.7%)		0/31 (0%)
Blood lactate dehydrogenase increased	1/12 (8.3%)		0/31 (0%)
Electrocardiogram QT prolonged	1/12 (8.3%)		0/31 (0%)
Gamma-glutamyltransferase increased	1/12 (8.3%)		3/31 (9.7%)
Hypophonesis	1/12 (8.3%)		0/31 (0%)
Lipase increased	1/12 (8.3%)		5/31 (16.1%)
Neutrophil count decreased	1/12 (8.3%)		0/31 (0%)
Weight decreased	1/12 (8.3%)		1/31 (3.2%)
Weight increased	0/12 (0%)		8/31 (25.8%)
White blood cell count decreased	1/12 (8.3%)		0/31 (0%)
Metabolism and nutrition disorders
Acidosis	1/12 (8.3%)		0/31 (0%)
Decreased appetite	5/12 (41.7%)		2/31 (6.5%)
Hypercholesterolaemia	0/12 (0%)		6/31 (19.4%)
Hyperglycaemia	0/12 (0%)		2/31 (6.5%)
Hypertriglyceridaemia	0/12 (0%)		18/31 (58.1%)
Hypoalbuminaemia	1/12 (8.3%)		2/31 (6.5%)
Hypocalcaemia	1/12 (8.3%)		1/31 (3.2%)
Hypoglycaemia	1/12 (8.3%)		1/31 (3.2%)
Hypokalaemia	0/12 (0%)		2/31 (6.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/12 (0%)		13/31 (41.9%)
Back pain	0/12 (0%)		4/31 (12.9%)
Groin pain	0/12 (0%)		2/31 (6.5%)
Joint swelling	0/12 (0%)		2/31 (6.5%)
Muscle spasms	0/12 (0%)		4/31 (12.9%)
Muscular weakness	0/12 (0%)		3/31 (9.7%)
Musculoskeletal pain	0/12 (0%)		2/31 (6.5%)
Myalgia	3/12 (25%)		6/31 (19.4%)
Pain in extremity	0/12 (0%)		4/31 (12.9%)
Nervous system disorders
Carpal tunnel syndrome	0/12 (0%)		2/31 (6.5%)
Dizziness	1/12 (8.3%)		4/31 (12.9%)
Dysgeusia	0/12 (0%)		2/31 (6.5%)
Headache	1/12 (8.3%)		4/31 (12.9%)
Hemiparesis	1/12 (8.3%)		1/31 (3.2%)
Lethargy	0/12 (0%)		3/31 (9.7%)
Memory impairment	0/12 (0%)		3/31 (9.7%)
Migraine	1/12 (8.3%)		0/31 (0%)
Neuropathy peripheral	0/12 (0%)		7/31 (22.6%)
Paraesthesia	0/12 (0%)		2/31 (6.5%)
Peripheral sensory neuropathy	0/12 (0%)		5/31 (16.1%)
Somnolence	1/12 (8.3%)		1/31 (3.2%)
Psychiatric disorders
Confusional state	0/12 (0%)		2/31 (6.5%)
Hallucination	0/12 (0%)		2/31 (6.5%)
Hallucination, visual	0/12 (0%)		2/31 (6.5%)
Insomnia	0/12 (0%)		5/31 (16.1%)
Renal and urinary disorders
Haematuria	0/12 (0%)		2/31 (6.5%)
Nephropathy toxic	1/12 (8.3%)		0/31 (0%)
Proteinuria	0/12 (0%)		2/31 (6.5%)
Reproductive system and breast disorders
Vaginal discharge	1/12 (8.3%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)		7/31 (22.6%)
Dyspnoea	2/12 (16.7%)		5/31 (16.1%)
Dyspnoea exertional	0/12 (0%)		2/31 (6.5%)
Haemoptysis	0/12 (0%)		4/31 (12.9%)
Lung opacity	1/12 (8.3%)		0/31 (0%)
Nasal congestion	0/12 (0%)		3/31 (9.7%)
Oropharyngeal pain	0/12 (0%)		2/31 (6.5%)
Pneumonitis	0/12 (0%)		2/31 (6.5%)
Productive cough	1/12 (8.3%)		0/31 (0%)
Skin and subcutaneous tissue disorders
Dry skin	1/12 (8.3%)		4/31 (12.9%)
Pruritus	1/12 (8.3%)		2/31 (6.5%)
Rash	4/12 (33.3%)		5/31 (16.1%)
Skin hypertrophy	0/12 (0%)		2/31 (6.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.