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)

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)

Population: 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.

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

Population: 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.

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)

Population: 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.

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

Population: 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.

AUCtau of crizotinib in the presence of avelumab was calculated 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

Population: 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.

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

Population: 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.

AUCtau of crizotinib metabolite PF-06260182 in the presence of avelumab was calculated 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

Population: 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.

AUCtau of lorlatinib in the presence of avelumab was calculated 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

Population: 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.

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

Population: 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.

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

Population: 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.

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.

Population: 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.

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

Population: 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.

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

Population: 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.

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)

Population: 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.

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)

Population: 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.

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)

Population: 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.

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

Population: 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.

MRAUCtau of metabolite PF-06260182 in the presence of avelumab was calculated (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

Population: 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.

MRCmax of metabolite PF-06260182 in the presence of avelumab was calculated (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

Population: 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.

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)

Population: 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.

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 up to end of treatment/withdrawal (maximum of 5 years)

Population: 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.

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

Population: 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.

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

Population: 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.

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 National Cancer Institute Common Terminology Criteria for Adverse Events (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)

Population: 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.

Pre-defined criteria in vital signs: pulse rate \<50 beats per minute, pulse rate \>120 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 up to end of treatment/withdrawal (maximum of 5 years)

Population: 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.

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)

Population: 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.

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

Population: 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.

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)

Population: 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.

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

Population: 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.

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

Population: 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.

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.

Population: 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.

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.

Population: 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.