Non-small Cell Lung Cancer, Urothelial Cancer
Conditions
Keywords
Avelumab, immunotherapy, PD-L1 inhibitor, non-small cell lung cancer (NSCLC), urothelial cancer (UC), carboplatin, pemetrexed, gemcitabine, cisplatin
Brief summary
This is a Phase 1b/2, open label, multicenter, safety and clinical activity study of avelumab in combination with chemotherapy as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and in combination with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial (bladder) cancer (UC) (Cohort A2). As more information is learned about other anti-cancer immunotherapy agents, in future portions of the study, avelumab may be combined with chemotherapy and other anti-cancer immunotherapy agents in patients with these same or different tumor types.
Detailed description
This is a Phase 1b/2, open label, multicenter, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of avelumab in combination with chemotherapy with or without other anti-cancer immunotherapies, as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial cancer (UC) (Cohort A2). Given the growing preclinical and clinical indications that combinations of anti-cancer immunotherapies potentially improve patient outcomes compared to results seen with single agents, in portions of the study to be added in the future, avelumab will be evaluated in combination with both standard-of-care chemotherapy and other anti-cancer immunotherapies in patients with advanced malignancies. Each cohort in the study will consist of a Phase 1b lead-in portion to evaluate safety and a Phase 2 cohort expansion to evaluate safety and efficacy. In the Phase 1b safety lead-in portion, up to 12 patients will be enrolled into each cohort and evaluated for dose-limiting toxicities (DLT) during the first 2 cycles of treatment. If investigational products administration in a cohort is deemed safe in the Phase 1b lead-in, enrollment may be expanded into the Phase 2 cohort expansion. Up to approximately 40 patients in each cohort (including those enrolled in the Phase 1b lead-in and those enrolled in the Phase 2 cohort expansion) will be enrolled and treated with avelumab plus chemotherapy in the initial portion of the study and, in future portions of the study, with avelumab plus chemotherapy with or without other anti-cancer immunotherapies. In the Phase 1b lead-in portions of NSCLC Cohort A1 and UC Cohort A2, avelumab is dosed at 800 mg fixed dose every 3 weeks. Under Protocol Amendment 4, avelumab is dosed at 1200 mg fixed dose every 3 weeks in the Phase 1b lead-in portions of NSCLC Cohort A3 and in UC Cohort A4, in combination with the same standard-of-care chemotherapy doublets used in Cohort A1 and Cohort A2, respectively. For each tumor type, the study treatment combination with the highest avelumab dose determined to be safe may be advanced into Phase 2 cohort expansion.
Interventions
DRUGAvelumab 800 mg in combination with pemetrexed / carboplatin
Avelumab Pemetrexed Carboplatin
DRUGAvelumab 800 mg in combination with gemcitabine / cisplatin.
Avelumab Gemcitabine Cisplatin
DRUGAvelumab 1200 mg in combination with pemetrexed/carboplatin
Avelumab Pemetrexed Carboplatin
DRUGAvelumab 1200 mg in combination with gemcitabine/cisplatin
Avelumab Gemcitabine Cisplatin
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumor that is not amenable for treatment with curative intent as follows: * For all groups: * Measurable disease by RECIST v1.1 with at least 1 measurable lesion, and availability of tumor specimen 18 months or less old. * No prior systemic treatment for unresectable locally advanced or metastatic disease for the tumor type under study. If prior systemic chemotherapy treatment was given in the adjuvant or neo-adjuvant setting or as part of radiotherapy chemotherapy treatment, disease-free interval after stop of systemic treatment must be more than 6 months for non-squamous NSCLC and more than 12 months for UC; * Cohort A1 and Cohort A3: Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is available as a standard of care treatment option, patients must have a tumor proportion score (TPS) \<50% for PD L1 (via the 22C3 pharmDx or the Ventana (SP263) PD L1 IHC assay). * Cohort A2 and Cohort A4: Transitional cell carcinoma of the urothelium including the bladder, urethra, renal pelvis, and ureter. 2. ECOG performance status 0 or 1 3. Estimated life expectancy of at least 90 days 4. Adequate bone marrow, renal, and liver function 5. Negative serum pregnancy test at screening 6. Signed and dated informed consent
Exclusion criteria
1. Prior immunotherapy with any antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways. 2. Patients with known symptomatic central nervous system metastases requiring steroids. 3. Diagnosis of other malignancy within 2 years prior to enrollment except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, breast, or cervix, or low grade (Gleason ≤6) prostate cancer 4. Use of immunosuppressive medication at the time of enrollment 5. Active or prior autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. 6. Prior organ transplantation including allogenic stem cell transplantation 7. Active infection requiring systemic therapy 8. Known history of HIV or AIDS 9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening 10. Administration of live vaccine within 4 weeks prior to study entry 11. Known prior severe hypersensitivity to the investigational products or any component in their formulations, 12. Known prior severe hypersensitivity to platinum-related compounds for all cohorts, to pemetrexed for patients enrolled in Cohort A1 and Cohort A3, and to gemcitabine for patients enrolled in Cohort A2 and Cohort A4 13. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade \> 1) 14. Known history of colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis. 15. Ongoing cardiac dysrhythmias of NCI CTCAE v4.03 Grade 2 or prolongation of the QTcF interval to \>480 msec. 16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (\<6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication. 17. Major surgery ≤28 days or major radiation therapy ≤14 days prior to enrollment. 18. Participation in other studies involving investigational drug(s) within 28 days prior to study entry. 19. Concurrent treatment with a prohibited medication. 20. Other acute or chronic medical or psychiatric condition 21. Pregnant female patients; breastfeeding female patients; fertile male patients and female patients of childbearing potential who are unwilling or unable to use at least 1 highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of chemotherapy (for male and female patients) or at least 30 days after the last dose of avelumab (for female patients), whichever is longer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT) | Day 1 up to Week 6 (first 2 treatment cycles; 1 cycle = 21 days) | DLTs=occurrence of any AEs attributable to study treatment in first 2 treatment cycles:Hematologic: grade(G)4 neutropenia lasting \>7days;febrile neutropenia with body temperature \>=38 degree Celsius for \>1hour; G\>=3 neutropenic infection(absolute neutrophil count \<1.0\*10\^9/L),G\>=3 thrombocytopenia (platelet count\<50.0-25.0\*10\^9/L)with bleeding;G4 thrombocytopenia(PC\<25.0\*10\^9/L),G4 anemia(life-threatening).Non-hematologic: any G4 toxicities;G3 toxicities persisting for \>3days despite medical treatment(nausea,vomiting,diarrhea)except endocrinopathies controlled with hormonal therapy;ALT/AST \>3\*upper limit of normal(ULN)if normal at baseline or 2\*Baseline(\>ULN at baseline)with total bilirubin \>2\*ULN and alkaline phosphatase \<2\*ULN;G3 QTcF prolongation after correction of any reversible cause(electrolyte abnormalities/hypoxia).Delay of \>=3weeks in scheduled administration/failure to deliver 75% of doses due to toxicities attributable to any study treatment. DLT-evaluable analysis set. |
| Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment | From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 3.5 years approximately) | OR: complete response(CR) or partial response(PR)determined by investigator according to RECIST v1.1 from date of first dose of study treatment until date of first documentation of progressive disease(PD),confirmed by repeat assessments performed no less than 4 weeks after first response. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately) | Adverse event (AE) was any untoward medical occurrence in a participants who received any study drug without regard to possibility of causal relationship. Serious adverse event was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. |
| Number of Participants With Treatment Related TEAEs | From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately) | A treatment related AE included AEs related to at least one study drug in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Relatedness to study drug was assessed by the investigator. |
| Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 | From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately) | AE was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using NCI CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of participants with grade 3 or higher TEAEs were reported. |
| Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | From screening up to 90 days after last dose of study drug (maximum up to 5 years approximately) | Participants with laboratory abnormalities of any Grade as per NCI CTCAE toxicity grading v4.03 were summarized:hematology(anemia,hemoglobin increased,lymphocyte count decreased,lymphocyte count increased, neutrophil count decreased,platelet count decreased and white blood cell decreased)and clinical chemistry(alanine aminotransferase increased,alkaline phosphatase,increased,aspartate,aminotransferase increased,blood bilirubin increased,cholesterol high,creatinine phosphokinase\[cpk\] increased,creatinine increased,gamma-glutamyl transferase\[ggt\] increased,hypercalcemia,hyperglycemia,hyperkalemia, hypermagnesemia,hypernatremia,hypertriglyceridemia,hypoalbuminemia,hypocalcemia,hypoglycemia,hypokalemia,hypomagnesemia,hyponatremia, hypophosphatemia,serum amylase increased and lipase increased).As per NCI CTCAE toxicity grading v4.03, Grade1=mild;Grade2=moderate;Grade3=severe;Grade4=life-threatening;Grade 5=death.Parameters with at least 1 participant with abnormal value are reported. |
| Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | From first dose of study drug up to last dose of study drug (maximum up to 5 years approximately) | Blood samples were collected for assessment of avelumab ADAs using a tiered assay and confirmed positive samples were tested for neutralizing antibodies (nAb). |
| Serum Concentration of Avelumab | Pre-dose, 1 hour post-dose on Day 1 of Cycle 1, 2, 3, 6, 10, 14; 336 hours post-dose on Day 15 of Cycle 1, 2, 3 (each cycle of 21 days) | The lower limit of quantification (LLOQ) for avelumab was 0.2 micrograms per milliliter. Pharmacokinetic concentration analysis set was subset of safety analysis set and included participants who had at least one concentration measurement for avelumab or other study drugs which they were assigned to receive. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. |
| Overall Survival (OS) | From first dose of study treatment until death due to any cause (maximum up to 5 years approximately) | OS was defined as the time from the first dose of study treatment to the date of death due to any cause. Participants last known to be alive were censored at the date of last contact. The median duration of OS was not derived for less than (\<) 10 participants. |
| Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment | From date of first documented response to date of first documented PD or death due to any cause, whichever occurred first (maximum up to 5 years approximately) | DOR was defined as time from first documentation of objective response (confirmed CR or PR) to the date of first PD documentation or death due to any cause, whichever occurs first. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. Median DOR was not derived for \< 5 participants. |
| Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment | From first dose of study treatment until first documentation of CR or PR (maximum up to 5 years approximately) | TTR was defined as the time from the date of first dose of study treatment to the first documentation of objective response (CR or PR) as assessed by investigator according to RECIST v 1.1. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. |
| Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline and Cycle 2 Day 8 (each cycle of 21 days) | PD-L1 expression was determined using the Ventana PD-L1 SP263 IHC assay. PD-L1-positive status in UC cohorts was defined using an algorithm that combines assessments of PD-L1 staining on tumor and immune cells scored by pathologists and in NSCLC cohorts was defined as PD-L1 expression on \>=1% of tumor cells. PD-L1 expression at baseline and on-treatment were reported in this outcome measure. |
| Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment | From start of treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5 years approximately) | PFS was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. The median duration of PFS was not derived for less than (\<) 10 participants. |
| Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue | Pre-dose on Day 1 of Cycle 1 | Mutational load within tumor tissue was defined as number per megabase of the genome, coding, base substitution, and indel mutations present in the sample. Mutational load was determined in whole blood samples using next generation deoxyribonucleic acid (DNA) sequencing followed by computational analysis. |
Countries
Australia, Canada, Czechia, Hungary, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 2 phases: Phase 1b (lead-in phase) and Phase 2 (cohort expansion phase). Phase 2 was conducted at the highest dose level of avelumab which was determined safe for participants in Phase 1b.
Pre-assignment details
Phase 1b lead-in:49 participants signed inform consent form(ICF).18 participants did not meet eligibility criteria and not enrolled,31 participants enrolled and assigned to treatment. Phase 2:52 participants signed ICF.16 participants did not meet eligibility criteria and not enrolled,36 participants enrolled,1 was not assigned to treatment and 35 assigned to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Participants with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m\^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose \[mg\] = target AUC \* glomerular filtration rate\[GFR\] milliliter per minute \[mL/min\] + 25, and maximum carboplatin dose = target AUC \[mg\*min/mL\] \* 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. | 6 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Participants (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m\^2 and gemcitabine 1000 mg/m\^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. | 13 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Participants with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m\^2 and carboplatin dose at AUC 5 (carboplatin dose \[mg\] = target AUC \* GFR mL/min + 25), and maximum carboplatin dose = target AUC \[mg\*min/mL\] \* 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. | 6 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin Participants (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m\^2 and gemcitabine 1000 mg/m\^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. Participants from both Phase 1b and Phase 2 Avelumab 1200 mg + Gemcitabine/Cisplatin were included in this arm. | 41 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase 1b Lead-in: Follow-up | Death | 3 | 8 | 4 | 4 | 0 |
| Phase 1b Lead-in: Follow-up | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Phase 1b Lead-in: Follow-up | Other | 0 | 1 | 0 | 1 | 0 |
| Phase 1b Lead-in: Follow-up | Study terminated by sponsor | 2 | 3 | 0 | 1 | 0 |
| Phase 1b Lead-in: Follow-up | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
| Phase 1b Lead-in: Treatment | Adverse Event | 3 | 4 | 1 | 1 | 0 |
| Phase 1b Lead-in: Treatment | Death | 0 | 0 | 1 | 0 | 0 |
| Phase 1b Lead-in: Treatment | Global deterioration of health status | 0 | 0 | 1 | 0 | 0 |
| Phase 1b Lead-in: Treatment | Other | 2 | 1 | 0 | 0 | 0 |
| Phase 1b Lead-in: Treatment | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Phase 1b Lead-in: Treatment | Progressive Disease | 1 | 6 | 3 | 4 | 0 |
| Phase 1b Lead-in: Treatment | Study terminated by sponsor | 0 | 1 | 0 | 1 | 0 |
| Phase 2: Follow-up | Death | 0 | 0 | 0 | 0 | 24 |
| Phase 2: Follow-up | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Phase 2: Follow-up | Other | 0 | 0 | 0 | 0 | 1 |
| Phase 2: Follow-up | Study terminated by sponsor | 0 | 0 | 0 | 0 | 7 |
| Phase 2: Treatment | Adverse Event | 0 | 0 | 0 | 0 | 6 |
| Phase 2: Treatment | Death | 0 | 0 | 0 | 0 | 1 |
| Phase 2: Treatment | Other | 0 | 0 | 0 | 0 | 4 |
| Phase 2: Treatment | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Phase 2: Treatment | Progressive disease | 0 | 0 | 0 | 0 | 22 |
| Phase 2: Treatment | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 3 Participants | 27 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 7 Participants | 3 Participants | 14 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 11 Participants | 6 Participants | 37 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 6 Participants | 11 Participants | 5 Participants | 37 Participants | 59 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 0 Participants | 10 Participants | 17 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 6 Participants | 31 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 8 / 13 | 5 / 6 | 29 / 41 |
| other Total, other adverse events | 6 / 6 | 13 / 13 | 6 / 6 | 40 / 41 |
| serious Total, serious adverse events | 3 / 6 | 9 / 13 | 5 / 6 | 20 / 41 |
Outcome results
Primary
Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment
OR: complete response(CR) or partial response(PR)determined by investigator according to RECIST v1.1 from date of first dose of study treatment until date of first documentation of progressive disease(PD),confirmed by repeat assessments performed no less than 4 weeks after first response. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD.
Time frame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 3.5 years approximately)
Population: The full analysis set (FAS) will include all participants who receive at least one dose of study drug. Participants will be classified according to the study treatment actually received. If a participant receives more than one treatment the participant will be classified according to the first study treatment received.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment | 50.0 Percentage of Participants | 95% Confidence Interval 11.8 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment | 53.8 Percentage of Participants | 95% Confidence Interval 25.1 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment | 33.3 Percentage of Participants | 95% Confidence Interval 4.3 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment | 39.0 Percentage of Participants | 95% Confidence Interval 24.2 |
Primary
Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT)
DLTs=occurrence of any AEs attributable to study treatment in first 2 treatment cycles:Hematologic: grade(G)4 neutropenia lasting \>7days;febrile neutropenia with body temperature \>=38 degree Celsius for \>1hour; G\>=3 neutropenic infection(absolute neutrophil count \<1.0\*10\^9/L),G\>=3 thrombocytopenia (platelet count\<50.0-25.0\*10\^9/L)with bleeding;G4 thrombocytopenia(PC\<25.0\*10\^9/L),G4 anemia(life-threatening).Non-hematologic: any G4 toxicities;G3 toxicities persisting for \>3days despite medical treatment(nausea,vomiting,diarrhea)except endocrinopathies controlled with hormonal therapy;ALT/AST \>3\*upper limit of normal(ULN)if normal at baseline or 2\*Baseline(\>ULN at baseline)with total bilirubin \>2\*ULN and alkaline phosphatase \<2\*ULN;G3 QTcF prolongation after correction of any reversible cause(electrolyte abnormalities/hypoxia).Delay of \>=3weeks in scheduled administration/failure to deliver 75% of doses due to toxicities attributable to any study treatment. DLT-evaluable analysis set.
Time frame: Day 1 up to Week 6 (first 2 treatment cycles; 1 cycle = 21 days)
Population: The DLT analysis set is a subset of the safety analysis set and includes all enrolled participants in the Phase 1b lead-in who are eligible for the study, receive at least one dose of the combination treatment, and either experience DLT during the first 2 cycles (6 weeks) of treatment, or complete the DLT observation period for the first 2 cycles of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT) | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT) | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT) | 0 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT) | 1 Participants |
Secondary
Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue
Mutational load within tumor tissue was defined as number per megabase of the genome, coding, base substitution, and indel mutations present in the sample. Mutational load was determined in whole blood samples using next generation deoxyribonucleic acid (DNA) sequencing followed by computational analysis.
Time frame: Pre-dose on Day 1 of Cycle 1
Population: The tumor tissue-based biomarker analysis set was subset of the safety analysis set and included participants who had at least one baseline and one on-treatment biomarker assessment for the same biomarker. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue | 4.3 Mutations per megabase | Standard Deviation 6.75 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue | 2.8 Mutations per megabase | Standard Deviation 2.76 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue | 4.4 Mutations per megabase | Standard Deviation 5.15 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue | 2.5 Mutations per megabase | Standard Deviation 2.88 |
Secondary
Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment
DOR was defined as time from first documentation of objective response (confirmed CR or PR) to the date of first PD documentation or death due to any cause, whichever occurs first. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. Median DOR was not derived for \< 5 participants.
Time frame: From date of first documented response to date of first documented PD or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
Population: The full analysis set (FAS) included all participants who received at least 1 dose of study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment | NA Months |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment | 9.6 Months |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment | NA Months |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment | NA Months |
Secondary
Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade
Participants with laboratory abnormalities of any Grade as per NCI CTCAE toxicity grading v4.03 were summarized:hematology(anemia,hemoglobin increased,lymphocyte count decreased,lymphocyte count increased, neutrophil count decreased,platelet count decreased and white blood cell decreased)and clinical chemistry(alanine aminotransferase increased,alkaline phosphatase,increased,aspartate,aminotransferase increased,blood bilirubin increased,cholesterol high,creatinine phosphokinase\[cpk\] increased,creatinine increased,gamma-glutamyl transferase\[ggt\] increased,hypercalcemia,hyperglycemia,hyperkalemia, hypermagnesemia,hypernatremia,hypertriglyceridemia,hypoalbuminemia,hypocalcemia,hypoglycemia,hypokalemia,hypomagnesemia,hyponatremia, hypophosphatemia,serum amylase increased and lipase increased).As per NCI CTCAE toxicity grading v4.03, Grade1=mild;Grade2=moderate;Grade3=severe;Grade4=life-threatening;Grade 5=death.Parameters with at least 1 participant with abnormal value are reported.
Time frame: From screening up to 90 days after last dose of study drug (maximum up to 5 years approximately)
Population: Safety analysis set included all participants who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | WHITE BLOOD CELL DECREASED | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOCALCEMIA | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPONATREMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CREATININE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOMAGNESEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LIPASE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ASPARTATE AMINOTRANSFERASE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOPHOSPHATEMIA | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | SERUM AMYLASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CPK INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALANINE AMINOTRANSFERASE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | PLATELET COUNT DECREASED | 3 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOKALEMIA | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | GGT INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALKALINE PHOSPHATASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT DECREASED | 3 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ANEMIA | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERGLYCEMIA | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | NEUTROPHIL COUNT DECREASED | 3 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERCALCEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERMAGNESEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERKALEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | BLOOD BILIRUBIN INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERNATREMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERTRIGLYCERIDEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALANINE AMINOTRANSFERASE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | BLOOD BILIRUBIN INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CREATININE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | GGT INCREASED | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERGLYCEMIA | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERKALEMIA | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOKALEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPONATREMIA | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LIPASE INCREASED | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | SERUM AMYLASE INCREASED | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOPHOSPHATEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOMAGNESEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOCALCEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERTRIGLYCERIDEMIA | 3 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERNATREMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERMAGNESEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERCALCEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ANEMIA | 5 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT DECREASED | 5 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALKALINE PHOSPHATASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ASPARTATE AMINOTRANSFERASE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CPK INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | NEUTROPHIL COUNT DECREASED | 8 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | PLATELET COUNT DECREASED | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | WHITE BLOOD CELL DECREASED | 7 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ANEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOMAGNESEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | NEUTROPHIL COUNT DECREASED | 3 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERCALCEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | PLATELET COUNT DECREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALKALINE PHOSPHATASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | GGT INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERMAGNESEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT DECREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ASPARTATE AMINOTRANSFERASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | SERUM AMYLASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERNATREMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LIPASE INCREASED | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALANINE AMINOTRANSFERASE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOPHOSPHATEMIA | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | WHITE BLOOD CELL DECREASED | 3 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CPK INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERGLYCEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | BLOOD BILIRUBIN INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOCALCEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CREATININE INCREASED | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOKALEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERTRIGLYCERIDEMIA | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPONATREMIA | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERKALEMIA | 0 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALKALINE PHOSPHATASE INCREASED | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERNATREMIA | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERGLYCEMIA | 4 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | WHITE BLOOD CELL DECREASED | 16 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERMAGNESEMIA | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERCALCEMIA | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | GGT INCREASED | 4 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | NEUTROPHIL COUNT DECREASED | 21 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ANEMIA | 6 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT DECREASED | 7 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ALANINE AMINOTRANSFERASE INCREASED | 3 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CREATININE INCREASED | 0 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOMAGNESEMIA | 2 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LIPASE INCREASED | 4 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOCALCEMIA | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | CPK INCREASED | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | ASPARTATE AMINOTRANSFERASE INCREASED | 2 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | BLOOD BILIRUBIN INCREASED | 0 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | PLATELET COUNT DECREASED | 11 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | SERUM AMYLASE INCREASED | 4 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOPHOSPHATEMIA | 3 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPONATREMIA | 4 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPOKALEMIA | 5 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERKALEMIA | 2 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | LYMPHOCYTE COUNT INCREASED | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade | HYPERTRIGLYCERIDEMIA | 2 Participants |
Secondary
Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03
AE was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using NCI CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of participants with grade 3 or higher TEAEs were reported.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
Population: Safety analysis set included all participants who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 | 5 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 | 12 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 | 6 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 | 37 Participants |
Secondary
Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab
Blood samples were collected for assessment of avelumab ADAs using a tiered assay and confirmed positive samples were tested for neutralizing antibodies (nAb).
Time frame: From first dose of study drug up to last dose of study drug (maximum up to 5 years approximately)
Population: The immunogenicity analysis set is a subset of the safety analysis set and will include participants who have at least one ADA/nAb sample collected for avelumab.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | NAB ever positive | NA Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | ADA ever positive | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | ADA ever positive | 5 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | NAB ever positive | NA Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | NAB ever positive | NA Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | ADA ever positive | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | NAB ever positive | NA Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab | ADA ever positive | 9 Participants |
Secondary
Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression
PD-L1 expression was determined using the Ventana PD-L1 SP263 IHC assay. PD-L1-positive status in UC cohorts was defined using an algorithm that combines assessments of PD-L1 staining on tumor and immune cells scored by pathologists and in NSCLC cohorts was defined as PD-L1 expression on \>=1% of tumor cells. PD-L1 expression at baseline and on-treatment were reported in this outcome measure.
Time frame: Baseline and Cycle 2 Day 8 (each cycle of 21 days)
Population: FAS included all participants who received at least one dose of study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Positive PD-L1 | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Negative PD-L1 | 4 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Unknown PD-L1 | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Positive PD-L1 | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Negative PD-L1 | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Unknown PD-L1 | 4 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Unknown PD-L1 | 10 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Positive PD-L1 | 2 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Positive PD-L1 | 6 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Unknown PD-L1 | 0 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Negative PD-L1 | 7 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Negative PD-L1 | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Negative PD-L1 | 4 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Unknown PD-L1 | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Positive PD-L1 | 1 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Unknown PD-L1 | 5 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Negative PD-L1 | 0 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Positive PD-L1 | 1 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Negative PD-L1 | 6 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Unknown PD-L1 | 32 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Negative PD-L1 | 13 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | On-treatment (Cycle 2 Day 8)- Positive PD-L1 | 3 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Positive PD-L1 | 28 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression | Baseline- Unknown PD-L1 | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Adverse event (AE) was any untoward medical occurrence in a participants who received any study drug without regard to possibility of causal relationship. Serious adverse event was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
Population: Safety analysis set included all participants who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 6 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 3 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 9 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 13 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 6 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 5 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 40 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 20 Participants |
Secondary
Number of Participants With Treatment Related TEAEs
A treatment related AE included AEs related to at least one study drug in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Relatedness to study drug was assessed by the investigator.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
Population: Safety analysis set included all participants who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Number of Participants With Treatment Related TEAEs | 6 Participants |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Number of Participants With Treatment Related TEAEs | 12 Participants |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Number of Participants With Treatment Related TEAEs | 6 Participants |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Number of Participants With Treatment Related TEAEs | 40 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the first dose of study treatment to the date of death due to any cause. Participants last known to be alive were censored at the date of last contact. The median duration of OS was not derived for less than (\<) 10 participants.
Time frame: From first dose of study treatment until death due to any cause (maximum up to 5 years approximately)
Population: The full analysis set (FAS) included all participants who received at least 1 dose of study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Overall Survival (OS) | NA Months |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Overall Survival (OS) | 18.1 Months |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Overall Survival (OS) | NA Months |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Overall Survival (OS) | 15.1 Months |
Secondary
Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment
PFS was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. The median duration of PFS was not derived for less than (\<) 10 participants.
Time frame: From start of treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
Population: The full analysis set (FAS) included all participants who received at least 1 dose of study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment | NA Months |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment | 9.8 Months |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment | NA Months |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment | 5.4 Months |
Secondary
Serum Concentration of Avelumab
The lower limit of quantification (LLOQ) for avelumab was 0.2 micrograms per milliliter. Pharmacokinetic concentration analysis set was subset of safety analysis set and included participants who had at least one concentration measurement for avelumab or other study drugs which they were assigned to receive. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
Time frame: Pre-dose, 1 hour post-dose on Day 1 of Cycle 1, 2, 3, 6, 10, 14; 336 hours post-dose on Day 15 of Cycle 1, 2, 3 (each cycle of 21 days)
Population: The PK concentration analysis sets are subsets of the safety analysis set including participants who have at least one concentration measurement for avelumab which they were assigned to receive,based on the treatment group.Overall number of participants analyzed=participants evaluable for this outcome measure and only those contributing to data for this outcome measure.Number analyzed=participants evaluable and contributing at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- 1 hour | 179.0 Micrograms per milliliter | Geometric Coefficient of Variation 38 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- pre-dose | 4.780 Micrograms per milliliter | Geometric Coefficient of Variation 44 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- pre-dose | 11.38 Micrograms per milliliter | Geometric Coefficient of Variation 24 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- pre-dose | 9.523 Micrograms per milliliter | Geometric Coefficient of Variation 33 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- 1 hour | 92.53 Micrograms per milliliter | Geometric Coefficient of Variation 203 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 1/Day 1- 1 hour | 173.3 Micrograms per milliliter | Geometric Coefficient of Variation 26 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- 1 hour | 164.2 Micrograms per milliliter | Geometric Coefficient of Variation 33 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 1/Day 15- 336 hours | 12.32 Micrograms per milliliter | Geometric Coefficient of Variation 47 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- 1 hour | 215.3 Micrograms per milliliter | Geometric Coefficient of Variation 20 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 2/Day 15- 336 hours | 16.87 Micrograms per milliliter | Geometric Coefficient of Variation 24 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- pre-dose | 8.122 Micrograms per milliliter | Geometric Coefficient of Variation 40 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- pre-dose | 14.97 Micrograms per milliliter | Geometric Coefficient of Variation 28 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- 1 hour | 147.0 Micrograms per milliliter | Geometric Coefficient of Variation 35 |
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 3/Day 15- 336 hours | 19.40 Micrograms per milliliter | Geometric Coefficient of Variation 14 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- pre-dose | 5.651 Micrograms per milliliter | Geometric Coefficient of Variation 75 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 3/Day 15- 336 hours | 17.15 Micrograms per milliliter | Geometric Coefficient of Variation 40 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 1/Day 1- 1 hour | 172.2 Micrograms per milliliter | Geometric Coefficient of Variation 18 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- pre-dose | 8.695 Micrograms per milliliter | Geometric Coefficient of Variation 115 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- 1 hour | 204.0 Micrograms per milliliter | Geometric Coefficient of Variation 28 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- pre-dose | 9.518 Micrograms per milliliter | Geometric Coefficient of Variation 65 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- pre-dose | 3.754 Micrograms per milliliter | Geometric Coefficient of Variation 115 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 2/Day 15- 336 hours | 13.55 Micrograms per milliliter | Geometric Coefficient of Variation 33 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 1/Day 15- 336 hours | 9.570 Micrograms per milliliter | Geometric Coefficient of Variation 92 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- 1 hour | 208.3 Micrograms per milliliter | Geometric Coefficient of Variation 23 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- pre-dose | 13.37 Micrograms per milliliter | Geometric Coefficient of Variation 77 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- 1 hour | 216.6 Micrograms per milliliter | Geometric Coefficient of Variation 22 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- 1 hour | 222.0 Micrograms per milliliter | Geometric Coefficient of Variation 27 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- 1 hour | 197.0 Micrograms per milliliter | Geometric Coefficient of Variation 18 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- 1 hour | 6.040 Micrograms per milliliter | — |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 1/Day 1- 1 hour | 284.1 Micrograms per milliliter | Geometric Coefficient of Variation 33 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 1/Day 15- 336 hours | 16.51 Micrograms per milliliter | Geometric Coefficient of Variation 68 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- pre-dose | 4.328 Micrograms per milliliter | Geometric Coefficient of Variation 332 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- 1 hour | 104.5 Micrograms per milliliter | Geometric Coefficient of Variation 1474 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 2/Day 15- 336 hours | 16.82 Micrograms per milliliter | Geometric Coefficient of Variation 137 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- pre-dose | 4.878 Micrograms per milliliter | Geometric Coefficient of Variation 662 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- 1 hour | 93.81 Micrograms per milliliter | Geometric Coefficient of Variation 2989 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 3/Day 15- 336 hours | 26.17 Micrograms per milliliter | Geometric Coefficient of Variation 74 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- pre-dose | 10.86 Micrograms per milliliter | Geometric Coefficient of Variation 165 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- 1 hour | 245.4 Micrograms per milliliter | Geometric Coefficient of Variation 6 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- pre-dose | 6.620 Micrograms per milliliter | — |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- pre-dose | 12.24 Micrograms per milliliter | Geometric Coefficient of Variation 523 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- 1 hour | 29.05 Micrograms per milliliter | Geometric Coefficient of Variation 20555 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- 1 hour | 402.2 Micrograms per milliliter | Geometric Coefficient of Variation 19 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- pre-dose | 18.55 Micrograms per milliliter | Geometric Coefficient of Variation 58 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- 1 hour | 296.8 Micrograms per milliliter | Geometric Coefficient of Variation 36 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 10/Day 1- 1 hour | 242.9 Micrograms per milliliter | Geometric Coefficient of Variation 121 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 3/Day 1- pre-dose | 6.771 Micrograms per milliliter | Geometric Coefficient of Variation 104 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 2/Day 15- 336 hours | 18.66 Micrograms per milliliter | Geometric Coefficient of Variation 75 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 1/Day 15- 336 hours | 14.71 Micrograms per milliliter | Geometric Coefficient of Variation 74 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 14/Day 1- pre-dose | 16.49 Micrograms per milliliter | Geometric Coefficient of Variation 57 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- 1 hour | 311.9 Micrograms per milliliter | Geometric Coefficient of Variation 36 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 2/Day 1- pre-dose | 5.013 Micrograms per milliliter | Geometric Coefficient of Variation 196 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 1/Day 1- 1 hour | 300.2 Micrograms per milliliter | Geometric Coefficient of Variation 32 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- 1 hour | 344.0 Micrograms per milliliter | Geometric Coefficient of Variation 27 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 6/Day 1- pre-dose | 10.39 Micrograms per milliliter | Geometric Coefficient of Variation 233 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Serum Concentration of Avelumab | Cycle 3/Day 15- 336 hours | 22.55 Micrograms per milliliter | Geometric Coefficient of Variation 79 |
Secondary
Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment
TTR was defined as the time from the date of first dose of study treatment to the first documentation of objective response (CR or PR) as assessed by investigator according to RECIST v 1.1. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD.
Time frame: From first dose of study treatment until first documentation of CR or PR (maximum up to 5 years approximately)
Population: The full analysis set (FAS) included all participants who received at least 1 dose of study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin | Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment | 2.8 Months | Full Range 1.3 |
| Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin | Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment | 1.4 Months | Full Range 1.1 |
| Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin | Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment | 1.3 Months | Full Range 1.3 |
| Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin | Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment | 1.5 Months | Full Range 1.3 |