A Study of Necitumumab in the First-Line Treatment of Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC)

DLT was defined as any of the following events graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, when the event occurred within 21 days from Day 1 in Cycle 1 and was considered to be definitely or probably related to necitumumab and/or gemcitabine-cisplatin chemotherapy: Grade 4 neutropenia ≥ 7 days, Grade ≥ 3 febrile neutropenia except for transient febrile neutropenia (Grade 3 neutropenia with fever ≥ 38.5 degrees Celsius (°C) for ≤ 24 hours), Grade 3 thrombocytopenia requiring platelet substitution, Grade 4 thrombocytopenia, ≥Grade 3 nonhematologic toxicity (excluding nausea, vomiting, arthralgia, myalgia, asthenia, fatigue, diarrhea, constipation, anorexia), any toxicity leading to the omission of necitumumab on Day 8 or 15 (for participants for whom necitumumab was delayed from Days 8 to 15) during the Cycle 1.

Time frame: Day 1 to Day 21 in Cycle 1 (Up To 21 days)

Population: All enrolled participants who received at least one dose of study drug during study Phase 1b.

OS defined as the time from the date of randomization to the date of death due to any cause. Participants who are alive at the time of study completion or are lost to follow-up will be censored at the time they were last known to be alive.

Time frame: From Date of Randomization until Death Due to Any Cause (Up To 39 Months)

Population: All randomized participants who received at least one dose of study drug during study Phase 2. Censored participants in the GC+N Arm = 27 and in the GC Arm = 17.

ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Time frame: Baseline to Measured Progressive Disease (Up To 39 Months)

Population: All randomized participants who received at least one dose of study drug during study Phase 1b.

The Cmax is observed maximum serum concentration, taken directly from the serum concentration-time profile.

Time frame: Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion

Population: All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b. In cohort 1 (cycle 3), zero participants were analyzed because no data was collected for the outcome measure.

The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time.

Time frame: Gemcitabine: C1D1: Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion

Population: All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b. In cohort 1 (cisplatin), zero participants were analyzed because no data was collected for the outcome measure.

The AUC(0-infinity) is area under the serum concentration-time curve from time zero to infinite time.

Time frame: Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion

Population: All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b. In cohort 1 and 2 (cycle 3), zero participants were analyzed because no data was collected for the outcome measure.

The Cmax is observed maximum plasma concentration, taken directly from the plasma concentration-time profile.

Time frame: Gemcitabine: Cycle 1(C1) Day1(D1): Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1 D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion

Population: All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b.

EQ-5D measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. The index score was calculated from a set of item weights to derive a score on a theoretical scale of 0 to 1, with 1 representing the best health status and zero representing death based on item weights for the Japanese population. One Cycle = 3 weeks and it can be delayed up to 6 weeks.

Time frame: Baseline, Cycle 4 (Cycle = 3 weeks)

Population: All randomized participants who received at least one dose of study drug and had evaluable baseline and post-baseline EQ-5D data during study Phase 2.

EQ-5D VAS allowed participants to rate their present health condition. Possible scores ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). One Cycle = 3 weeks and it can be delayed up to 6 weeks.

Time frame: Baseline, Cycle 4 (Cycle = 3 weeks)

Population: All randomized participants who received at least one dose of study drug and had had evaluable baseline and post-baseline EQ-5D data during study Phase 2.

The LCSS is a validated and reliable instrument to assess lung cancer-specific symptoms and their impact on QOL.The LCSS total score was defined as the mean of the 9 items of the scale and the average symptom burden index (ASBI) is defined as the mean of 6 symptom-specific lung cancer questions. Each of the 9 symptom or summary items is assessed on a 100-mm visual analogue scale (VAS), with 0 representing no symptoms or better QOL.

Time frame: Baseline, Cycle 4 (Cycle = 3 weeks)

Population: All randomized participants who received at least one dose of study drug had evaluable baseline and post-baseline LCSS data. One Cycle = 3 weeks and it can be delayed up to 6 weeks.

A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point.

Time frame: Baseline up to 30 Days Post Last Infusion (estimated up to 39 months)

Population: All enrolled participants who received at least 1 dose of drug and had evaluable data for antibodies during study Phase 2.

ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Time frame: Baseline to Measured Progressive Disease (Up To 39 Months)

Population: All randomized participants who received at least one dose of study drug during study Phase 2.

The minimum observed serum concentration (Ctrough) of Necitumumab was evaluated.

Time frame: Predose Day 1 of Cycle 1, 2, 3, 4, and every 2 cycles after Cycle 5

Population: All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 2.

PFS defined as time from date of randomization until first radiographic documentation of measured progressive disease(PD) defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. PD was at least 20% increase in sum of diameters of target lesions with reference being smallest sum on study and an absolute increase of at least 5 mm,or unequivocal progression of non-target lesions,or 1 or more new lesions.If participant does not have complete baseline disease assessment,PFS time censored at date of randomization,regardless of whether or not objectively determined disease progression or death observed for participant.If participant was not known to have died or have objective progression as of data inclusion cutoff date for analysis,the PFS time censored at last adequate tumor assessment date.The use of new anticancer therapy prior to occurrence of PD resulted in censoring at the date of last radiographic assessment prior to initiation of new therapy.

Time frame: From Date of Randomization to Measured Progressive Disease or Death Due to Any Cause (Up To 39 Months)

Population: All randomized participants who received at least one dose of study during study Phase 2. Censored participants in the GC+N Arm = 6 and in the GC Arm = 10.

TTF was time from the date of randomization until the date of the first observation of radiographically documented progressive disease (PD), death due to any cause, discontinuation of treatment for any reason, or initiation of new anticancer therapy. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Time to treatment failure was censored at the date of the last follow-up visit for participants who did not discontinue early, who were still alive, and who have not progressed.

Time frame: From Date of Randomization to Measured Progressive Disease, Death Due to Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up To 39 Months)

Population: All randomized participants who received at least one dose of study drug during study Phase 2. Censored participants in the GC+N Arm = 1 and in the GC Arm = 0.