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Frontline Pembrolizumab Combo Approved by FDA for NSCLC

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Pembrolizumab (Keytruda) has been granted an accelerated approval by the FDA for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous non–small cell lung cancer (NSCLC), regardless of PD-L1 expression.

The approval was based on part 2 of cohort G in the KEYNOTE-021 trial, in which the pembrolizumab triplet elicited an objective response rate (ORR) of 55% compared with 29% with the chemotherapy agents alone (P = .0016). The median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy alone (HR, 0.53; 95% CI, 0.31-0.91; P = .0205).

In the open-label phase II KEYNOTE-021 cohort study, 123 patients were randomized to receive pemetrexed and carboplatin alone (n = 63) or in combination with pembrolizumab (n = 60). In both groups, carboplatin was given at AUC 5 mg/mL per min and pemetrexed was given at 500 mg/m2 every 3 weeks for 4 cycles followed by indefinite pemetrexed maintenance. In the investigational arm, pembrolizumab was continued for 24 months.

The baseline characteristics were balanced between the 2 arms. The average age of participants was 62.5 years versus 63.2 years for the control arm. The ECOG performance status was 0 (40% vs 46%) and 1 (58% and 54%) for those in the pembrolizumab and control arms, respectively. Eighteen percent of those in the pembrolizumab arm were of non-white ethnic origin compared with 8% in the control arm. Additionally, 25% of those in the pembrolizumab arm were never smokers versus 14% in the control group.

After 10.6 months of follow-up, 88% remained alive and progression free compared with 78% for the chemotherapy agents alone. The median time to response was 1.5 months  compared with 2.7 months for the chemotherapy agents alone. Overall, a response of at least 6 months was seen for 92% of patients in the first group compared with 81% of those in the control arm. The 6-month PFS rate was 77% with pembrolizumab (95% CI, 64-86) compared with 63% for chemotherapy alone (95% CI, 49-74). At the time of the analysis, 78% of patients remained alive in each arm, with no discernible differences in survival between the two groups (HR, 0.90; 95% CI, 0.42-1.91; P = .39). The 6-month overall survival was 92% in both arms. However, this analysis was likely confounded by crossover, since 74% of patients in the chemotherapy alone arm went on to receive a subsequent PD-1 or PD-L1 inhibitor compared with none in the pembrolizumab arm.

In assessments of PD-L1 staining, those with expression of less than 1% had an ORR of 57% with the pembrolizumab combination (12 of 21) compared with 13% in the chemotherapy arm (3 of 23). In those with expression on greater than 1% of cells, the ORR was 54% with pembrolizumab and chemotherapy (21 of 39). The ORRs were 80% and 35% in those with ≥50% expression for the pembrolizumab (16 of 20) and chemotherapy arms (6 of 17), respectively.

The most frequently observed all-grade treatment-related adverse events (AEs) in the pembrolizumab and chemotherapy arms, respectively, were fatigue (64% vs 40%), nausea (58% vs 44%), anemia (32% vs 53%), vomiting (25% vs 18%), rash (27% vs 15%), decreased appetite (19% vs 18%), and diarrhea (20% vs 10%). AEs led to treatment discontinuations for 10% of those in the pembrolizumab arm versus 13% in the control group. There were more grade 3/4 treatment-related AEs in the pembrolizumab arm (39% vs 26%). The most common grade ≥3 treatment-related AEs were anemia (12% vs 15%, respectively), decreased neutrophil count (5% vs 3%), thrombocytopenia (3% vs 3%), decreased lymphocyte count (3% vs 2%), neutropenia (3% vs 2%), and sepsis (3% vs 2%).

The accelerated approval is contingent on results from a confirmatory trial. A phase III study is currently exploring platinum-based chemotherapy plus pemetrexed with or without pembrolizumab for patients with untreated squamous NSCLC. In this study, investigators will be able to pick between cisplatin or carboplatin as their platinum-based chemotherapy of choice. The primary endpoint of the study is PFS, with an accrual goal of 570 patients and an estimated completion date of March 2019 (NCT02578680)