First-line treatment with pembrolizumab in combination with chemotherapy improves the outcomes in advanced NSCLC
In the phase II KEYNOTE-021 study, the addition of pembrolizumab to platinum-based chemotherapy almost doubled the response rate (55% vs. 29%) and led to 4 months of additional progression-free survival (PFS) in a population of patients that was not selected for PD-L1 expression. Moreover, the combination was shown to be tolerable with a manageable toxicity profile. These findings will now be validated in a larger phase III study.
In the phase II KEYNOTE-021 study, the combination of pembrolizumab with platinum-based chemotherapy was assessed among 123 patients with stage IIIB/IV chemotherapy-naive, non-squamous NSCLC. Patients in the trial were treated with four cycles of carboplatin (AUC 5) and pemetrexed (500 mg/m2 q3w), with or without 24 months of pembrolizumab (200 mg q3w). Maintenance pemetrexed was allowed in both treatment arms. In this study, patients were not selected by the amount of PD-L1 expression and the randomization was stratified according to the PD-L1 tumor proportion score (TPS) (at least 1%, or below 1%). Patients with disease progression on chemotherapy were allowed to cross-over to pembrolizumab. The primary endpoint was objective response rate (ORR), with PFS as key secondary objective.
The median exposure to the pembrolizumab-chemotherapy combination in this study was 8.0 months as compared to 4.9 months when only chemotherapy was given. After a median follow-up of 10.6 months, the pembrolizumab-chemotherapy combination was shown to be associated with a significantly higher objective response rate (ORR) than chemotherapy alone (55% vs. 29%; p=0.0016). In the subgroup of patients with a PD-L1 TPS of 50% or more, the ORR with pembrolizumab-chemotherapy was 80%.
Adding pembrolizumab to chemotherapy also led to a significant prolongation of the PFS with more than 4 months (median PFS: 13.0 vs. 8.9 months; HR[95%CI]: 0.53[0.31-0.91]; p=0.012). At 6 months, 77% of patients in the pembrolizumab-chemotherapy arm were still alive and free of progression compared to 63% in the chemotherapy arm. The combination was associated with a higher rate of grade 3/4 adverse events (39% vs. 26%), but this did not lead to more toxicity-related treatment discontinuations (10% vs. 13%).
In summary, adding pembrolizumab to standard chemotherapy with carboplatin and pemetrexed nearly doubled the chance of a response to therapy and reduced the risk of progression of death by almost 50% over carboplatin and pemetrexed given alone as first line therapy for advanced non-squamous NSCLC. Moreover, the combination was shown to be tolerable with a manageable side effect profile. These encouraging data will now be further investigated in a randomized phase III study with a similar design.
Langer C, Gadgeel S, Borghaei H, et al. Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. Presented at ESMO 2016; Abstract LBA46_PR.