Merck Withdraws EU Application for Frontline Pembrolizumab Combo in NSCLC

Merck has announced that it has withdrawn its European application for pembrolizumab (Keytruda) in combination with pemetrexed and carboplatin as a first-line treatment for metastatic nonsquamous non—small cell lung cancer (NSCLC).

A Merck spokesperson told OncLive that the company withdrew the application “based on discussions with the European regulatory authorities,” but did not give any further explanation. The company reported in a press release that it was “confident” in the results from KEYNOTE-021.

As part of its application in the European Union, Merck submitted findings from the G cohort of KEYNOTE-021 that showed significant improvements in overall response rate (ORR) and progression-free survival (PFS). The FDA approved the combination in this setting based on these results in May.

Data presented at the 2017 ASCO Annual Meeting from KEYNOTE-021 showed that the pembrolizumab combination reduced the risk for progression or death by 50% compared with chemotherapy alone.

Patients in cohort G (n = 123) were randomly assigned to 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 at a fixed 200 mg dose every 3 weeks.

After 14.5 months of follow-up, the median PFS was not yet reached in the pembrolizumab arm (95% CI, 8.5-not reached) compared with 8.9 months with chemotherapy alone (95% CI, 6.2-10.3). The 12-month PFS rate was 56% in the pembrolizumab arm compared with 34% with chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.84; P = .0038). The ORR with pembrolizumab was 56.7% compared with 30.2% for chemotherapy alone (P = .0016).

The 12-month OS rate with pembrolizumab was 76% compared with 69.3% for patients treated with chemotherapy alone. At the 14.5-month follow-up, there had been 16 deaths in the pembrolizumab arm and 23 in the chemotherapy group. Median OS had not yet been reached at the time of the analysis. There was a nonstatistically significant 31% reduction in the risk of death with pembrolizumab (HR, 0.69; 95% CI, 0.36-1.31; P = .13).

Crossover to pembrolizumab was permitted following progressive disease. Seventy-five percent of those who discontinued chemotherapy alone went on to receive a PD-1 or PD-L1 inhibitor, with 22 patients receiving pembrolizumab as part of the crossover.

The median age of patients was 62.5 years in the pembrolizumab group versus 66.0 years for the control arm. Fifty-eight percent of patients had an ECOG performance status of 1 in the pembrolizumab group compared with 54% with chemotherapy alone. More patients were current or former smokers in the chemotherapy alone arm (75% vs 86%) and more patients had stable brain metastases in the pembrolizumab group (15% vs 10%).

The median duration of response was not reached in the PD-1 arm compared with 16.2 months for chemotherapy alone. Overall, 59% of patients in the pembrolizumab arm continued to respond versus 47% with chemotherapy alone.

Patients with both PD-L1—positive and –negative NSCLC benefited more from the pembrolizumab combination compared with chemotherapy alone. In those with PD-L1 expression on <1% of cells, the ORR with pembrolizumab was 62% (13 of 21 patients; 95% CI, 38%-82%) versus 13% with chemotherapy alone (3 of 23; 95% CI, 3%-34%). Those with the highest level of PD-L1 expression (≥50%), had an ORR of 80% with pembrolizumab (16 of 20; 95% CI, 56%-94%) versus 41% with chemotherapy alone (7 of 17; 95% CI, 18%-67%).

Grade ≥3 treatment-related adverse events (AEs) were experienced by 39% of those in the pembrolizumab arm versus 29% of those treated with chemotherapy alone. The most common grade ≥3 AEs with pembrolizumab plus chemotherapy and chemotherapy alone, respectively, were anemia (12% vs 15%), neutrophil count decrease (7% vs 3%), fatigue (3% vs 0%), nausea (2% vs 0%), rash (2% vs 0%), vomiting (2% vs 0%), aspartate aminotransferase increase (2% vs 2%), and alanine aminotransferase increase (2% vs 2%).

Papadimitrakopoulou V, Gadgeel SM, Borghaei H, et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G. J Clin Oncol. 2017;35 (suppl; abstr 9094).