Merck Withdraws EU Application for Frontline Pembrolizumab Combo in NSCLC

lung cancer

Merck has announced that it has withdrawn its European application for pembrolizumab (Keytruda) in combination with pemetrexed and carboplatin as a first-line treatment for metastatic nonsquamous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