Merck has announced plans to withdraw the accelerated approval indication for pembrolizumab in the treatment of select patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express a PD-L1 combined positive score of 1 or more, and who have progressed on or after 2 or more previous lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy, and HER2-/neu-targeted therapy, if appropriate.
Merck has announced plans to withdraw the accelerated approval indication for pembrolizumab (Keytruda) in the treatment of select patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express a PD-L1 combined positive score (CPS) of 1 or more, and who have progressed on or after 2 or more previous lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy, and HER2-/neu-targeted therapy, if appropriate.1
The September 2017 approval of pembrolizumab had been based on primary data from cohort 1 of the phase 2 KEYNOTE-059 trial (NCT02335411). In this cohort of patients with PD-L1–positive tumors and microsatellite stable (MSS) tumor status of undetermined microsatellite instability or mismatch repair status, the agent elicited an objective response rate (ORR) of 13.3% (n = 143; 95% CI, 8.2%-20.0%).2 In those with known MSS/mismatch repair proficient status and a CPS of 1 or greater (n = 100), the ORR was 11.0% (95% CI, 5.6%-18.8%).
Among 19 responders, the median duration of response ranged from 2.8+ months to 19.4+ months. Responses were 6 months or longer in 58% of patients (n = 11) and 12 months or longer in 26% of patients (n = 5).
The continued approval of the agent was contingent on positive findings from the phase 3, second-line KEYNOTE-061 (NCT02370498) and frontline KEYNOTE-062 (NCT02494583) trials. However, the immunotherapy missed each trial’s primary end point of overall survival (OS) and progression-free survival (PFS) in patients who had a PD-L1 CPS of 1 or greater.
Because the agent failed to meet the post-marketing requirement of demonstrating an OS benefit in a phase 3 study, in April 2021, the Oncologic Drugs Advisory Committee met to evaluate the third-line cancer indication; they voted 6 to 2 against maintaining the approval in this population.3
Merck will initiate the withdrawal of the agent in this indication in 6 months. The decision does not impact other indications for pembrolizumab.
“While there remains an unmet need for heavily pretreated patients with advanced gastric cancer, we recognize that the treatment landscape has evolved and we respect the FDA’s efforts to continually evaluate accelerated approvals,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “Our research with [pembrolizumab] has contributed to recent advances in the treatment of gastric cancer, and we are continuing to advance studies to help more patients with this disease.”
In KEYNOTE-061, patients with gastric/GEJ cancer were randomized to receive 200 mg of pembrolizumab every 3 weeks (n = 296) or 80 mg/m2 of paclitaxel on days 1, 8, and 15 every 4 weeks (n = 296). The hazard ratio (HR) for OS and PFS was 0.82 (95% CI, 0.66-1.03) and 1.27 (95% CI, 1.03-1.57), respectively.
In KEYNOTE-062, patients with gastric/GEJ cancer who had a PD-L1 CPS of at least 1 were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks (n = 256), pembrolizumab plus 5-fluorouracil (5-FU)/cisplatin (n = 257), or 5-FU/cisplatin (n = 250). The HR for OS and PFS for pembrolizumab vs 5-FU/cisplatin was 0.91 (95% CI, 0.69-1.182) and 1.64 (95% CI, 1.36-1.98), respectively.
In April 2021, the paradigm shifted when the FDA approved nivolumab (Opdivo) for use in combination with select types of chemotherapyin the frontline treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma based on findings from the phase 3 CheckMate-649 trial (NCT02872116).4
Results indicated that nivolumab plus leucovorin, 5-FU, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOX) significantly improved survival in treatment-naïve patients compared with chemotherapy alone. The median OS with nivolumab/chemotherapy was 13.8 months vs 11.6 months with chemotherapy alone (HR, 0.80; 95% CI, 0.71-0.94; P = .0002).
“The landscape of both therapeutics and even companion diagnostics looks so different now than when the accelerated approval was first granted,” Mark Lewis, MD, had stated during the ODAC meeting. “The timing of this meeting is providential coming after the seismic CheckMate-649 data and subsequent approval. I think we are going to see immunotherapy move earlier in treatment lines, and frankly the main reason I voted no, and it’s not to cast a deaf ear on the unmet needs of the patients, is that none of the pending studies as best I could tell would definitively answer the question of either monotherapy or the position in terms of lines of therapeutic sequencing of this agent.”
The following 4 ongoing, randomized phase 3 trials still have the potential to confirm the clinical benefit of the agent in gastric cancer within 1 to 3 years: KEYNOTE-859 (NCT03675737), KEYNOTE-811 (NCT03615326), KEYNOTE-585 (NCT03221426), and LEAP-015 (NCT04662710). However, none of these trials will examine single-agent pembrolizumab.