The Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion for pembrolizumab plus fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of adult patients with HER2-negative gastric or gastroesophageal junction adenocarcinoma.
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion for pembrolizumab (Keytruda) plus fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of adult patients with HER2-negative, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma expressing a PD-L1 combined positive score (CPS) of at least 1.1
The endorsement was based on overall survival (OS) findings from the phase 3 KEYNOTE-859 (NCT03675737) trial. Data presented during the 2023 ASCO Annual Meeting showed that at the October 3, 2022, data cutoff, patients with a PD-L1 CPS of at least 1 treated in the pembrolizumab arm (n = 618) achieved a median OS of 13.0 months (95% CI, 11.6-14.2) compared with 11.4 months (95% CI, 10.5-12.0) among those treated with placebo plus chemotherapy (n = 617; HR, 0.74; 95% CI, 0.65-0.84; P < .0001). The 12- and 24-month OS rates in the pembrolizumab arm were 52.4% and 29.6% respectively, compared with 45.7% and 17.7%, respectively, in the placebo arm. Moreover, pembrolizumab plus chemotherapy displayed an OS benefit over placebo plus chemotherapy in each prespecified patient subgroup that was examined.2
“This positive CHMP opinion builds on our efforts to treat advanced gastric and GEJ cancer in Europe, including in patients with HER2-negative disease, which accounts for the vast majority of gastric cancer cases,” Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, said in a news release.1 “We look forward to the European Commission’s decision and are excited to potentially provide an immunotherapy regimen to patients in the European Union with locally advanced unresectable or metastatic HER2-negative gastric or GEJ cancer, whose tumors express PD-L1 with a CPS ≥ 1.”
KEYNOTE-859 was a global, double-blind trial that enrolled patients with treatment-naïve, histologically or cytologically confirmed, locally advanced, unresectable, or metastatic HER2-negative gastric GEJ adenocarcinoma and an ECOG performance status of 1 or less. PD-L1 status was assessed locally via immunohistochemistry.2
Eligible patients were randomly assigned in a 1:1 manner to receive chemotherapy with 5-flourouracil or CAPOX in combination with either intravenous pembrolizumab at 200 mg once every 3 weeks for a maximum of 35 cycles or placebo given at the same dosing schedule as pembrolizumab.
The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and safety.
Additional findings from KEYNOTE-859 demonstrated that patients in the overall population who received pembrolizumab plus chemotherapy (n = 790) achieved a median OS of 12.9 months (95% CI, 11.9-14.0) compared with 11.5 months (95% CI, 10.6-12.1) among patients treated with placebo plus chemotherapy (n = 789; HR, 0.78; 95% CI, 0.70-0.87; P < .0001). The 12- and 24-month OS rates in the pembrolizumab arm were 52.7% and 28.2% respectively, compared with 46.7% and 18.9%, respectively, in the placebo arm.
Additionally, the median PFS in patients with a PD-L1 CPS of at least 1 was 6.9 months (95% CI, 6.0-7.2) vs 5.6 (95% CI, 5.4-5.7) in the pembrolizumab and placebo arms, respectively (HR, 0.72; 95% CI, 0.63-0.82; P < .0001). The ORR in these patients was 52.1% (95% CI, 48.1%-56.1%) vs 42.6% (95% CI, 38.7%-46.6%), respectively (P = .00041). The median DOR was 8.3 months (95% CI, 1.2+ to 41.5+) vs 5.6 months (95% CI, 1.3+ to 34.2+), respectively.
In the overall safety population, patients in the pembrolizumab arm (n = 785) experienced any-grade treatment-related adverse effects (TRAEs) at a rate of 95.7% compared with 93.5% in the placebo arm (n = 787). Patients in both arms experienced grade 3 to 5 TRAEs (59.4% vs 51.1%, respectively), TRAEs that led to death (1.0% vs 2.0%), and TRAEs that led to treatment discontinuation (26.4% vs 20.1%).
The recommendation from the CHMP will be reviewed by the European Commission for marketing authorization in the European Union. A final decision on the endorsement is expected in the 4th quarter of 2023.1