CHMP Recommends First-Line Pembrolizumab Plus Chemotherapy for PD-L1+, HER2– Advanced Gastric/GEJ 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

References

1. Merck receives positive EU CHMP opinion for Keytruda (pembrolizumab) plus chemotherapy as first-line treatment for HER2-negative advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma expressing PD-L1 (CPS ≥1). News release. October 13, 2023. Accessed October 13, 2023. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-keytruda-pembrolizumab-plus-chemotherapy-as-first-line-treatment-for-her2-negative-advanced-gastric-or-gastroesophageal-junction-gej-adenocarcinom/
2. Rha SY, Wyrwicz L, Weber PEY, et al. KEYNOTE-859 study of pembrolizumab plus chemotherapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: outcomes in the protocol-specified PD-L1–selected populations. J Clin Oncol. 2023;41(suppl 16):4014. doi:10.1200/JCO.2023.41.16_suppl.4014