In a phase III, international, double-blind, randomised, placebo-controlled KEYNOTE-811 study, adding pembrolizumab to trastuzumab and chemotherapy provided a significant improvement in overall survival (OS) as compared with trastuzumab and chemotherapy alone as first-line therapy for patients with unresectable or metastatic HER2-positive gastric or gastro-oesophageal junction (GEJ) adenocarcinoma.
Findings from the final OS analysis are reported at the ESMO Congress 2024 along with a simultaneous publication by Dr. Yelena Y. Janjigian of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 13 September 2024 in The New England Journal of Medicine.
Data from a previous interim analyses showed that the addition of pembrolizumab to trastuzumab and chemotherapy resulted in superior progression-free survival (PFS) and improved the objective response with durable responses as compared with placebo plus trastuzumab and chemotherapy in eligible patients, particularly in patients with a PD-L1 combined positive score (CPS) of 1 or more. These data supported the approval of a new first-line treatment option of pembrolizumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or GEJ adenocarcinoma with a PD-L1 CPS of 1 or more.
In the KEYNOTE-811 study, a total of 350 patients were assigned to receive pembrolizumab and 348 to receive placebo. As of the data cut-off date on 20 March 2024, the median follow-up was 50.2 months (range, 31.1 to 64.4). The characteristics of the patients were well balanced between the two groups.
At the final analysis, OS was significantly longer with pembrolizumab than with placebo. The median OS was 20.0 months in the pembrolizumab group, as compared with 16.8 months in the placebo group (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.67 to 0.94; p = 0.004). In patients with a PD-L1 CPS of 1 or more, the median OS was 20.1 months in the pembrolizumab group, as compared with 15.7 months in the placebo group (HR for death 0.79; 95% CI 0.66 to 0.95; p = 0.006).
Benefit in PFS was similar to that observed in previous analyses — among all the patients who underwent randomisation, the HR for progression or death was 0.73 (95% CI 0.61 to 0.87), and among patients with a PD-L1 CPS of 1 or more, the HR was 0.72 (95% CI 0.60 to 0.87). The overall response benefit was also similar to the benefit observed in previous analyses.
Adverse events of grades 3 through 5 occurred in 59% of the patients in the pembrolizumab group and in 51% of the patients in the placebo group. No new safety concerns were identified.
The authors concluded that the data support the approval of pembrolizumab plus trastuzumab and chemotherapy in patients with HER2-positive metastatic gastric/GEJ cancer and confirm this regimen as standard-of-care in the first-line setting.
The study was supported by Merck Sharp and Dohme and by a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center from the US National Cancer Institute of the National Institutes of Health.
References
- Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med 2024;391:1360-1362.
- 1400O - Janjigian YY, Kawazoe A, Bai Y, et al. Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma. Annals of Oncology 2024;35(Suppl 2):S877-878.