Episode 3: Pembrolizumab with chemotherapy in first line treatment of metastatic gastric cancer

Presented by Prof Eric Van Cutsem (University Hospitals Leuven) and Prof Marc Van den Eynde (Cliniques Universitaires Saint-Luc)

The KEYNOTE-859 trial explores the integration of immune therapy with chemotherapy in the first-line management of metastatic gastric cancer. Employing a double-blind phase 3 design, patients were randomized to receive IV with 200 mg pembrolizumab or placebo every 3 weeks, in conjunction with the investigator’s chosen chemotherapy.

The primary endpoint for this investigation encompassed OS in the ITT population, along with subpopulations characterized by PD-L1 CPS scores of ≥1 or ≥10. Additionally, pertinent secondary parameters, such as PFS and response rate, were systematically evaluated.

Results from the trial affirm the viability of immune therapy as a first-line intervention, as evidenced by an increase in OS. Notably, in patients with higher PD-L1 CPS scores, the magnitude of this benefit was further amplified. Beyond OS, both PFS and response rate exhibited heightened benefits with immunotherapy as the threshold for PD-L1 status increased.

This study unequivocally establishes the positioning of the pembrolizumab-chemotherapy combination in the first-line treatment of metastatic gastric cancer. However, ongoing discussions persist regarding the optimal threshold for maximal patient benefit. While prior studies with nivolumab established a threshold CPS ≥5, there is a notable absence of data in this study for a CPS ≥5 benchmark, as observed in nivolumab trials.

Exploration of data about patients with MSI-H tumours was also included. Despite the relatively low occurrence of MSI-H tumours in gastric cancer, the administration of a checkpoint inhibitor was deemed crucial and beneficial for these patients.

A key question arises regarding whether MSI-H patients with metastatic gastric cancer would derive superior benefits from first-line treatment with chemotherapy and pembrolizumab or nivolumab compared to treatment with a checkpoint inhibitor alone or dual checkpoint inhibition. While the presented results do not definitively answer this question, it is highlighted that, presently, there is a lack of data suggesting a lack of benefit when initiating immunotherapy without prior chemotherapy. Consequently, chemotherapy retains a role in treatment, and the combination of chemotherapy with immunotherapy emerges as the current optimal treatment strategy. Patient-specific factors, such as age and tolerability, further influence treatment decisions.

Concerning dual immunotherapy, considerations are akin to those in colorectal cancer. Expert opinions converge on the notion that the answer is more closely linked to the MSI status than the anatomical location of the disease, underscoring the diagnostic nature of this inquiry. Although data supporting the combination of chemotherapy and immunotherapy yield favourable outcomes in colorectal cancer, extrapolation to gastric cancer lacks robust supporting evidence.

In summary, experts concur that pembrolizumab demonstrates activity in the first-line treatment of metastatic gastric cancer, enhancing the efficacy of chemotherapy. Optimal patient selection, incorporating MSI status and PD-L1 CPS scores, is deemed pivotal in determining treatment strategies.

References:

Rha SY. et al. (2023) Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 24(11): 1181-1195