KEYNOTE 859

Recent progress in metastatic gastric cancer treatment has begun to shift the outlook for patients, particularly in the HER2-negative population. Traditionally, median survival for metastatic gastric cancer has remained around 12 months, with few effective therapies beyond cytotoxic chemotherapy. However, in the last two to three years, a significant development has been the incorporation of immune checkpoint inhibitors, specifically PD-1 inhibitors, into treatment regimens for these patients.

For HER2-negative gastric cancer, pembrolizumab has demonstrated meaningful survival benefits when added to chemotherapy. This approach was tested in the KEYNOTE 859 study, which compared pembrolizumab plus chemotherapy to chemotherapy alone. The study showed improved overall survival in the overall population, with even greater benefits in patients whose tumours expressed higher levels of PD-L1, as measured by the Combined Positive Score. In gastric cancer, CPS-1 is often considered the threshold for defining a positive tumour microenvironment that is amenable to immune modulation. Notably, as CPS expression rises above 10, the survival benefit of pembrolizumab becomes especially pronounced. Five-year follow-up data from these studies show that more than 20% of patients with HER2-negative gastric cancer achieve long-term survival, representing a substantial improvement compared to historical outcomes. These data demonstrate a clear survival advantage for patients with higher CPS expression who are treated with pembrolizumab-based combination therapy.

Importantly, the toxicity profile of pembrolizumab in these combinations is generally manageable and consistent with what is observed in other tumour types, without adding excessive complexity to standard chemotherapy regimens. This means that pembrolizumab can be integrated into treatment plans for HER2-negative gastric cancer without a significant additional burden, offering a new standard of care for a broader global patient population.