Episode 7: The KEYNOTE 811 trial

In the KEYNOTE 811 study, a randomised, double-blind phase 3 trial, the combination of trastuzumab plus pembrolizumab was investigated in patients with HER2-positive metastatic gastroesophageal junction or gastric cancer in the first-line treatment. The trial included patients treated with chemotherapy (capecitabine and oxaliplatin, or 5-FU and cisplatin) with trastuzumab, randomised between the addition of pembrolizumab or placebo.

The primary endpoints were PFS and OS, with the primary analysis revealing a significant improvement in PFS with a hazard ratio of around 0.70, representing a 30% reduction in the risk of progression. Although OS did not reach statistical significance, there was a clear separation of curves, indicating a numerical benefit. The patients with PD-L1 positivity (CPS ≥ 1) showed substantial benefits from the addition of pembrolizumab, while those with PD-L1 negativity did not demonstrate the same benefits.

The overall response rate (ORR) increased by 15%, reaching 75% with the combination of pembrolizumab, trastuzumab, and chemotherapy. Safety results indicated no new concerns, with some immune-related side effects observed.

The trial set a new standard, and the FDA initially approved it for all HER2-positive tumours but later restricted it to patients with PD-L1-positive tumours, which constituted around 85% of HER2-positive cases.

The study’s findings suggest that excluding PD-L1-negative patients is a logical strategy based on the observed lack of benefit in this subgroup. The trial’s significance is underscored by its approval by regulatory authorities and the observed magnitude of benefit for patients. Looking ahead, the bar is set high for new treatments to surpass the efficacy of chemo doublet plus trastuzumab and pembrolizumab in HER2-positive, PD-L1-positive patients. Ongoing trials with bispecific antibodies face the challenge of surpassing this established standard, and comparisons may be complicated due to the design of control arms.

In conclusion, the KEYNOTE 811 trial stands as a pivotal study, reshaping standards for HER2-positive metastatic gastric cancer.