FDA Restricts Pembro/Chemo Use for Gastric Cancer

• On November 7, 2023, the FDA updated the current indication of pembrolizumab (Keytruda) and trastuzumab (Herceptin), fluoropyrimidine, and platinum-containing chemotherapy for first-line treatment of HER2-expressing locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
• The new indication limits the combination’s use to patients with tumors expressing PD-L1.
• The FDA also approved the Agilent PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to identify patients with PD-L1-expressing gastric or GEJ adenocarcinoma.

The FDA restricted the existing indication of pembrolizumab plus trastuzumab and chemotherapy for first-line treatment of locally advanced unresectable or metastatic HER2-expressing gastric or GEJ adenocarcinoma to tumors expressing PD-L1 (combined positive score [CPS] ≥ 1) as determined by an FDA-approved test.¹

In addition to this updated indication, the FDA approved of the Agilent PD-L1 IHC 22C3 pharmDx companion diagnostic for use in this intent-to-treat population. The device identifies patients with high tumor PD-L1 expression.

In May 2021, the FDA approved pembrolizumab in combination with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy based on interim analysis results from the phase 3 KEYNOTE-811 trial (NCT03615326).² Findings presented at the 2023 European Society for Medical Oncology Congress from the second interim analysis at a follow-up of 28.3 months (interquartile range [IQR], 19.4-34.3) for the pembrolizumab arm and 28.5 months (IQR, 20.1-34.3) for the placebo arm demonstrated a median progression-free survival (PFS) of 10.0 months (95% CI, 8.6-11.7) with pembrolizumab vs 8.1 months (95% CI, 7.0-8.5) with placebo (n = 348; HR, 0.72; 95% CI, 0.60-0.87); P =.0002). In patients with a PD-L1 CPS ≥ 1, the median PFS was 10.8 months (95% CI, 8.5-12.5) in the pembrolizumab arm (n = 298) and 7.2 months (95% CI, 6.8-8.4) in the placebo arm (n = 296; HR, 0.70; 95% CI, 0.58-0.85).

Findings from the third interim analysis at a median follow-up of 38.4 months (IQR, 29.5-44.4) in the pembrolizumab arm and 38.6 months (IQR, 30.2-44.4) in the placebo arm showed a median PFS of 10.0 months (95% CI, 8.6-12.2) in the pembrolizumab arm compared with 8.1 months (95% CI, 7.1-8.6) in the placebo arm (HR, 0.73; 95% CI, 0.61-0.87). In the PD-L1 CPS ≥ 1 population, the median PFS was 10.9 months (95% CI, 8.5-12.5) for patients treated with the pembrolizumab/chemotherapy combination vs 7.3 months (95% CI, 6.8-8.5) for patients in the placebo arm (HR, 0.71; 95% CI, 0.59-0.86).^2,3

Data from the third interim analysis also demonstrated a median overall survival (OS) of 20.0 months (95% CI, 17.8-22.1) for patients treated with the pembrolizumab regimen vs 16.8 months (95% CI, 15.0-18.7) with placebo (HR, 0.84; 95% CI, 0.70-1.01). The median OS in the PD-L1 CPS ≥ 1 population was 20.0 months (95% CI, 17.9-22.7) in the pembrolizumab arm vs 15.7 months (95% CI, 13.5-18.5) in the placebo arm (HR, 0.81; 95% CI, 0.67-0.98).

The safety profile of the pembrolizumab regimen was consistent with the known safety profiles of the individual agents.¹

REFERENCES:

1. FDA amends pembrolizumab’s gastric cancer indication. News release. U.S. Food & Drug Administration. November 7, 2023. Accessed November 9, 2023. https://tinyurl.com/bdf8vvmc

2. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424

3. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: survival results from the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Lancet Oncol. Published online October 20, 2023. doi:10.1016/S0140-6736(23)02033-0