Based on tumor response rate and durability of response, KEYTRUDA with trastuzumab and chemotherapy received accelerated approval by the US FDA in 2021, and in November 2023, the US FDA revised the existing indication of KEYTRUDA with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This updated indication, which remains approved under accelerated approval regulations, restricts its use to patients whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test.

In this clinical trial, eligible participants aged 18 years and above with first-line, locally advanced unresectable, or metastatic HER2+ mG/GEJ adenocarcinoma, irrespective of PD-L1 status, were randomly assigned to receive either KEYTRUDA at 200 mg IV every 3 weeks or a placebo IV every 3 weeks. This was administered in conjunction with standard chemotherapy (5-FU and cisplatin [FP] or capecitabine and oxaliplatin [CAPOX]) and trastuzumab (standard of care [SOC]). The trial's dual primary endpoints were progression-free survival (PFS) and overall survival (OS).

The interim analysis, conducted up to March 29, 2023, included 698 randomized patients with a median follow-up of 38.5 months. Across all patients, KEYTRUDA + SOC demonstrated a significant improvement in PFS compared to placebo + SOC (10.0 vs. 8.1 months). In patients with PD-L1 CPS ≥1, the median PFS was 10.9 vs. 7.3 months. Overall survival was prolonged with KEYTRUDA + SOC compared to placebo + SOC in all patients (20.0 vs. 16.8 months) and in patients with PD-L1 CPS ≥1 (median 20.0 vs. 15.7 months). Although the prespecified criteria for significance were not met, OS analysis continued to the final stage. The overall response rate was 73% vs. 60% with KEYTRUDA + SOC vs. placebo + SOC, and the median duration of response was 11.3 months vs. 9.5 months. 

Adverse-event incidence was similar between treatment arms, and the observed AEs were as expected, with no new safety concerns identified. 

KOL insights

“The ORR has increased from 50% to 73%. Previously, the cancer was only reduced by half, but now it has been reduced by three quarters. There is no reason not to use this drug, so it was approved in the United States in 2021.” – Professor, Yonsei Cancer Hospital, South Korea

Conclusion

In 2021, KEYTRUDA, combined with trastuzumab and chemotherapy, received accelerated approval from the US FDA based on promising tumor response rates and response durability. In November 2023, the FDA updated the indication for KEYTRUDA in first-line treatment for HER2-positive gastric or gastroesophageal junction adenocarcinoma. This revised approval, under accelerated approval regulations, specifically applies to patients whose tumors express PD-L1 (CPS ≥ 1). 

In summary, the introduction of pembrolizumab alongside first-line trastuzumab and chemotherapy yielded significant enhancements in progression-free survival (PFS) and overall response rate (ORR), particularly notable in tumors expressing both HER2 and PD-L1. The PFS showed an improvement from 7.3 to 10.9 months, and the ORR increased from 58% to 73%, with an extended overall survival (OS) from 15.7 to 20.0 months in the CPS ≥1 population. Adverse event incidence was comparable between the treatment arms, and the observed adverse events were as anticipated, without unveiling any new safety concerns. The ongoing KEYNOTE-811 study continues as planned, with the final analysis of OS to be conducted according to the protocol.

For more insight into the patient's burden, epidemiological factors, treatment options, and evolving developments in the market landscape, refer to the Gastroesophageal Junction Adenocarcinoma Market Insight, Epidemiology and Market Forecast Report, Gastric Cancer Market Insight, Epidemiology, And Market Forecast Report, and HER2+ Gastric Cancer Market Insight, Epidemiology, And Market Forecast Report