Pembrolizumab/Trastuzumab/Chemo Enhances Survival in HER2+ Gastric Cancer

Pembrolizumab (Keytruda) combined with trastuzumab (Herceptin) and chemotherapy led to a clinically meaningful and statistically significant improvement in overall survival (OS) vs placebo in patients with HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, meeting the primary end point of the phase 3 KEYNOTE-811 trial (NCT03615326).¹

In addition to the OS improvement seen with the combination in the intention-to-treat population at the final analysis of this trial, patients whose tumors expressed PD-L1 (combined positive score [CPS] ≥1) had the most benefit with pembrolizumab plus trastuzumab and chemotherapy. Additionally, the safety profile of pembrolizumab was consistent in this trial with that seen in previously reported studies, and no new safety signals were observed.

Results will be presented at an upcoming medical meeting and shared with regulatory authorities worldwide.

“Patients diagnosed with advanced gastric cancer often face a poor prognosis, underscoring the need for treatment options that have the potential to extend patients’ lives,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in a press release. “These overall survival results from KEYNOTE-811 are encouraging and build on the positive progression-free survival, overall response rate and duration of response data from this study.”

These data for OS build upon positive data which were previously reported from the phase 3 trial. At the third interim analysis, the pembrolizumab regimen elicited a median OS of 20.0 months (95% CI, 17.8-22.1) vs 16.8 months (95% CI, 15.0-18.7) for the placebo regimen in the overall population (HR, 0.84; 95% CI, 0.70-1.01).^2,3 In patients with a PD-L1 CPS of 1 or more, the median OS was 20.0 months (95% CI, 17.9-22.7) vs 15.7 months (95% CI, 13.5-18.5) for the pembrolizumab and placebo arms, respectively (HR, 0.81; 95% CI, 0.67-0.98).

In May 2021, the FDA granted accelerated approval to pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced, unresectable, or metastatic HER2-positive gastric or GEJ adenocarcinoma, based on ORR data from the first interim analysis of KEYNOTE-811.⁴ Ongoing approval for this indication will rely on verification and description of clinical benefit at the final analysis of the KEYNOTE-811 study.¹

Additional data from the randomized, placebo-controlled study were presented at the 2023 European Society of Medical Oncology Congress and simultaneously published in The Lancet.^2,3 At the second interim analysis conducted at a median follow-up of 28.3 months (IQR, 19.4-34.3) for the pembrolizumab arm and 28.5 months (IQR, 20.1-34.3) for the placebo arm, the pembrolizumab regimen (n = 350) led to a median progression-free survival (PFS) of 10.0 months (95% CI, 8.6-11.7) compared with 8.1 months (95% CI, 7.0-8.5) for the placebo regimen (n = 348; HR, 0.72; 95% CI, 0.60-0.87; P = .0002).

Among those with a PD-L1 CPS of 1 or more, the median PFS was 10.8 months (95% CI, 8.5-12.5) in the pembrolizumab arm (n = 298) vs 7.2 months (95% CI, 6.8-8.4) in the placebo arm (n = 296; HR, 0.70; 95% CI, 0.58-0.85).

At the third interim analysis, which took place at a median follow-up 38.4 months (IQR, 29.5-44.4) in the pembrolizumab group and 38.6 months (IQR, 30.2-44.4) in the placebo group, the median PFS was 10.0 months (95% CI, 8.6-12.2) compared with 8.1 months (95% CI, 7.1-8.6) for the overall populations in the pembrolizumab and placebo arms, respectively (HR, 0.73; 95% CI, 0.61-0.87). For patients who had a PD-L1 CPS of at least 1, the median PFS was 10.9 months (95% CI, 8.5-12.5) among those given the pembrolizumab regimen vs 7.3 months (95% CI, 6.8-8.5) for the placebo regimen (HR, 0.71; 95% CI, 0.59-0.86).

REFERENCES:

1. Merck announces phase 3 KEYNOTE-811 trial met dual primary endpoint of overall survival (OS) as first-line treatment in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. May 1, 2024. Accessed May 1, 2024. https://tinyurl.com/bdvc86tw

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

4. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed May 1, 2024. https://tinyurl.com/mrfy6eu8