Frontline Pembrolizumab Plus Trastuzumab/Chemo Meets OS End Point in HER2+ Gastric/GEJ Cancer

Marjorie Green, MD

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

In the final analysis of the trial, pembrolizumab plus trastuzumab and chemotherapy improved OS in the intention-to-treat (ITT) population, with the most substantial benefit seen in patients whose tumors had a PD-L1 combined positive score (CPS) of at least 1.

“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,” Marjorie Green, MD, senior vice president and head of late-stage oncology and global development at Merck Research Laboratories, said in the press release. “These OS results from KEYNOTE-811 are encouraging and build on the positive progression-free survival [PFS], overall response rate [ORR], and duration of response [DOR] data from this study.”

In May 2021, the FDA approved pembrolizumab for use in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic, HER2-positive gastric or GEJ adenocarcinoma, based on prior data from KEYNOTE-811.²

Data from prior interim analyses of the phase 3 trial presented at the 2023 ESMO Congress showed that the study met the other dual primary end point of PFS. These findings, which were simultaneously published in The Lancet, demonstrated that at a median 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 at the second interim analysis, patients treated with the pembrolizumab regimen (n = 350) experienced a median PFS of 10.0 months (95% CI, 8.6-11.7) vs 8.1 months (95% CI, 7.0-8.5) for patients given the placebo regimen (n = 348; HR, 0.72; 95% CI, 0.60-0.87; P = .0002).^3,4

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

Findings from the third interim analysis also presented at the 2023 ESMO Congress and published simultaneously in The Lancet demonstrated that 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 for the ITT population in the pembrolizumab arm was 10.0 months (95% CI, 8.6-12.2) compared with 8.1 months (95% CI, 7.1-8.6) for those in the placebo arm (HR, 0.73; 95% CI, 0.61-0.87). In patients with a PD-L1 CPS of at least 1, the median PFS was 10.9 months (95% CI, 8.5-12.5) for the pembrolizumab arm vs 7.3 months (95% CI, 6.8-8.5) for the placebo arm (HR, 0.71; 95% CI, 0.59-0.86).

KEYNOTE-811 was a randomized, double-blind trial evaluating pembrolizumab in combination with trastuzumab and chemotherapy in the first-line treatment of locally advanced, unresectable, or metastatic HER2-positive gastric or GEJ adenocarcinoma, with dual primary end points of PFS per RECIST v1.1 criteria as assessed by blinded independent central review and OS. Secondary end points included ORR, DOR, and safety.¹

To enroll, patients needed to be at least 18 years of age with a confirmed diagnosis of previously untreated, unresectable or metastatic gastric or GEJ adenocarcinoma that was HER2 positive (immunohistochemistry 3+ or 2+/in situ hybridization–positive). They needed to have measurable disease; an ECOG performance status of 0 or 1; a life expectancy of more than 6 months; and satisfactory organ function.^1,2

Eligible patients were randomly assigned to receive pembrolizumab at 200 mg once every 3 weeks in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy (investigator’s choice of 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin), or placebo in combination with trastuzumab and chemotherapy. Patients were treated for up to 35 cycles or until disease progression, intolerable toxicity, or study withdrawal.^1,3

Updated safety data from the final OS analysis remained consistent with previous studies, and no new safety signals emerged.¹

The final OS results of KEYNOTE-811 will be presented at an upcoming medical meeting and shared with regulatory authorities.

References

1. Merck announces phase 3 KEYNOTW-811 trial met dual primary end point of overall survival (OS) as first-line treatment in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Merck. News release. May 1, 2024. Accessed May 1, 2024. https://www.merck.com/news/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/
2. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed May 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer
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 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
4. 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. 2023;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0