Pembrolizumab/Chemotherapy Meets Survival End Point in HER2– Advanced/Metastatic Gastric/GEJ Adenocarcinoma

Pembrolizumab (Keytruda) and chemotherapy combination therapy yielded a statistically significant and clinically meaningful improvement in the primary end point of overall survival (OS) compared with placebo with chemotherapy in patients with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a press release from Merck on topline results from the phase 3 KEYNOTE-859 trial (NCT03675737).

In addition to the OS improvement, the pre-specified interim analysis by independent data monitoring committee review also highlighted a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall response rate (ORR) in patients treated with pembrolizumab plus chemotherapy. Moreover, pembrolizumab produced a safety profile that was consistent with findings from previously reported trials assessing the agent, and no new safety signals were seen. Investigators of the KEYNOTE-859 trial will present these results at an upcoming medical meeting followed by submission to regulatory authorities.

“Despite improvements in cancer care, advanced gastric cancer continues to have one of the lowest 5-year survival rates, and new interventions are urgently needed,” Eliav Barr, MD, senior vice president and head of global clinical development and chief medical officer of Merck Research Laboratories, said in the press release. “The results from KEYNOTE-859 show the potential of [pembrolizumab] plus chemotherapy to improve survival beyond chemotherapy alone for patients with HER2-negative locally advanced unresectable or metastatic gastric or [GEJ] adenocarcinoma, regardless of PD-L1 expression.”

The randomized, double-blind phase 3 KEYNOTE-859 trial was designed to evaluate pembrolizumab and chemotherapy compared with placebo plus chemotherapy for the first-line treatment of patients with HER2-negative unresectable or metastatic gastric or GEJ adenocarcinoma. Investigators enrolled a total of 1579 patients. In the experimental arm, patients received 200 mg of pembrolizumab intravenously once every 3 weeks for up to 35 cycles plus physician’s choice of either 80 mg/m2 of intravenous cisplatin once every 3 weeks plus 800 mg/m2 of intravenous 5-fluorouracil on days 1 to 5 every 3 weeks, or 130 mg/m2 of intravenous oxaliplatin once every 3 weeks plus 1000 mg/m2 of oral capecitabine twice a day on days 1 to 14 every 3 weeks. Patients in the comparator arm received matched placebo along with the same chemotherapy backbone.

Secondary end points of the KEYNOTE-859 trial included PFS, ORR, duration of response, and safety.

Patients were eligible to enroll on the trial if they had a histologically confirmed diagnosis of HER2-negative locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma with known PD-L1 expression. Additional inclusion criteria included having measurable disease per RECIST v1.1 guidelines, providing an archival tumor sample deemed adequate for PD-L1 biomarker analysis, having an ECOG performance status of 0 or 1 within 3 days prior to study randomization, and adequate organ function.

Patients were not able to enroll on the trial if they had squamous cell or undifferentiated gastric cancer or underwent major surgery, an open biopsy, or had a significant traumatic injury 28 days before randomization. Patients were also unsuitable for enrollment if they had higher than grade 1 peripheral neuropathy, received previous therapy with an anti–PD-1 or –PD-L1 agent, prior systemic anticancer therapy 4 weeks before randomization, or previous radiotherapy within 2 weeks before randomization.

Reference

Merck announces phase 3 KEYNOTE-859 trial met primary endpoint of overall survival in patients with HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. November 22, 2022. Accessed November 22, 2022. bit.ly/3AB1sRM