Pembrolizumab/Chemo Regimen Meets pCR End Point, But Misses EFS Goal in Resectable Gastric/GEJ Adenocarcinoma

Neoadjuvant treatment with pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab plus chemotherapy, then pembrolizumab monotherapy, led to a statistically significant improvement in pathological complete response (pCR) rates vs neoadjuvant chemotherapy alone in patients with locally advanced, resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma, meeting one of the primary end points of the phase 3 KEYNOTE-585 trial (NCT03221426).¹

Findings from a prespecified interim analysis also showed that patients in the pembrolizumab arm experienced an improvement in event-free survival (EFS); however, these results did not reach statistical significance. As a result, the overall survival (OS) end point was not formally tested since superiority was not demonstrated in EFS.

Full data from the analysis will be presented at an upcoming medical meeting.

“While a statistically significant improvement in pCR was observed in this study, we are disappointed that the [pembrolizumab] regimen did not significantly improve EFS, a result that underscores the challenges in treating locally advanced resectable gastric cancer,” Scot Ebbinghaus, MD, vice president of Global Clinical Development at Merck Research Laboratories, stated in a news release. “Innovative research in earlier stages of cancer is critical to help patients achieve better outcomes, and our efforts continue in earnest. We are grateful to the patients and investigators for their participation in this study.”

The randomized, double-blind, placebo-controlled trial enrolled patients at least 18 years of age with previously untreated localized gastric or GEJ adenocarcinoma defined by a T3 or higher primary lesion or the presence of any positive lymph nodes.² Other key inclusion criteria included a plan to proceed to surgery following neoadjuvant chemotherapy, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of more than 6 months.

Patients were excluded if they had a history of non-infectious pneumonitis, had an active infection requiring systemic therapy, or received prior treatment with pembrolizumab, an anti–PD-1/PD-L1/PD-L2 agent, or an anti–CTLA-4 agent.

Patients randomly assigned to the experimental arm received neoadjuvant treatment consisting of 200 mg of intravenous (IV) pembrolizumab on day 1 of each 3-week cycle, plus 80 mg/m2 of IV cisplatin on day 1 and 1000 mg/m2 of oral capecitabine (Xeloda) twice per day on days 1 to 14 of each 3-week cycle, or 80 mg/m2 of IV cisplatin on day 1 and 800 mg/m2 of IV 5-fluorouracil on days 1 to 5 of each 3-week cycle.

Following resection, patients received 3 more cycles of the same pembrolizumab plus chemotherapy regimen, followed by pembrolizumab monotherapy given at 200 mg once every 3 weeks for up to 11 additional cycles.

Those randomly assigned to the placebo arm received 1 of the 2 chemotherapy regimens plus placebo for 3 cycles both before and after surgery, followed by placebo monotherapy given once every 3 weeks for up to 11 additional cycles.

Along with pCR rate and EFS, OS served as another primary end point. Secondary end points included the percentage of patients who experience 1 or more adverse effects (AE), percentage of patients who discontinue treatment due to AEs, and disease-free survival.

Regarding safety, the toxicity profile for pembrolizumab was consistent with data from previously reported studies.

References

1. Merck provides update on phase 3 KEYNOTE-585 trial in locally advanced resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. June 20, 2023. Accessed June 20, 2023. https://www.merck.com/news/merck-provides-update-on-phase-3-keynote-585-trial-in-locally-advanced-resectable-gastric-and-gastroesophageal-junction-gej-adenocarcinoma/
2. Study of pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy in participants with gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-585/KEYNOTE-585). ClinicalTrials.gov. Updated August 19, 2022. Accessed June 20, 2023. https://clinicaltrials.gov/ct2/show/NCT03221426