Perioperative Pembrolizumab Falls Short in Gastric, GEJ Cancer

Adding pembrolizumab to perioperative chemotherapy did not improve survival outcomes in patients with resectable gastric or gastroesophageal junction (GEJ) cancer in the phase 3 KEYNOTE-585 study.

The addition of perioperative pembrolizumab to chemotherapy did improve the pathological complete response (pCR) rate, but this did not translate to improvements in event-free survival (EFS) or overall survival (OS).

Researchers reported these results in The Lancet Oncology.

KEYNOTE-585 (ClinicalTrials.gov Identifier: NCT03221426) included 1254 patients with locally advanced, resectable gastric or GEJ adenocarcinoma.

In the main cohort, 804 patients were randomly assigned to receive 3 cycles of neoadjuvant pembrolizumab (n=402) or placebo (n=402), each in combination with cisplatin plus capecitabine or fluorouracil.

After surgery, patients received an additional 3 cycles of pembrolizumab or placebo, each in combination with chemotherapy. This was followed by pembrolizumab or placebo alone for 11 cycles.

A cohort of 203 patients received different neoadjuvant and adjuvant chemotherapy. They received pembrolizumab (n=100) or placebo (n=103), each in combination with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT) every 2 weeks for 4 cycles in the neoadjuvant and adjuvant phases.

Efficacy Results

In the main cohort, the pCR rate was 12.9% in the pembrolizumab arm and 2.0% in the placebo arm (P <.00001).

The median EFS was 44.4 months in the pembrolizumab arm and 25.3 months in the placebo arm (hazard ratio [HR], 0.81; 95% CI, 0.67-0.99; P =.0198), which did not meet prespecified criteria for significance.

The median OS was 60.7 months in the pembrolizumab arm and 58.0 months in the placebo arm (HR, 0.90; 95% CI 0.73-1.12; P =.174).

When the researchers combined the main cohort and the FLOT cohort, the pCR rate was 13.0% in patients who received pembrolizumab and 2.4% in those who received placebo.

The median EFS in the combined cohort was 45.8 months for patients who received pembrolizumab and 25.7 months for those who did not (HR, 0.81; 95% CI, 0.68-0.97). The median OS was 60.7 months and not reached, respectively (HR, 0.93; 95% CI, 0.76-1.12).

Safety Results

In the main cohort, the rate of treatment-related adverse events (TRAEs) was 95% in the pembrolizumab arm and 96% in the placebo arm. The rate of grade 3 or higher TRAEs was 65% and 63%, respectively.

The most common grade 3 or higher TRAEs (in the pembrolizumab and placebo arms, respectively) were neutrophil count decrease (26% vs 23%), neutropenia (18% vs 17%), anemia (5% vs 8%), nausea (6% in both arms), and decreased appetite (4% vs 6%).

There were 4 fatal TRAEs in the pembrolizumab arm (interstitial ischemia, pneumonia, decreased appetite, and acute kidney injury) and 2 fatal TRAEs in the placebo arm (neutropenic sepsis and neutropenic colitis).

In the FLOT cohort alone, the rate of grade 3 or higher TRAEs was 76% in the pembrolizumab arm and 63% in the placebo arm.

The most common grade 3 or higher TRAEs (in the pembrolizumab and placebo arms, respectively) were neutrophil count decrease (27% vs 30%) and neutropenia (17% vs 14%). There were 3 fatal TRAEs in the pembrolizumab arm and 1 in the placebo arm.

The researchers noted that, to their knowledge, KEYNOTE-585 “is the first phase 3 study to investigate the efficacy and safety of adding an anti-PD1 monoclonal antibody to perioperative chemotherapy for gastric or gastro-esophageal junction adenocarcinoma.”

They added that, although pembrolizumab did not improve EFS in this study, “the increased pathological responses and acceptable safety profile suggests further exploration of anti-PD1 therapy might be beneficial in this setting.”

Disclosures: This research was supported by Merck Sharp & Dohme. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

This article originally appeared on Cancer Therapy Advisor