Esophagus to Small Intestine
Lancet Oncol. 2024;25(2):212–24
Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastroesophageal cancer (KEYNOTE-585): An interim analysis of the multicenter, double-blind, randomized phase 3 study
Background: The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma is unknown. The authors assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastroesophageal adenocarcinoma.
Methods: The KEYNOTE-585 study is a multicenter, randomized, placebo-controlled, double-blind, phase 3 study done at 143 medical centers in 24 countries. Eligible patients were aged ≥ 18 years with untreated, locally advanced, resectable gastric or gastroesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0–1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for 4 cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for 4 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumor stage, and chemotherapy backbone. Primary end points were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least 1 dose of study treatment.
Findings: Between October 9, 2017, and January 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47.7 months (interquartile range, 38.0–54.8), pembrolizumab was superior to placebo for pathological complete response (52/402 [12.9%; 95% confidence interval {CI}: 9.8–16.6] vs. 8/402 [2.0%; 95% CI: 0.9–3.9]; difference 10.9%, 95% CI: 7.5–14.8; p < 0.00001). Median event-free survival was longer with pembrolizumab versus placebo (44.4 months, 95% CI: 33.0–not reached vs. 25.3 months, 95% CI: 20.6–33.9; hazard ratio [HR] = 0.81, 95% CI: 0.67–0.99; p = 0.0198) but did not meet the threshold for statistical significance (p = 0.0178). Median overall survival was 60.7 months (95% CI: 51.5–not reached) in the pembrolizumab group versus 58.0 months (95% CI: 41.5–not reached) in the placebo group (HR = 0.90, 95% CI: 0.73–1.12; p = 0.174). Grade 3 or worse adverse events of any cause occurred in 312 of 399 patients (78%) in the pembrolizumab group and 297 of 400 patients (74%) in the placebo group; the most common were nausea (240 [60%] vs. 247 [62%]), anemia (168 [42%] vs. 158 [40%]), and decreased appetite (163 [41%] vs. 172 [43%]). Treatment-related serious adverse events were reported in 102 (26%) and 97 patients (24%). Treatment-related adverse events that led to death occurred in 4 patients (1%) patients in the pembrolizumab group (interstitial ischemia, pneumonia, decreased appetite, and acute kidney injury [n = 1 each]) and 2 patients (< 1%) in the placebo group (neutropenic sepsis and neutropenic colitis [n = 1 each]).
Interpretation: Although neoadjuvant and adjuvant pembrolizumab versus placebo improved the pathological complete response, it did not translate to significant improvement in event-free survival in patients with untreated, locally advanced resectable gastric or gastroesophageal cancer.