KEYNOTE-585 final analysis support perioperative pembrolizumab-chemo for G/GEJ cancer

Perioperative pembrolizumab plus chemotherapy confers survival benefit in individuals with locally advanced gastric and gastroesophageal junction (G/GEJ) cancer in the final analysis of the phase III KEYNOTE-585 trial.

“The overall benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in locally advanced, resectable G/GEJ adenocarcinoma is unknown,” noted Dr Kohei Shitara from the National Cancer Center Hospital East, Kashiwa, Japan, at ESMO GI 2024.

Hence, Shitara and colleagues sought to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor (ICI), and chemo in the perioperative setting in this patient population.

KEYNOTE-585 comprised 1,007 patients (median age 64 years, 72 percent men) with localized G/GEJ adenocarcinoma who has had no prior therapy. Thirty-eight percent of the participants were from Asia. A majority (>75 percent) of the participants had stage III tumours, stomach cancer, and non-MSI-H* disease. Participants were divided according to chemo backbone: the main (n=804) and FLOT** cohorts (n=203).

In the main cohort, patients were randomized 1:1 to receive XP/FP*** chemo with either IV pembrolizumab 200 mg or placebo Q3W. FLOT participants were randomized 1:1 to receive FLOT chemo with either pembrolizumab or placebo at similar doses. Following surgery, these regimens were continued for up to three cycles. Participants then went on to receive either adjuvant pembrolizumab or placebo for up to 11 cycles. Median follow-up was 59.9 months. [ESMO GI 2024, abstract LBA3]

OS, safety

The median overall survival (OS) with perioperative pembrolizumab-chemo in the main cohort was 71.8 months. With placebo-chemo, median OS was 55.7 months. A comparison between arms yielded a hazard ratio (HR) of 0.86 (95 percent confidence interval [CI], 0.71–1.06). The pembrolizumab arm was consistently favoured over placebo across most of the key subgroups evaluated.

This treatment effect favouring the pembrolizumab-based regimen was also observed in the main plus FLOT cohort, both in the overall population (median OS not reached vs 55.7 months; HR, 0.86, 95 percent CI, 0.71–1.03) and in key subgroups.

Safety-wise, the pembrolizumab and placebo arms had similar incidences of grade 3–4 treatment-related adverse events (TRAEs; 64 percent vs 63 percent), but the former had higher rates of grade 3–4 immune-related AEs (11 percent vs 3 percent) and TRAEs leading to drug discontinuations (26 percent vs 20 percent).

“Nonetheless, there were no new safety concerns with additional follow-up … The observed safety profile was consistent with prior reports for pembrolizumab plus chemotherapy in metastatic disease,” said Shitara.

Bolsters previous pCR, EFS results

In the interim analysis, perioperative pembrolizumab plus chemo outdid chemo alone in terms of pathologic complete response (pCR; 12.9 percent vs 2 percent; p<0.0001) and event-free survival (EFS; median 44.4 vs 25.3 months; HR, 0.81; p=0.0198). [Lancet Oncol 2024;25:212-224]

These were further supported by the current results, both in the main (13.4 percent vs 2 percent; difference, 11.4 percent [pCR] and median 44.4 vs 25.7 months; HR, 0.81 [EFS]) and main plus FLOT cohorts (14.2 percent vs 2.8 percent; difference, 11.4 percent and median 47 vs 26.9 months; HR, 0.80, respectively).

Taken together, the efficacy outcomes in this final analysis correlate with those reported previously. Shitara called for more studies to further shed light on the efficacy of ICIs in this disease setting.