The addition of pembrolizumab to standard-of-care FLOT (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) prolongs pathologic complete response (pCR) and event-free survival (EFS) in patients with resectable gastric and gastroesophageal junction (G/GEJ) adenocarcinoma.
In the double-blind, international, phase 3 FLOT cohort of the KEYNOTE-585 study, at a median follow-up of 31.6 months, the pCR rate by blinded independent central review was more than double among patients randomized to pembrolizumab plus FLOT versus FLOT alone (17.0% vs 7.0%), reported Kohei Shitara, MD, at the 2024 ASCO Gastrointestinal Cancers Symposium.
Further, median EFS was not reached in the pembrolizumab arm versus 31 months in the placebo arm (hazard ratio [HR], 0.79; 95% CI, 0.52-1.22). Among patients with a combined positive score (CPS) ≥1, the HR in favor of pembrolizumab was 0.72. In the population with CPS <1, the HR was 1.07.
Distant disease eradication rather than prevention of local recurrence is likely needed to improve survival.
The data presented here were from a cohort of 203 patients with locally advanced, resectable G/GEJ cancer who were randomized to pembrolizumab plus FLOT or to placebo plus FLOT.
In the FLOT cohort, patients were randomized 1:1 to intravenous neoadjuvant pembrolizumab, 200 mg every 3 weeks, or intravenous placebo every 3 weeks for 3 cycles plus FLOT every 2 weeks for 4 cycles. After surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for 3 cycles plus FLOT every 2 weeks for 4 cycles, then adjuvant pembrolizumab or placebo every 3 weeks for 11 cycles.
Of the overall FLOT cohort, 95% completed neoadjuvant treatment and 88% underwent surgery with curative intent. Following surgery, nearly 80% received neoadjuvant treatment and 50% completed adjuvant treatment. These proportions were not significantly different between the 2 treatment arms.
About 80% of patients in each group achieved R0 resection.
The 24-month EFS rates were 66% in the pembrolizumab arm and 57% in the placebo arm, said Dr Shitara, from the National Cancer Center Hospital East, Kashiwa, Japan. Median overall survival (OS) was not reached in either group (HR, 1.04; 95% CI, 0.66-1.66), and the 24-month OS rates were 72% and 73%, respectively.
Adverse events (AEs) leading to discontinuation of any study drug occurred in 32% of the pembrolizumab arm versus 18% of the placebo arm. The rate of grade ≥3 AEs was 20% in the pembrolizumab arm and 9% in the placebo arm. Most immune-related AEs in the pembrolizumab arm were grade 1 or 2.
The results of KEYNOTE-585 are consistent with those from the MATTERHORN study, which examined the addition of durvalumab to FLOT. Interim results from MATTERHORN were presented at the 2023 meeting of the European Society for Medical Oncology and showed that the addition of durvalumab significantly improved the pCR rate by an absolute difference of 12% (7% pCR rate with FLOT vs 19% with durvalumab plus FLOT; odds ratio was 3.08, P<.00001).
EFS and OS data from MATTERHORN are forthcoming.
Insufficient adjuvant treatment is a potential explanation for the disconnect between an improvement in EFS and no difference in OS in KEYNOTE-585, said discussant Alexander Raufi, MD, from the Warren Alpert Medical School of Brown University, Providence, RI.
“About 10% fewer patients in the pembrolizumab plus FLOT arm were able to complete adjuvant therapy, and we know that dose intensity matters,” he said. “In addition, perhaps like in the metastatic setting, there may be no benefit for those with [PD-1] CPS scores <5 or <10, and this may have also played a role. And ultimately, different tumor biology at primary versus distant site and sites of disease may be playing a role.”
Distant disease eradication rather than prevention of local recurrence is likely needed to improve survival, said Dr Raufi, who added that an improvement in OS must be demonstrated before either pembrolizumab or durvalumab can be adopted as standard of care.