First-line pembrolizumab plus chemotherapy as a standard of care in advanced oesophageal cancer
With an additional twelve months of follow-up of the Keynote-590 trial, pembrolizumab plus chemotherapy continued to provide significant and clinically meaningful improvements in overall survival, progression-free survival and objective response rates versus chemotherapy alone in patients with untreated advanced oesophageal and oesophagogastric junction adenocarcinoma. In addition, combination treatment resulted in a manageable safety profile and stable quality of life in this patient population.
Pembrolizumab alone or in combination with chemotherapy has shown antitumour activity with an acceptable safety profile in advanced/metastatic oesophageal cancer. In Keynote-590, a statistically significant and clinically meaningful improvement in antitumour activity with first-line pembrolizumab plus chemotherapy versus chemotherapy in all patients with locally advanced or metastatic oesophageal or gastro-oesophageal junction (GEJ) carcinoma was reported. At ASCO GI 2022, Prof. Metges presented efficacy, safety and health-related quality of life (HRQoL) data from the Keynote-590 study with an additional twelve months of follow-up.
Keynote-590 study design
Keynote-590 is a randomised, placebo-controlled, double-blind, phase III study in patients with untreated, locally advanced/unresectable or metastatic adenocarcinoma or oesophageal squamous cell carcinoma (ESCC) or Siewert type 1 GEJ adenocarcinoma. All patients were 18 years or older, had an ECOG performance status of 0-1 and were randomly assigned (1:1) to intravenous pembrolizumab (200 mg) or placebo, plus 5-fluorouracil (800 mg/m2 for days 1-5,) and cisplatin (80 mg/m2), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Treatment was continued until progression, unacceptable toxicity, withdrawal, or after two year. Primary endpoints were overall survival (OS) in patients with ESCC and PD-L1 combined positive score (CPS) of 10 or more, and OS and progression-free survival (PFS) in patients with ESCC, PD-L1 CPS of 10 or more, and in all randomised patients.
Results
In total, 749 patients were enrolled in the trial. Median follow-up was 34.8 months and median time on therapy was 8.0 months for pembrolizumab plus chemotherapy (PEMBRO + chemo) vs. 5.9 months for chemo alone. In the PEMBRO + chemo arm, 33 patients completed treatment, versus only five in the chemo arm. Baseline and demographic characteristics were well balanced between both treatment arms. With an additional twelve months of follow-up, the benefit of PEMBRO + chemo vs. chemo that was observed in the previous analysis was maintained, with a relative risk reduction of 27% for OS and 36% for PFS. For the pre-specified subgroups evaluated, median OS was longer with PEMBRO + chemo vs. chemo in patients with ESCC PD-L1 CPS ≥10 (HR[95%CI]: 0.59[0.45-0.76]), ESCC (HR[95%CI]: 0.73[0.61-0.88]) and PD-L1 CPS ≥10 (HR[95%CI]: 0.64[0.51-0.80]). Similarly, among pre-specified subgroups, PFS favoured PEMRO + chemo vs. chemo, with a HR of 0.65 for patients with ESCC and of 0.51 for patients with PD-L1 CPS ≥10. Also for patients with adenocarcinoma, there was a benefit of the PEMBRO + chemo combination, both in terms of OS (HR[95%CI]: 0.73[0.55-0.99]) and in terms of PFS (HR[95%CI]: 0.61[0.45-0.84]).
Confirmed ORR was 45.0% (6.7% complete response [CR]) vs. 29.3% (2.4% CR), with median DOR of 8.3 vs. 6.0 months for PEMBRO + chemo vs. chemo alone. Approximately 20% vs. 6% of patients had a response duration of at least 24 months. Grade 3-5 drug-related AE rates were reported in 71.7% vs. 67.6% of patients in the combination and chemo monotherapy arms, respectively. Discontinuation rates from drug-related AEs were 21.1% vs. 12.4%. There was no significant difference in least square mean (LSM) change from baseline to week 18 between arms in EORTC QLQ-C30 global health status/quality-of-life (LSM difference[95%CI]: -0.10[ -3.40 to -3.20]). Finally, LSM change from baseline to week 18 was better with PEMBRO + chemo vs. chemo for QLQ-OES 18 pain (-2.94; 95%CI: -5.86 to -0.02) and dysphagia (-5.54; 95%CI: -10.92 to -0.16).
Conclusion
With an additional twelve months of follow-up, first-line pembrolizumab plus chemotherapy continued to provide a clinically meaningful benefit in all patients with locally advanced and metastatic oesophageal cancer, including GEJ adenocarcinoma. Furthermore, there were no new safety signals detected and a similar QoL was maintained with pembrolizumab plus chemotherapy versus chemotherapy. These longer-term data therefore further support first-line pembrolizumab plus chemotherapy as a new standard of care in patients with locally advanced or metastatic oesophageal cancer including GEJ adenocarcinoma.
Reference
Metges JP, Kato K, Sun JM, et al. First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: Longer-term efficacy, safety, and quality-of-life results from the phase 3 KEYNOTE-590 study. Presented at ASCO GI 2022; Abstract 241.
