Pembrolizumab regimen superior to chemotherapy alone in advanced esophageal cancer
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The addition of pembrolizumab to chemotherapy improved OS, PFS and objective response rates among patients with untreated, advanced esophageal and esophagogastric junction adenocarcinoma, results of the phase 3 KEYNOTE-590 study showed.
The combination also had an acceptable safety profile and represents a new standard of care for this patient population, according to the findings, presented at ESMO Virtual Congress 2020.
“Unfortunately, for esophageal cancer, the standard of care has remained relatively unchanged for a long period of time,” Peter C. Enzinger, MD, director of the Center for Esophageal and Gastric Cancer at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, said during a press conference. “Fluoropyrimidine plus platinum-based chemotherapy has been the standard in the first line, [whereas] docetaxel, paclitaxel, irinotecan and ramucirumab [Cyramza, Eli Lilly] with or without paclitaxel is standard in the second line or for adenocarcinoma.”
Two previous KEYNOTE studies showed monotherapy with the anti-PD-1 agent pembrolizumab (Keytruda, Merck) induced antitumor activity in advanced or metastatic esophageal cancer.
The international, double-blind KEYNOTE-590 trial analyzed pembrolizumab plus chemotherapy vs. chemotherapy alone among 749 patients (83% men) with locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC, 73%) or Siewert type I esophagogastric junction adenocarcinoma.
Enzinger and colleagues randomly assigned patients to either pembrolizumab dosed at 200 mg every 3 weeks for up to 2 years (n = 373) or placebo (n = 376) with 80 mg/m2 cisplatin every 3 weeks plus 800 mg/m2 5-FU on days 1 to 5 every 3 weeks.
They stratified randomization by Asia vs. the rest of the world, adenocarcinoma vs. ESCC, and ECOG performance status of 0 vs. 1.
Patients continued treatment for 2 years or until progression, unacceptable toxicity or study withdrawal. Crossover was prohibited.
OS among patients with ESCC and a PD-L1 combined positive score (CPS) of 10 or greater, as well as OS and PFS among patients with ESCC, a PD-L1 CPS of 10 or greater and all patients, served as primary endpoints of this study. ORR served as a secondary endpoint.
Median follow-up was 10.8 months.
Results showed the pembrolizumab regimen demonstrated superior median OS compared with the placebo regimen among patients with ESCC and a PD-L1 CPS of 10 or greater (13.9 months vs. 8.8 months; HR = 0.57; 95% CI, 0.43-0.75), those with ESCC (12.6 months vs. 9.8 months; HR = 0.72; 95% CI, 0.6-0.88), those with a PD-L1 CPS of 10 or greater (13.5 months vs. 9.4 months; HR = 0.62; 95% CI, 0.49-0.78) and all patients (12.4 months vs. 9.8 months; HR = 0.73; 95% CI, 0.62-0.86).
The pembrolizumab regimen also demonstrated superior median PFS among patients with ESCC (6.3 months vs. 5.8 months; HR = 0.65; 95% CI, 95% CI, 0.54-0.78), a PD-L1 CPS of 10 or greater (7.5 months vs. 5.5 months; HR = 0.51; 95% CI, 0.41-0.65) and all patients (6.3 months vs. 5.8 months; HR = 0.65; 95% CI, 0.55-076).
Researchers reported confirmed ORRs among all patients of 45% with pembrolizumab vs. 29.3% with placebo (P < .0001), with a median duration of response of 8.3 months vs. 6 months.
Grade 3 to grade 5 drug-related adverse events occurred among 72% of patients who received pembrolizumab and 68% of those who received placebo, with 19% vs. 12% of patients discontinuing treatment due to such events.
“Pembrolizumab [in combination with] chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastatic esophageal cancer, including gastroesophageal junction carcinoma, regardless of histology and biomarker status,” Enzinger said.
Perspective
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Syma Iqbal, MD
Two first-line, potentially practice-changing studies in advanced/metastatic esophagogastric cancer were presented at ESMO this year. For the first time in many years, therapy for advanced disease is taking a step forward and the addition of immunotherapy has made an impact on the treatment of this most difficult disease.
CheckMate 649 — the largest randomized, global phase 3 trial of a PD-1 inhibitor in the first-line setting — is evaluating chemotherapy (fluoropyrimidine/oxaliplatin) vs. chemotherapy plus nivolumab (Opdivo, Bristol Myers Squibb) and a third arm of nivolumab with ipilimumab (Yervoy, Bristol Myers Squibb). Moehler and colleagues presented data on the chemotherapy-alone vs. chemotherapy-nivolumab groups.
This trial, KEYNOTE-590, is a randomized, phase 3, double-blind, placebo-controlled study that evaluated pembrolizumab plus chemotherapy (5-FU/cisplatin) vs. chemotherapy alone in advanced esophageal cancer in the first-line setting.
Both studies met their primary endpoints and provided statistically significant, clinically meaningful improvements in outcome for patients with advanced/metastatic esophagogastric cancers. These data will lead to a change in the first-line standard of care.
The nuances will be in how these combinations receive their indication. It is thought that approximately 30% to 40% patients have a PD-L1 CPS greater than 5, but the enriched population of CheckMate 649 had 60% with that level of PD-L1 expression. This may have affected the results for those subgroups evaluated, including all patients and those with a CPS greater than 1. We still need data for the third arm of the combination of nivolumab with ipilimumab.
In KEYNOTE-590, the majority of patients had squamous cell cancer, yet the overall population still achieved benefit. Further details about PD-L1 CPS are still to be presented, as well as data about the adenocarcinoma population.
Clearly, these trials will have an impact on care, but we will see how these are incorporated into practice as the only biomarker or predictor of outcome, PD-L1 CPS, is not enough. Further, these trials will affect the conduct of ongoing studies and will challenge investigators as to how to move forward. For now, this success after years of just fluoropyrimidine/platinum is welcome.
Reference:
- Moehler M, et al. Abstract LBA6_PR. Presented at European Society of Medical Oncology Virtual Congress; Sept. 19-21, 2020.
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Kato K, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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