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Adding Pembrolizumab to Chemotherapy Improves Overall and Progression-Free Survival in First-Line Treatment of Advanced Esophageal Cancer


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As reported in The Lancet by Jong-Mu Sun, MD, of Samsung Medical Center, Sungkyunkwan University, Seoul, and colleagues, an interim analysis in the phase III KEYNOTE-590 trial has shown that the addition of first-line pembrolizumab to chemotherapy resulted in improved overall and progression-free survival in patients with advanced esophageal and Siewert type 1 gastroesophageal junction (GEJ) cancers.1

Jong-Mu Sun, MD

Jong-Mu Sun, MD

The trial supported the March 2021 approval of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1–5 cm above the GEJ [Siewert type 1]) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

Study Details

In the double-blind trial, 749 patients (irrespective of PD-L1 status) from sites in 26 countries were randomly assigned to receive pembrolizumab at 200 mg (n = 373) or placebo (n = 376) every 3 weeks for up to 35 cycles, both combined with fluorouracil at 800 mg/m2 on days 1 to 5 plus cisplatin at 80 mg/m2 on day 1 every 3 weeks for up to six cycles.

Randomization was stratified by geographic region, histology, and Eastern Cooperative Oncology Group (ECOG) performance status. For the pembrolizumab vs control groups, 73% vs 73% had esophageal squamous cell carcinoma (SCC) and 27% vs 27% had adenocarcinoma, including 11% vs 13% with Siewert type 1 GEJ adenocarcinoma. Overall, 54% vs 53% of patients were Asian, and 82% vs 85% were male. The primary endpoints were overall survival in patients with esophageal SCC and a PD-L1 combined positive score (CPS) ≥ 10 and overall and progression-free survival in patients with esophageal SCC, patients with a PD-L1 CPS ≥ 10, and all randomly assigned patients.

Primary Endpoints

At the first interim analysis at a median follow-up of 22.6 months, the median overall survival was 13.9 months (95% confidence interval [CI] = 11.1–17.7 months) among 143 patients treated with pembrolizumab vs 8.8 months (95% CI = 7.8–10.5 months) among 143 control group patients with esophageal SCC and a PD-L1 CPS ≥ 10 (hazard ratio [HR] = 0.57, 95% CI = 0.43–0.75, P < .0001). The rate at 24 months was 31% vs 15%.

Among 274 pembrolizumab vs 274 control patients with esophageal SCC, median overall survival was 12.6 months (95% CI = 10.2–14.3 months) in the pembrolizumab group vs 9.8 months (95% CI = 8.6–11.1 months) in the control group (HR = 0.72, 95% CI = 0.60–0.88, P = .0006). The rate at 24 months was 29% vs 17%. Median progression-free survival was 6.3 months (95% CI = 6.2–6.9 months) in the pembrolizumab group vs 5.8 months (95% CI = 5.0–6.1 months) in the control group (HR = 0.65, 95% CI = 0.54–0.78, P < .0001).

Among 186 vs 197 patients with a PD-L1 CPS ≥ 10, median overall survival was 13.5 months (95% CI = 11.1–15.6 months) in the pembrolizumab group vs 9.4 months (95% CI = 8.0–10.7 months) in the control group (HR = 0.62, 95% CI = 0.49–0.78, P < .0001). The rate at 24 months was 31% vs 15%. Median progression-free survival was 7.5 months (95% CI = 6.2–8.2 months) in the pembrolizumab group vs 5.5 months (95% CI = 4.3–6.0 months) in the control group (HR = 0.51, 95% CI = 0.41–0.65, P < .0001).

Among all randomly assigned patients, median overall survival was 12.4 months (95% CI = 10.5–14.0 months) vs 9.8 months (95% CI = 8.8–10.8 months) in the control group (HR = 0.73, 95% CI = 0.62–0.86, P < .0001). The rate at 24 months was 28% vs 16%. Median progression-free survival was 6.3 months (95% CI = 6.2–6.9 months) vs 5.8 months (95 CI = 5.0–6.0 months; HR = 0.65, 95% CI = 0.55–0.76, P < .0001). Subsequent anticancer therapy was received by 43% of patients in the pembrolizumab group vs 47% in the control group, including immunotherapy in 6% vs 9%.

Among patients with adenocarcinoma, including esophageal and Siewert type 1 GEJ adenocarcinoma, median overall survival was 11.6 months (95% CI = 9.7–15.2 months) in the pembrolizumab group vs 9.9 months (95% CI = 7.8–12.3 months) in the control group (HR = 0.74, 95% CI = 0.54–1.02). In an analysis of additional stratification subgroups in the intent-to-treat population, hazard ratios were 0.64 (95% CI = 0.51–0.81) among 393 patients in Asian regions and 0.83 (95% CI = 0.66–1.05) among 356 from non-Asian regions and 0.72 (95% CI = 0.55–0.94) among 299 with an ECOG performance status of 0 and 0.73 (95% CI = 0.59–0.90) among 448 with an ECOG performance status of 1.

Adverse Events

Grade ≥ 3 adverse events occurred in 86% of the pembrolizumab group vs 83% of the control group and were considered treatment-related in 72% vs 68%; the most common treatment-related grade ≥ 3 events in both groups were decreased neutrophil count (23% vs 17%), neutropenia (14% vs 16%), and anemia (12% vs 15%). Adverse events led to treatment discontinuation in 24% vs 20% of patients. Fatal adverse events occurred in 8% vs 10% of patients and were considered related to treatment in 2% vs 1%.

KEY POINTS

  • The addition of pembrolizumab to chemotherapy improved overall and progression-free survival among all patients with advanced esophageal cancer in KEYNOTE-590.
  • Significant benefits were observed among all patients with esophageal SCC and a PD-L1 CPS ≥ 10, all patients with esophageal SCC, and all patients with a CPS ≥ 10.

Immune-mediated adverse events and infusion reactions of any grade occurred in 26% vs 12% of patients, with the most common in the pembrolizumab group being hypothyroidism (11% vs 7%), pneumonitis (6% vs 1%), and hyperthyroidism (6% vs 1%).

The investigators concluded: “Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy [significantly improved overall survival and progression-free survival] in patients with untreated, advanced esophageal squamous cell carcinoma and a PD-L1 CPS of 10 or more, and in all randomized patients regardless of histology, with a manageable safety profile in the total as-treated population.” 

DISCLOSURE: The study was funded by Merck Sharp & Dohme. Dr. Sun has received institutional research funding from Merck Sharp & Dohme, AstraZeneca, and Ono Pharmaceuticals. For disclosures of all study authors, visit thelancet.com.

REFERENCE

1. Sun JM, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021.


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