Pembro+Chemo as First-Line Standard of Care for Esophageal Cancer

SAN FRANCISCO — Pembrolizumab (Keytruda) plus chemotherapy should be considered the new first-line standard of care in advanced esophageal cancer, according to the final results of a large phase 3 study.

An interim analysis of the KEYNOTE-590 study, published in 2020, found that the combination of pembrolizumab and chemotherapy in the first-line setting proved superior to chemotherapy alone in all outcome measures.

The updated analysis, which adds 12 months of follow-up data, shows "first-line pembrolizumab plus chemotherapy continued to provide clinically meaningful benefits in all patients with locally advanced and metastatic esophageal cancer, including [gastro-esophageal junction] adenocarcinoma," said lead author Jean-Philippe Metges, MD, of the CHU Brest-Institut de Cancerologie et d'Hematologie ARPEGO Network, Brest, France.

Similar quality-of-life and safety data were also observed with pembrolizumab plus chemotherapy vs chemotherapy alone, Metges added.

"These longer-term data further support first-line pembrolizumab plus chemotherapy as a new standard of care in patients with locally advanced and metastatic esophageal cancer," he said.

The updated analysis was presented at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Pembro for Esophageal Cancer

Pembrolizumab first received regulatory approval in 2019 as monotherapy in the second-line setting to treat recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in tumors with PD-L1 expression.

In response to the interim KEYNOTE-590 data, the FDA expanded the indication last year, granting accelerated approval for pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy in the first-line setting for patients who were not candidates for surgical resection or definitive chemoradiotherapy.

The updated KEYNOTE-590 data lend greater weight for the use of pembrolizumab plus chemotherapy as first-line standard of care in advanced esophageal cancer.

In the analysis, a total of 749 eligible patients with previously untreated locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC), adenocarcinoma, or Siewert type 1 esophagogastric junction adenocarcinoma, regardless of PD-L1 status, were randomly assigned (1:1) to pembrolizumab 200 mg or placebo plus 5-fluorouracil and cisplatin once every 3 weeks for up to 35 cycles.

The authors evaluated overall survival in all patients as well as subgroups including those with ESCC, ESCC PD-L1 combined positive score (CPS) ≥10 tumors, and PD-L1 CPS ≥10 tumors. The research team also looked at progression-free survival in most groups and overall response rate, duration of response, safety, and health-related quality of life.

Treatment continued until progression, unacceptable toxicity, withdrawal, or until 2 years, with no crossover permitted.

At the median follow-up of 34.8 months, median overall survival was longer for all patients receiving the combination therapy (hazard ratio [HR], 0.73) as well as patients with ESCC (HR, 0.73), ESCC CPS ≥10 (HR, 0.59), CPS ≥10 (HR, 0.64), and adenocarcinoma (HR, 0.73).

For progression-free survival, pembrolizumab plus chemotherapy was superior in all patients (HR, 0.64), the ESCC group (HR, 0.65), as well as the PD-L1 CPS ≥10 tumor group (HR, 0.51).

The 24-month overall survival in all patients was also notably higher for those receiving the combination therapy — 26.3% vs 16.1% — as was 24-month progression-free survival — 11.6% vs 3.3%.

The overall response rate was 45.0% in the combination group, with 25 complete responses (6.7%), vs 29.3% in the control group, with nine complete responses (2.4%). The median duration of response was 8.3 months in the combination group vs 6.0 months in the chemotherapy group. About 20% of patients in the combination group had a response rate lasting 24 months or longer, compared to 6% who received chemotherapy alone.

As for safety, grade 3–5 drug-related adverse events were similar in both arms — 72% for the combination vs 68% for chemotherapy alone. However, more patients in the combination group discontinued treatment due to drug-related adverse events — 21% vs 12%.

No additional or surprise adverse events occurred with the longer follow-up, plus quality of life was comparable between groups, Metges noted.

Stefano Cascinu, MD, Università Vita-Salute, San Raffaele Hospital, Milan, who was not involved in the analysis, reiterated that this update confirms the findings from earlier analyses and shows a benefit across all subgroups.

"One of the most relevant findings was that 20% of patients were responding for more than 24 months," he said. "It is also important that a similar quality of life was maintained."

Although Cascinu emphasized that this is a landmark trial in advanced esophageal and gastric cancers, he indicated to several points that remain to be investigated. These include the reproducibility of the findings in common clinical situations — such as a patient with impaired performance status, malnutrition, or peritoneal involvement — as well as the role of PD-L1.

The efficacy of the combination therapy across all subgroups led to a wide FDA approval, though the European Medicines Agency limited its approval to patients with PD-L1 CPS ≥10 tumors.

"Even though all subgroups did well, patients with [PD-L1] CPS ≥10 did better," said Cascinu. "[And] in reality, the benefit may only be driven by a specific subpopulation."

Cascinu added: "PD-L1 may be a negative biomarker and may be informative about the magnitude of benefit. This may be useful to discuss with patients regarding the expected benefit [of this therapeutic option]."

The study was supported by Merck & Co, Inc. Metges has disclosed the following: Travel, accommodations, expenses from companies including Amgen; LEO Pharma; MSD Oncology; MSD Oncology; Honoria- BMS; Lilly; Novartis; Sanofi; Syncore. Casinu has disclosed honoraria from BMS, Lilly, MSD Oncology, and others as well as a consulting or advisory role for many of these same manufacturers and serving on the speakers' bureau of Lilly and SERVIER.

2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium: Abstract 241. Presented January 20, 2022.

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