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First-Line Checkpoint Inhibitors May Improve Survival in Gastroesophageal Cancers


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Immune therapy for advanced gastroesophageal cancer has taken a leap forward by showing its value in the first-line setting, according to two studies in which nivolumab and pembrolizumab, both given with chemotherapy, significantly improved overall survival vs chemotherapy alone. The studies, featured in the ESMO Virtual Congress 2020 Presidential Symposium, were previewed during an ESMO press briefing.

“CheckMate 649 and KEYNOTE-590 are practice-changing trials,” commented Salah-Eddin Al-Batran, MD, Director of the Institute of Clinical Cancer Research and Director of GI Oncology at Krankenhaus Nordwest-University Cancer Center, Frankfurt, at the press briefing.

Salah-Eddin Al-Batran, MD

Salah-Eddin Al-Batran, MD

Although there were some differences in the trial populations and in the cut points for PD-L1 expression, “both were clearly positive,” Dr. Al-Batran said.

In CheckMate 649, nivolumab plus chemotherapy reduced the mortality risk by 29% in patients with a PD-L1 Combined Positive Score (CPS) ≥ 5 (Abstract LBA6_PR). In KEYNOTE-590, pembrolizumab plus chemotherapy reduced mortality by 27%, with an even greater benefit seen in patients with PD-L1 CPS ≥ 10 (Abstract LBA8_PR). In both studies, no new safety signals were observed.

CheckMate 649

Markus Moehler, MD, Professor of Medicine at Johannes-Gutenberg University Clinic, Mainz, Germany, reported the prespecified interim analysis of overall survival and the final progression-free survival analysis of CheckMate 649.

Markus Moehler, MD

Markus Moehler, MD

“Nivolumab is the first PD-1 inhibitor to demonstrate superior overall survival and progression-free survival in combination with chemotherapy vs chemotherapy alone in previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma,” he said. “The study achieved statistical significance for both primary endpoints and all formally tested secondary endpoints. Nivolumab plus chemotherapy represents a potential standard first-line treatment.”

The phase III trial included 1,581 patients with previously untreated HER2-negative advanced/unresectable or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma, of whom 955 patients (60%) had a PD-L1 CPS ≥ 5.

Patients were randomly assigned to receive:

  • Nivolumab at 260 mg every 3 weeks or 240 mg every 2 weeks plus chemotherapy
  • Chemotherapy alone
  • Nivolumab plus ipilimumab (nivolumab/ipilimumab data will be presented at a later date).

The chemotherapy regimen was either FOLFOX (fluorouracil, leucovorin, oxaliplatin) every 2 weeks or XELOX (capecitabine, oxaliplatin) every 3 weeks. The dual primary endpoints were overall survival and progression-free survival in patients with a PD-L1 CPS ≥ 5. 

Median overall survival was 14.4 months with nivolumab/chemotherapy vs 11.1 months for chemotherapy in the PD-L1 CPS ≥ 5 population (hazard ratio [HR] = 0.71, P < .0001). The differences were also statistically significant for the PD-L1 CPS ≥ 1 population (HR = 0.77, P = .0001) and for all randomly assigned patients (HR = 0.80, P = .0002). Median progression-free survival was 7.7 and 6.1 months, respectively (HR = 0.68, P < .0001), Dr. Moehler reported.

KEYNOTE-590

The phase III KEYNOTE-590 trial enrolled 749 patients, regardless of PD-L1 expression, with previously untreated advanced/unresectable or metastatic esophageal adenocarcinoma or esophageal squamous cell carcinoma or esophagogastric junction Siewert type 1 adenocarcinoma. Patients were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus chemotherapy (fluorouracil plus cisplatin) for up to 6 cycles or chemotherapy alone. As in CheckMate 649, overall survival and progression-free survival were the dual primary endpoints.

In all patients, median overall survival was 12.4 months with pembrolizumab/chemotherapy vs 9.8 months with chemotherapy (HR = 0.73, P < .0001). Survival rates were 51% and 39%, respectively, at 1 year, and 28% and 16%, respectively, at 2 years, reported Peter Enzinger, MD, Director of the Center for Esophageal and Gastric Cancer at Dana-Farber Cancer Institute.

Peter Enzinger, MD

Peter Enzinger, MD

Median progression-free survival was 6.3 vs 5.8 months, respectively (HR = 0.65, P < .0001), with 1-year rates of 25% and 12%.

“Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy for patients with locally advanced/unresectable or metastatic esophageal cancer, including the GEJ, regardless of histology and biomarker status,” said Dr. Enzinger.

In his comments during the press briefing, Dr. Al-Batran agreed that first-line therapy should include a checkpoint inhibitor, but at this time, said he would restrict this treatment to patients with PD-L1 CPS ≥ 1, where the greatest benefit was seen. “For other groups, I think we wait for more data,” he said. 

Disclosure: For full disclosures of the study authors, visit oncologypro.esmo.org (LBA6_PR and LBA8_PR).

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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