The first results from the phase III CheckMate 648 study represent significant progress in the treatment of patients with advanced esophageal squamous cell carcinoma. The trial evaluated first-line treatment with nivolumab plus chemotherapy or nivolumab plus ipilimumab in patients with advanced disease. The findings show that both treatments demonstrated superior overall survival compared with chemotherapy alone; the combination therapies also demonstrated a significant durable objective response benefit and an acceptable safety profile. These results were presented by Ian Chau, MD, and colleagues at the 2021 ASCO Annual Meeting (Abstract LBA4001).

Esophageal cancer is the sixth most common cause of cancer-related deaths and the eighth most common cancer worldwide, with a 5-year survival rate of less than 25%. Each year, about 19,260 people in the United States are diagnosed with esophageal cancer and over 15,000 die from the disease. The most common subtype of esophageal cancer is squamous cell carcinoma, which accounts for 90% of all esophageal cancers each year.

Ian Chau, MD

Study Methodology

The researchers enrolled 970 adults with previously untreated, unresectable, advanced, recurrent or metastatic esophageal squamous cell carcinoma, regardless of tumor cell PD-L1 expression. The patients were randomly assigned to nivolumab plus fluorouracil and cisplatin chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone.

The primary endpoints for both comparisons were overall survival and progression-free survival per blinded independent center review in patients with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included overall survival and progression-free survival in all randomly assigned patients.

CheckMate 648 Results

The researchers found with 13 months minimum follow-up, nivolumab plus chemotherapy and nivolumab plus ipilimumab led to a statistically significant improvement in overall survival vs chemotherapy in patients with tumor cell PD-L1 ≥ 1% and all randomly assigned patients.

A statistically significant progression-free survival benefit was also observed for nivolumab and chemotherapy vs chemotherapy alone (hazard ratio = 0.65, 98.5% confidence interval = 0.46–0.92, P = .0023) in patients with tumor cell PD-L1 ≥ 1%. Progression-free survival with nivolumab plus ipilimumab vs chemotherapy in patients with tumor cell PD-L1 ≥1% did not meet the prespecified boundary for significance.

The objective response rate (per blinded independent central review) was 53% (nivolumab/chemotherapy), 35% (nivolumab/ipilimumab), and 20% (chemotherapy) in patients with tumor cell PD-L1 ≥ 1%. In all randomly assigned patients, rates were 47%, 28%, and 27%, respectively. Longer median (95% confidence interval) duration of response was observed vs chemotherapy for patients with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1– 27.4), and 5.7 (4.4–8.7) months, and for all randomly assigned patients, 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) months, respectively. No new safety signals were identified.

Clinical Significance

“Nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated superior overall survival vs chemotherapy, along with durable objective responses and acceptable safety, in patients with advanced esophageal squamous cell carcinoma, and each represents a potential new first-line treatment option,” concluded the study authors.

Julie R. Gralow, MD, FACP, FASCO

Commenting on this study’s findings during an ASCO press briefing, Julie R. Gralow, MD, FACP, FASCO, ASCO Chief Medical Officer and Executive Vice President, said, “The CheckMate 648 study found two regimens that improved overall survival beyond the current standard of care, which is chemotherapy alone for recurrent or metastatic esophageal cancers, particularly those that express PD-L1, which was found in about half of the tumors. The addition of the PD-1 immune checkpoint inhibitor nivolumab with chemotherapy, as well as the combination of two immune checkpoint inhibitors without chemotherapy, nivolumab and ipilimumab, a CTLA-4 inhibitor, both significantly extended survival and should be considered superior treatment as first-line treatment of esophageal squamous cell carcinoma. This dual immunotherapy combination without chemotherapy is the first chemotherapy-free first-line treatment showing benefit for these patients.”

Disclosure: Funding for this study was provided by Bristol Myers Squibb. For full disclosures of the study authors, visit coi.asco.org.