Nivolumab Combinations Superior to Chemotherapy Alone for Metastatic Esophageal Cancer

Survival outcomes improved when nivolumab was added to either ipilimumab or chemotherapy versus chemotherapy alone in advanced/metastatic esophageal squamous cell carcinoma

Patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) benefited from the addition of nivolumab (Opdivo) to either chemotherapy or ipilimumab (Yervoy) with better overall survival (OS) outcomes versus those receiving chemotherapy alone, according to updated findings from the CheckMate-648 trial (NCT03143153) presented at a presscast ahead of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

The randomized phase 3 trial evaluated the efficacy of the treatment regimens in adult patients with histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus that is deemed inoperable and cannot be treated with chemoradiation with curative intent

“Advanced esophageal squamous cell carcinoma carries a poor prognosis, with a median survival of around 10 months,” said Ian Chau, MD, FRCP, consultant medical oncologist at the Royal Mardsen Hospital in the United Kingdom, while presenting the findings during the presscast.

Patients in the nivolumab plus chemotherapy treatment arm receive nivolumab at 240 mg on day 1 and 15, fluorouracil at 800 mg/m2 per day for 5 days, and cisplatin at 80 mg/m2 on day 1 of each 4-week cycle (n = 321). Those getting chemotherapy alone receiving the same doses of cisplatin and fluorouacil (n = 324). In the nivolumab/ipilimumab treatment arm, patients had nivolumab at 3 mg/kg every 2 weeks followed by ipilimumab at 1mg/kg every 6 weeks until unacceptable toxicity or disease progression (n = 325).

Eligible patients had an ECOG performance score of 0 to 1, measurable disease, and no prior systemic treatment for advanced disease. The primary end points of the trial were OS and progression-free survival (PFS) in patients whose tumors had PD-L1 expression of 1% or more. Secondary end points were OS and PFS in all patients, as well as objective response rate (ORR), both in patients with PD-L1 of 1% or more and in all patients.

At a minimum follow-up of 12.9 months, median OS in patients with PD-L1 expression of 1% or greater in the nivolumab plus chemotherapy arm (n = 158) was 15.4 months (95% CI, 11.9-19.5) versus 13.7 months (95% CI, 11.2-17.0) with nivolumab plus ipilimumab (n = 158). In the PD-L1-positive patients in the chemotherapy alone arm (n = 157), median OS was 9.1 months (95% CI, 7.7-10.0; P < .0001).

“This translates into over 6 months [of] improvement in median overall survival [when comparing nivolumab plus chemotherapy to chemotherapy alone],” Chau said. “But importantly, if you look at the latter parts of the overall survival curve, they’re widely separated in favor of nivolumab plus chemotherapy, meaning that there were more patients with prolonged overall survival.”

In the overall study population–regardless of PD-L1 expression–the median OS in the nivolumab plus chemotherapy arm was 13.2 months (95% CI, 11.1-15.7); 12.8 months in the nivolumab plus ipilimumab arm (95% CI, 11.3-15.5 months); and 10.7 months in the chemotherapy arm (95% CI, 9.4-11.9; P = .0021).

The primary end point of PFS per blind independent committee review was not met in patients whose tumors were PD-L1 positive (HR, 1.02; 95% CI, 0.73-1.43).

The ORR in patients with PD-L1-positive tumors given nivolumab plus ipilimumab was 35% (95% CI, 28-43). In the chemotherapy arm it was 20% (95% CI, 14-27). In all patients, ORR was 28% (95% CI, 23-33) and 27% (95% CI, 22-32) in the nivolumab plus ipilimumab and nivolumab plus chemotherapy arms, respectively.

Regarding safety, the most common (occurring in 10% or more) treatment-related adverse events (TRAEs) for the chemotherapy-containing arms were nausea, decreased appetite, and stomatitis. For the nivolumab/ipilimumab arm, common TRAEs were rash, pruitis, and hypothyroidism. Notably, incidence of TRAEs was consistent with all treated patients across all arms for patients whose tumor cell had PD-L1 expression ³ 1%.

Ultimately, nivolumab-containing regimens have the potential to drastically improve outcomes in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma–a group that tends to have poor prognoses.

“Nivolumab plus chemotherapy [and] nivolumab plus ipilimumab each represents a new potential first-line standard of care for patients with advanced esophageal squamous cell carcinoma, based on the results of CheckMate-648, the largest randomized control trial conducted in this setting to date,” Chau said.


Chau I. First results from the CheckMate 648 study evaluating nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Presented at: 2021 ASCO Annual Meeting Press Program, May 28, 2021.

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