Survival in Advanced ESCC Improved With Frontline Nivolumab Plus Ipilimumab or Chemotherapy

Improved survival outcomes were reported with the addition of nivolumab (Opdivo) to either ipilimumab (Yervoy) or chemo-therapy vs chemotherapy alone in the frontline treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). Updated data from the phase 3 CheckMate 648 trial (NCT03143153) were presented at the 2021 American Society of Clinical Oncology Annual Meeting.^1,2

“Advanced [ESCC] carries a poor prognosis, with a median survival of around 10 months,” said Ian Chau, MD, consultant medical oncologist at the Royal Mardsen Hospital in the United Kingdom.

CheckMate 648 is a randomized phase 3 trial evaluating the efficacy of the following 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:

1. Nivolumab plus chemotherapy: nivolumab 240 mg on day 1 and day 15; fluorouracil 800 mg/m² per day on day 1 -5 for 5 days; and cisplatin 80 mg/m² on day 1 of the 4-week cycle (n = 321).
2. Nivolumab plus ipilimumab: nivolumab 3 mg/kg every 2 weeks, followed by ipilimumab 1mg/kg every 6 weeks until unacceptable toxicity or disease progression (n = 325).
3. Chemotherapy alone: cisplatin and fluorouracil (n = 324).

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 in the trial were overall survival (OS) and progression-free survival (PFS) in patients whose tumors had PD-L1 expression greater than or equal to 1%.

Secondary end points were OS and PFS in all patients, as well as objective response rate (ORR), both in patients with PD-L1 greater than or equal to 1% and all patients.

At a minimum follow-up of 12.9 months, median OS in patients with PD-L1 greater than or equal to 1% in the nivolumab plus chemotherapy arm (n = 158) was 15.4 months (95% CI, 11.9-19.5), and was 13.7 months (95% CI, 11.217.0) in the nivolumab plus ipilimumab arm (n = 158). In the patients who were PD-L1 positive in the chemotherapy alone arm (n = 157) median OS was 9.1 months (95% CI, 7.7-10.0; P < .0001; FIGURE1).

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

In the overall study population, 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 chemo arm (95% CI, 9.4-11.9; P = .0021; FIGURE1).

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 ipili-mumab 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 (occur-ring in 10% or more) treatment-related adverse events (TRAEs) for the chemotherapy-contain-ing 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 greater than or equal to 1%.

Ultimately, these 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 represent a new potential first-line standard of care for patients with advanced [ESCC], based on the results of CheckMate 648, the largest randomized control trial conducted in this setting to date,” Chau said.

_REFERENCES:

_{1. Chau I. First results from the CheckMate 648 study evaluating nivolumab plus ipilimumab or nivolumab plus chemotherapy versus che-motherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Presented at: 2021 ASCO Annual Meeting Press Program, May 28, 2021.}

_{2. A study to evaluate efficacy in subjects with esophageal cancer treat-ed with nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin (CheckMate 648). Clinical-Trials.gov. Updated May 7, 2021. Accessed June 1, 2021. https://clinical-trials.gov/ct2/show/NCT03143153}