Biologics License Applications Accepted for Nivolumab/Ipilimumab and Nivolumab/Chemo for Unresectable Advanced ESCC

Treatment with nivolumab/ipilimumab and nivolumab/chemotherapy has demonstrated efficacy in unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma, with results from the CheckMate-648 trial leading to the acceptance of the regimens’ applications by the FDA.

The FDA has accepted supplemental biologics license applications for nivolumab (Opdivo) in combination with either ipilimumab (Yervoy) or fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC), according to a press release from developer developer Bristol Myers Squibb.1

The decision was based on the results of the phase 3 CheckMate-648 trial (NCT03143153) which indicated that patients who had a tumor cell PD-L1 expression of 1% or more experienced superior overall survival (OS) when treated with the nivolumab/chemotherapy combination.2 In this patient subgroup, nivolumab/chemotherapy elicited a median OS of 15.4 months (95% CI, 11.9-19.5) compared with 9.1 months (95% CI, 7.7-10.0) in the chemotherapy-alone group (HR, 0.54; 99.5% CI, 0.37-0.80; P <.0001). In all randomized patients, the regimen yielded a median OS of 13.2 months (95% CI, 11.1-15.7) compared with 10.7 months (95% CI, 9.4-11.9) in the chemotherapy-alone arm (HR, 0.74; 99.1% CI, 0.58-0.96; P = .0021). This translated to a 46% reduction in the risk of death for patients with PD-L1 expression of 1% or more and 26% risk reduction in the general population.

Additionally, the combination of nivolumab plus ipilimumab resulted in a median OS of 13.7 months (95% CI, 11.2-17.0) in patients who had a tumor cell PD-L1 of 1% or more, resulting in a 36% reduction in the risk of death versus the chemotherapy group (HR, 0.64; 98.6%, 0.46-0.90; P = .0010). In the general population, nivolumab/ipilimumab yielded a median OS of 12.8 months (95% CI, 11.3-15.5) for a 22% reduction in the risk of death versus chemotherapy (HR, 0.78; 98.2%, 0.62-0.98; P = .0110).

The organization has since given the therapies an anticipated Prescription Drug User Fee Act date of May 28, 2022.

“Last year, over 19,000 people were diagnosed with esophageal cancer in the United States, and 15,000 people died as a result of this very aggressive disease,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, said in a press release. “Additional treatment options are needed to improve upon outcomes achieved with the current standard of care. We are confident that our immunotherapy-based combinations can provide further clinical benefit and address this critical need.”

In the nivolumab/ipilimumab arm, patients were treated with 3 mg/kg of nivolumab every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks for up to 24 months or until disease progression or unacceptable toxicity. Moreover, in the other treatment arm, patients receive 240 mg of nivolumab on day 1 and day 15, as well as 800 mg/m2 of fluorouracil days 1 through day 5, as well as 80 mg/m2 of cisplatin on day 1 of every 4-week cycle. Treatment continued for 24 months or until disease progression of unacceptable toxicity.

Other findings from the study indicated that nivolumab/chemotherapy results in a median progression-free survival (PFS) of 6.9 months (95% CI, 5.7-8.3) in the experimental arm vs 4.4 months (95% CI, 2.9-5.8) in the chemotherapy arm (HR, 0.65; 95% CI, 0.46-0.92; P = .0023) in those with PD-L1 expression of 1% or greater. In the overall patient population, the media PFS was 5.8 months (95% CI, 5.6-7.0) in the combination arm vs 5.6 months (95% CI, 4.3-5.9) in the chemotherapy arm (HR, 0.81; 98.5% CI, 0.64-1.04; P = .0355).

In terms of safety, the most common any-grade and grade 3/4 adverse effects (AEs) in the nivolumab/chemotherapy arm were in the kidney (24% and 2%), gastrointestinal tract (21% and 2%), and the skin (17% and 2%). Additionally, the most common any-grade and grade 3/4 AEs in the nivolumab/ipilimumab arm were related to the skin (34% and 4%), endocrine system (27% and 6%), and hepatic function (13% and 4%).


  1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s applications for Opdivo (nivolumab) + Yervoy (ipilimumab) and Opdivo + chemotherapy for unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb. September 27, 2021. Accessed October 4, 2021.
  2. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study. J Clin Oncol. 2021;39(Suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001