FDA Approves Nivolumab for Esophageal Cancer


The FDA has approved nivolumab for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma.

The FDA has approved nivolumab (Opdivo) for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.1

In the 419-patient study, 31% of patients in the nivolumab arm were alive at 18 months compared with 21% in the arm that received docetaxel or paclitaxel. At 12 months, 47% and 34%, respectively, were alive.

The improvement in median OS occurred despite a nearly identical objective response rate (ORR) between the 2 treatment arms and a progression-free survival (PFS) that favored chemotherapy. The ORR was 33% in the nivolumab arm and 34% in the chemotherapy arm, and the median PFS rates were 1.7 months and 3.4 months (HR, 1.08; 95% CI, 0.87-1.34), respectively.

“Many cases of esophageal cancer are diagnosed at the advanced stage, when the disease could have a significant impact on a patient’s health.3 Treatment options can be limited once patients with advanced esophageal squamous cell carcinoma progress,” Adam Lenkowsky, general manager and head, US, Oncology, Immunology, Cardiovascular, Bristol Myers Squibb, stated in a press release. “The approval of Opdivo as a new treatment option for previously treated patients with advanced esophageal squamous cell carcinoma, regardless of PD-L1 expression, highlights our commitment to providing new options to address the unmet needs of patients and brings us another step closer to understanding the full potential of immunotherapy for gastrointestinal cancers.”

Metastatic esophageal cancer has a poor prognosis. The 5-year relative survival rate is ≤8%. ESCC is the dominant histologic subtype, accounting for approximately 90% of all esophageal cancer worldwide. Current chemotherapy options in the second-line setting offer poor long-term survival and are associated with toxicity.

ATTRACTION-3 builds on the phase II ATTRACTION-1 study that showed that nivolumab had promising antitumor activity with a manageable safety profile with advanced ESCC refractory to or intolerant of standard chemotherapies.2

ATTRACTION-3 enrolled 419 patients with unresectable advanced or recurrent ESCC refractory to or intolerant of 1 prior fluoropyrimidine/platinum-based chemotherapy. They were randomized in a 1:1 ratio to nivolumab at 240 mg intravenously every 2 weeks, or investigator’s choice of taxane chemotherapy that consisted of either docetaxel at 75 mg/m2 intravenously every 3 weeks, or paclitaxel at 100 mg/m2 intravenously every week for 6 weeks, then 1 week off.

The primary endpoint was OS. The data cutoff for this analysis was November 2018. Of the 419 patients randomized, 417 received at least one dose of their assigned treatment.

Baseline characteristics were well balanced between the 2 arms. Nearly 90% of the patients were male and 96% were Asian. Patients were split evenly between an ECOG performance status of 0 or 1. About half of patients had prior surgery and about 70% had prior radiotherapy. Approximately half of patients had tumor PD-L1 expression ≥1%. About 85% of patients were current or former smokers.

The median duration of treatment was 2.6 months in either arm. The median relative dose intensity was 100% in the nivolumab arm and 81% in the chemotherapy arm. More than 90% in either arm discontinued treatment, with the most common reason being disease progression (64% in the nivolumab arm and 66% in the chemotherapy arm).

OS consistently favored nivolumab versus chemotherapy across multiple prespecified subgroups, including tumor PD-L1 expression.

The best overall response was a complete response in 1% in each arm (P = .63), a partial response in 19% of the nivolumab arm and 20% of the chemotherapy arm, and stable disease in 18% and 41%, respectively. The disease control rate was 37% in the nivolumab group and 63% in the chemotherapy group.

The median time to response was 2.6 months in the nivolumab arm and 1.5 months in the chemotherapy arm. However, responses were substantially more durable with nivolumab compared to chemotherapy, with a median duration of response of 6.9 months and 3.9 months, respectively. Some 21% of patients in the nivolumab arm have ongoing responses, compared with 6% in the chemotherapy arm.

Exploratory analyses revealed a significant overall improvement in health-related quality of life with nivolumab versus chemotherapy using the EQ-5D-3L Visual Analog Scale.

Grade 3/4 treatment-related adverse events (TRAEs) occurred at a rate that was more than 3 times lower with nivolumab, and TRAEs occurred at a rate that was less than half in the nivolumab group compared with chemotherapy (18% vs 63%). The most common TRAEs with nivolumab were rash (n = 11), diarrhea (n = 11), and fatigue (n = 7), compared with alopecia (n = 47), a decline in neutrophil count (n = 37), a decline in white blood cell count (n = 35), decreased appetite (n = 27), anemia (n = 24), peripheral sensory neuropathy (n = 23), malaise (n = 22), fatigue (n = 21), and neutropenia (n = 19) in the chemotherapy arm. Endocrine disorders of any grade occurred more frequently in the nivolumab arm (11% vs <1%).


  1. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) for the Treatment of Patients with Advanced Esophageal Squamous Cell Carcinoma (ESCC) After Prior Fluoropyrimidine- and Platinum-based Chemotherapy. Published June 10, 2020. https://bit.ly/3dRhSI1. Accessed June 10, 2020.
  2. Cho BC, Kato K, Takahashi M, et al. Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): the phase 3 ATTRACTION-3 study. Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA 11.


The approval is based on data from the phase 3 ATTRACTION-3 study, in which nivolumab extended overall survival (OS) compared with chemotherapy in patients with previously treated advanced ESCC. At a minimum follow-up of 17.6 months, the median OS improved from 8.4 months in patients randomized to chemotherapy to 10.9 months in those randomized to nivolumab, corresponding to a significant 23% reduction in the risk of death (HR, 0.77; 95% CI, 0.62-0.96; P = .019).2 The OS benefit with nivolumab was evident regardless of PD-L1 expression.

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