November 24, 2020 - The European Commission has approved nivolumab for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma following prior fluoropyrimidine- and platinum-based combination chemotherapy.
November 24, 2020 - The European Commission has approved nivolumab (Opdivo) for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) following prior fluoropyrimidine- and platinum-based combination chemotherapy.1
The approval is based on findings from the phase 3 ATTRACTION-3 trial, which showed that nivolumab led to a 23% reduction in the risk of death compared with chemotherapy, which was found to be a statistically significant and clinically meaningful improvement in overall survival (OS).2 The median OS was 10.9 months with nivolumab compared with 8.4 months with chemotherapy alone (HR, 0.77; 95% CI, 0.62-0.96; P = .019).
Additionally, the safety profile of nivolumab was favored over chemotherapy and was consistent with prior studies of the PD-1 inhibitor.
“Today’s approval marks a critically important milestone for those living with esophageal squamous cell carcinoma, as this is the first time an immunotherapy treatment option has been approved in the European Union for this patient population,” said Ian M. Waxman, MD, development lead, gastrointestinal cancers, Bristol Myers Squibb, the manufactuer of nivolumab. “We are proud of our work in advancing treatment options for people living with upper gastrointestinal cancers, and we look forward to working with European stakeholders to bring Opdivo to more eligible patients who may benefit.”
In June 2020, the FDA approved nivolumab for the treatment of patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy, also based on the ATTRACTION-3 findings.
In the ATTRACTION-3 study, 419 patients with unresectable advanced or recurrent ESCC refractory to or intolerant of 1 prior fluoropyrimidine/platinum-based chemotherapy were randomized 1:1 to receive 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 1 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, and about half of patients had prior surgery and about 70% had prior radiotherapy. Approximately half of patients had tumor PD-L1 expression ≥1%, and 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).
Thirty-one percent of patients in the nivolumab arm were alive at 18 months compared with 21% in the arm who received docetaxel or paclitaxel. At 12 months, 47% and 34%, respectively, were alive. OS favored nivolumab versus chemotherapy across multiple prespecified subgroups, including tumor PD-L1 expression.
The objective response rate was 19% in the nivolumab arm and 33% in the chemotherapy arm.
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.
Regarding safety, 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%).