The European Commission has approved the dual immunotherapy combination of nivolumab and ipilimumab for use in the frontline treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma who had a PD-L1 expression of 1% or higher on tumor cells.
The European Commission has approved the dual immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for use in the frontline treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) who had a PD-L1 expression of 1% or higher on tumor cells.1
The regulatory decision was supported by data from the phase 3 CheckMate-648 trial (NCT03143153), the median overall survival (OS) was 13.70 months (95% CI, 11.24-17.02) with nivolumab/ipilimumab vs 9.7 months (95% CI, 7.69-9.95) with chemotherapy in this patient population (HR, 0.64; 95% CI, 0.46-0.90; P = .0010).2
The median progression-free survival (PFS) was 4.04 months (95% CI, 2.40-4.93) with the combination vs 4.44 months (95% CI, 2.89-5.82) with chemotherapy in the population (HR, 1.02; 95% CI, 0.74-1.43; P = .8958).
Additionally, the dual immunotherapy combination elicited an objective response rate (ORR) of 35.4% (95% CI, 28.0%-43.4%) vs 19.7% (95% CI, 13.8%-26.8%) with chemotherapy.
“[Nivolumab] plus [ipilimumab] is 1 of 2 newly-approved [nivolumab]-based combination treatments in the European Union to show superior survival benefit to chemotherapy alone in this group of patients,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “ESCC is an incredibly aggressive cancer and as the disease progresses, it becomes even harder to treat. The ability to use [nivolumab] plus [ipilimumab] in the first-line setting for these advanced patients may help improve their survival outcomes compared with chemotherapy alone.”
CheckMate-648 trial enrolled patients with unresectable advanced, recurrent, or metastatic ESCC with measurable disease and an ECOG performance status of 0 or 1. Patients were not permitted to have received prior systemic therapy for advanced disease.
A total of 970 patients were randomized 1:1:1 to nivolumab at 240 mg every 2 weeks plus chemotherapy every 4 weeks (n = 321), nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n = 325), or chemotherapy alone every 4 weeks (n = 324). Those who received chemotherapy were given fluorouracil at 800 mg/m2 on days 1 to 5 and cisplatin at 80 mg/m2 on day 1 of a 4-week cycle. Nivolumab was given up to 24 months or until disease progression, unacceptable toxicity, or withdrawn consent.
Key stratification factors included PD-L1 expression (≥1% vs <1%), region (East Asia vs rest of Asia vs rest of world), ECOG performance status (0 vs 1), and the number of organs with metastases (≤1 vs ≥2).
The primary end points of the trial included OS and PFS in patients with a PD-L1 expression of 1% or higher, and secondary end points included OS and PFS in the all-randomized population, and ORR in both populations.
Baseline characteristics were noted to be balanced across the 3 treatment arms and it was also noted that they were consistent with that of those with a PD-L1 expression of 1% or higher. In the nivolumab/ipilimumab arm, the median age was 63 years (range, 28-81), 83% were male, 70% were Asian, 54% had an ECOG performance status of 1, and 99% had ESCC. Fifty-one percent of these patients had a PD-L1 expression of less than 1% on tumor cells, and 49% had an expression of 1% or higher.
Sixty percent of patients had de novo metastatic disease, 22% had recurrent distant disease, 10% had unresectable advanced disease, and 8% had recurrent locoregional disease. Additionally, 51% had 2 or more organs with metastases and 49% had 0 or 1 organs with metastases. Eighty-two percent of patients in this subset were current or former smokers.
In the 322 patients within the nivolumab/ipilimumab arm, the median duration of treatment was 2.8 months (range, 0.0-24.0). In this subset, 93% of patients discontinued treatment with the combination; 54% of patients did so because of disease progression, 18% because of treatment-related adverse effects, 6% because of a toxicity not related to treatment, 4% because of a patient request, and 11% because of another unspecified reason.
In the all-randomized population, the median OS was 12.8 months (95% CI, 11.3-15.5) with nivolumab/ipilimumab (n = 325) compared with 10.7 months (95% CI, 9.4-11.9) with chemotherapy (n = 324; HR, 0.78; 98.2% CI, 0.62-0.98; P = .0110). The OS rates at 12 months in the nivolumab/ipilimumab and chemotherapy arms were 54% and 44%, respectively.
The PFS per BICR was not hierarchically tested in this population, but the median PFS with nivolumab/ipilimumab was 2.9 months (95% CI, 2.7-4.2) vs 5.6 months (95% CI, 4.3-5.9) with chemotherapy (HR, 1.26; 95% CI, 1.05-1.52).
In the all-randomized population, the dual immunotherapy combination produced an ORR of 28% (95% CI, 23%-33%) vs 27% (95% CI, 22%-32%) with chemotherapy. The median duration of response in those with PD-L1 positivity who received nivolumab/ipilimumab was 11.8 months (95% CI, 7.1-27.4) vs 5.7 months (95% CI, 4.4-8.7) with chemotherapy. In the all-randomized population, the median DOR was 11.1 months (95% CI, 8.3-14.0) in the investigative arm and 7.1 months (95% CI, 5.7-8.2) in the control arm.
Eighty percent of patients who received nivolumab/ipilimumab experienced any-grade treatment-related adverse effects (TRAEs), 32% of whom had effects that were grade 3 or 4 in severity. Serious TRAEs were experienced by 32% of patients, with 23% experiencing grade 3 or 4 serious effects. Eighteen percent of patients experienced TRAEs that led to treatment discontinuation; 13% of patients had grade 3 or 4 TRAEs that resulted in discontinuation. Five treatment-related deaths were reported.
Previously, in September 2021, the FDA accepted supplemental biologics license applications for nivolumab plus ipilimumab and nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy in the frontline treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC based on data from CheckMate-648 trial.3 The agency is expected to make a decision by May 28, 2022, under the Prescription Drug User Fee Act.