CheckMate 648: Nivo + chemo and nivo + ipi continue to improve OS vs chemo in ESCC at 29-month follow-up

After 29 months of minimum follow‐up, nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful overall survival (OS) benefit vs chemotherapy in patients with previously untreated, unresectable, advanced, recurrent, or metastatic oesophageal squamous-cell carcinoma (ESCC), according to results of the global, open-label, phase III CheckMate 648 trial.

Until recently, fluoropyrimidine plus platinum‐based chemotherapy was the only recommended first‐line treatment option for advanced ESCC, which was associated with a poor OS of <1 year. “PD‐1 inhibitor–based therapies, including nivolumab, have helped to address the high unmet need for first‐line treatment of advanced ESCC. … Following 13 months of minimum follow‐up, CheckMate 648 met the primary endpoint of superior OS with nivolumab plus chemotherapy vs chemotherapy and nivolumab plus ipilimumab vs chemotherapy,” wrote the study investigators. [Lancet Oncol 2019;20:1506‐1517; Lancet 2021;398:759‐771; JAMA 2021;326:916‐925; N Engl J Med 2022;386:449‐462]

On the basis of CheckMate 648’s earlier results, nivolumab plus chemotherapy and nivolumab plus ipilimumab were approved as first‐line standard treatments for patients with advanced ESCC in Hong Kong.

CheckMate 648 investigators randomly assigned 970 patients with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC to receive nivolumab (240 mg every 2 weeks) plus chemotherapy (4‐week cycle of fluorouracil 800 mg/m² [day 1 through day 5] and cisplatin 80 mg/m² [day 1]) (n=321), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) (n=325), or chemotherapy (n=324). The majority of patients (70 percent) were from Asian countries, and 49 percent had tumour-cell PD‐L1 expression ≥1 percent.

The primary endpoints were OS and progression-free survival (PFS) by blinded independent central review (BICR) per RECIST version 1.1 in patients with tumour-cell PD‐L1 expression ≥1 percent. Secondary endpoints were OS and PFS by BICR in the overall population and rate of objective response by BICR in patients with PD‐L1 expression ≥1 percent and in the overall population.

After 29 months of minimum follow-up, patients with PD‐L1 expression ≥1 percent treated with nivolumab plus chemotherapy vs chemotherapy alone achieved a median OS of 15.0 vs 9.1 months (hazard ratio [HR], 0.59; 95 percent confidence interval [CI], 0.46–0.76]). Median OS was 13.1 vs 9.1 months in patients treated with nivolumab plus ipilimumab vs chemotherapy (HR, 0.62; 95 percent CI, 0.48–0.80). [Cancer Med 2024;13:e7235.]

Patients in the overall population treated with nivolumab plus chemotherapy also continued to demonstrate improvement in median OS vs patients who received chemotherapy (12.8 vs 10.7 months; HR, 0.78; 95 percent CI, 0.65–0.93). The findings were similar for patients treated with nivolumab plus ipilimumab vs chemotherapy (12.7 vs 10.7 months; HR, 0.77; 95 percent CI, 0.65–0.92).

In patients with PD‐L1 expression ≥1 percent, median PFS per BICR was 6.8 vs 4.4 months in those treated with nivolumab plus chemotherapy vs chemotherapy (HR, 0.67; 95 percent CI 0.51–0.89). Median PFS per BICR in the overall population treated with nivolumab plus chemotherapy vs chemotherapy was 5.8 vs 5.6 months (HR, 0.83; 95 percent CI, 0.68–1.00). PFS benefit was not observed with nivolumab plus ipilimumab vs chemotherapy.

Grade 3/4 treatment‐related adverse events (TRAEs) were reported in 49, 32, and 36 percent of patients in the nivolumab plus chemotherapy, nivolumab plus ipilimumab, and chemotherapy groups, respectively. The most common TRAEs were nausea and decreased appetite in the nivolumab plus chemotherapy and chemotherapy groups, and rash, pruritus, and hypothyroidism with nivolumab plus ipilimumab.