Early results from the CheckMate-648 clinical trial, which evaluated the efficacy and safety of Opdivo (nivolumab), a PD-1 inhibitor, plus Yervoy (ipilimumab), a CTLA-4 inhibitor, or nivolumab plus chemotherapy, suggest a potential new standard of care for the first-line treatment of patients with advanced esophageal squamous-cell carcinoma (ESCC). These findings were presented at the ASCO 2021 virtual annual meeting by Ian Chau, MD, Consultant Medical Oncologist, Gastrointestinal and Haemato-Oncology, Royal Marsden Hospital, Sutton, United Kingdom, and lead investigator of the trial.
“Nivolumab plus chemotherapy and nivolumab plus ipilimumab each represent a new potential first-line standard of care for patients with ESCC,” he said.
Esophageal cancer accounts for more than half a million deaths each year globally, and ESCC accounts for approximately 85% of all esophageal cancers. “Standard first-line chemotherapy for advanced or metastatic ESCC carries a poor prognosis, with a median OS [overall survival] of approximately 1 year,” said Dr Chau.
CheckMate-648 is the first global phase 3 study to evaluate the efficacy and safety of dual checkpoint inhibition along with a checkpoint inhibitor plus chemotherapy combination. In total, 970 patients with unresectable advanced recurrent or metastatic ESCC were randomized to 1 of 3 treatment arms: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; nivolumab 240 mg every 2 weeks plus chemotherapy; or chemotherapy alone. Patients randomized to the investigational arms were able to receive treatment up to 24 months or until disease progression or unacceptable toxicity. The median duration of treatment was 5.7 months in the nivolumab plus chemotherapy arm, 2.8 months in the nivolumab plus ipilimumab arm, and 3.4 months for the chemotherapy-alone arm.
Approximately 49% of patients in the trial had tumor-cell PD-L1 expression ≥1%.
The primary end points of the trial were OS and progression-free survival (PFS) in patients whose tumors express PD-L1 ≥1% for both nivolumab-based combinations versus chemotherapy. Secondary end points included OS and PFS in the all-randomized population. At a minimum follow-up of 12.9 months, OS was significantly longer among the all-randomized patients treated with nivolumab plus chemotherapy versus chemotherapy alone (13.2 months vs 10.7 months; hazard ratio [HR], 0.74; P = .0021).
“This translated into more than 6 months improvement in median OS in favor of nivolumab,” said Dr Chau. “At 12 months, there was an absolute improvement of OS in 21% in favor of nivolumab.”
The regimen of nivolumab plus ipilimumab also improved OS versus chemotherapy alone (12.8 months vs 10.7 months; HR, 0.78; P = .0110) among the all-randomized patient population.
The benefit with immunotherapy was enhanced in patients with tumor-cell PD-L1 expression ≥1%. In this population, median OS was significantly prolonged in patients treated with nivolumab plus chemotherapy and nivolumab plus ipilimumab compared with those treated with chemotherapy alone—15.4 months (HR, 0.54; P <.0001) and 13.7 months (HR, 0.64; P = .001), respectively—compared with 9.1 months.
“The clinically meaningful improvements in survival of these two treatment regimens highlight immunotherapy’s impact on cancer care and should bring new therapeutic options to a group of patients that are often diagnosed when disease has already spread,” said Dr Chau.
In addition to the extension in median OS, median PFS was also improved significantly in the nivolumab plus chemotherapy arm compared with chemotherapy alone in the subgroup of patients with positive PD-L1 expression. Among all-randomized patients, there was a trend toward improved median PFS in the immunotherapy arms versus chemotherapy. However, there was no significant improvement in median PFS with nivolumab plus ipilimumab compared with chemotherapy in the PD-L1–positive population.
The safety profiles of nivolumab plus chemotherapy and nivolumab plus ipilimumab were consistent with those previously reported with these treatments in other tumor types. Grade 3/4 treatment-related adverse events were 47% in the nivolumab plus chemotherapy arm, 32% in the nivolumab plus ipilimumab arm, and 36% in the chemotherapy arm. Disease progression was the most frequent reason for treatment discontinuation in all 3 cohorts.
“Certain patients with advanced esophageal cancer, who currently have few treatment options, now stand to gain from immunotherapy. The dual immunotherapy combination of nivolumab and ipilimumab is the first chemotherapy-free first-line treatment showing benefit for these patients,” said ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO.