Nivolumab-based regimen confers OS benefit, durable responses in advanced ESCC

First-line treatment with nivolumab – be it in combination with chemotherapy (CT) or with ipilimumab – provided overall survival (OS) benefit and durable responses than CT alone in patients with advanced oesophageal squamous cell carcinoma (ESCC), according to findings from the phase III CheckMate 648 trial.

“Many oesophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually have a relapse,” said the researchers. Moreover, first-line CT for advanced or metastatic ESCC often result in poor survival outcomes. [BMC Cancer 2015;15:693; Ann Oncol 2020;31:228-235]

The team sought to evaluate the efficacy and safety of both an immune checkpoint inhibitor in combination with CT and a dual immune checkpoint inhibitor combination in adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC. Participants (n=970; 49 percent with tumour-cell PD-L1 expression of ≥1 percent) were randomized 1:1:1 to receive IV nivolumab Q2W either in combination with CT (NIVO-CT*) or ipilimumab (NIVO-IPI**), or CT alone. [N Engl J Med 2022;386:449-462]

At a minimum follow-up of 13 months, OS was significantly longer with NIVO-CT (median 13.2 vs 10.7 months; hazard ratio [HR], 0.74; p=0.002) and NIVO-IPI (median 12.7 vs 10.7 months; HR, 0.78; p=0.01) than with CT alone in the overall cohort. Both nivolumab-containing regimens also fared better than CT alone in the PD-L1 expression subgroup (median 15.4 vs 9.1 months; HR, 0.54; p<0.001 [NIVO-CT] and median 13.7 vs 9.1 months; HR, 0.64; p=0.001 [NIVO-IPI]).

A significant progression-free survival (PFS) benefit was also seen with NIVO-CT vs CT alone (median 6.9 vs 4.4 months; HR for disease progression or death, 0.65; p=0.002) in the PD-L1 expression subgroup, but not in the overall cohort. This was also not seen with NIVO-IPI. “[The] lack of PFS benefit despite longer OS has previously been observed with immunotherapies and is probably attributable to their delayed treatment effect relative to CT,” said the researchers.

In the overall cohort, objective response rate (ORR) was highest in the NIVO-CT arm (47 percent), followed by NIVO-IPI (28 percent) and CT alone (27 percent). In the PD-L1 expression subgroup, both nivolumab-containing arms had higher ORRs than the CT-alone arm (53 percent [NIVO-CT] and 35 percent [NIVO-IPI] vs 20 percent [CT alone]).

Nivolumab-based regimens also outdid CT alone in terms of the fraction of participants achieving complete response, both in the overall cohort (13 percent [NIVO-CT] and 11 percent [NIVO-IPI] vs 6 percent [CT alone]) and the PD-L1 expression subgroup (16 percent and 18 percent vs 5 percent).

More patients in the NIVO-CT arm reported grade 3/4 treatment-related adverse events (TRAEs; 47 percent) and any-grade TRAE leading to withdrawal of any drug in the regimen (34 percent), as opposed to NIVO-IPI (32 percent and 18 percent, respectively) and CT alone (36 percent and 19 percent). “[Nonetheless,] the safety profiles of each treatment were consistent with the known safety profiles of the individual components in each regimen,” said the researchers.

“[Taken together, the current] findings show the benefit of adding a PD-1 inhibitor to CT,” the researchers noted. These also reinforce data reflecting the survival benefit with NIVO-IPI seen in multiple solid tumours. [N Engl J Med 2019;381:2020-2031; N Engl J Med 2017;377:1345-1356; Lancet 2021;397:375-386] “Longer follow-up will further elucidate the magnitude of long-term clinical benefit with NIVO-IPI,” said the researchers.

“[However,] the trial was not designed to compare outcomes between NIVO-CT and NIVO-IPI or to determine which treatment should be used for specific subgroups,” they pointed out. “Multiple factors may influence the choice of regimen in clinical practice, including an individual patient’s need for a relatively rapid treatment effect and the occurrence of side effects associated with CT that a patient considers to be unacceptable.”

Further analyses may help shed light on disease or demographic characteristics that may predict efficacy outcomes for each nivolumab-containing regimen, they added.