Adjuvant nivolumab: a new SoC for resected oesophageal or GEJ cancer?

In individuals with resected oesophageal or gastro-oesophageal junction (GEJ) cancer who have received neoadjuvant chemoradiotherapy (CRT), adjuvant nivolumab therapy demonstrated superior efficacy over placebo, according to the CheckMate 577 trial.

Neoadjuvant CRT and subsequent surgery is the known standard of care (SoC) for resectable, locally advanced oesophageal/GEJ cancer. [J Natl Compr Canc Netw 2019;17:855-883; J Clin Oncol 2020; 38: 2677-2694] However, the recurrence risk remains high, especially in patients without pathological complete response, more so among those with lymph node-positive disease. [J Thorac Dis 2018;10:2771-2778; Cancer 2017;123:4106-4113]

“[M]ost patients have a poor prognosis … [As such,] adjuvant treatments to improve outcomes are clearly needed,” the researchers stressed. “Currently, the standard management after neoadjuvant CRT and surgery is surveillance. The development of an effective adjuvant treatment has been an elusive goal.”

With no established adjuvant therapy for oesophageal/GEJ cancer patients who are at high risk for recurrence following neoadjuvant CRT and surgery, the researchers sought to evaluate a novel approach using the checkpoint inhibitor nivolumab as adjuvant therapy in this setting.

A total of 794 individuals with resected stage II/III oesophageal/GEJ cancer who had received neoadjuvant CRT and had residual pathological disease and a high recurrence risk were included. Within 4–16 weeks post-surgery, participants were randomized 2:1 to either IV nivolumab (240 mg Q2W for 16 weeks; 480 mg Q4W from week 17) or matching placebo for a year or until the emergence of recurrence or unacceptable toxicities, or withdrawal of consent. [N Engl J Med 2021;384:1191-1203]

After a median follow-up of 24.4 months, disease-free survival (DFS) was twice as long in the nivolumab as in the placebo arm (median, 22.4 vs 11.0 months; hazard ratio [HR] for disease recurrence or death, 0.69; p<0.001).

“More than half of the participants had lymph node-positive disease, which is associated with particularly poor outcomes. Despite the poor prognostic factors … nivolumab was associated with a significant [DFS] improvement,” the researchers explained. “[Moreover, there was] a sustained separation of the DFS curves, [which] indicates durable benefit.”

DFS also consistently favoured nivolumab over placebo across multiple* prespecified subgroups (HRs ranging from 0.35 to 0.87).

On top of the DFS benefit, distant metastasis-free survival was longer with nivolumab vs placebo (median, 28.3 vs 17.6 months), with a 26-percent reduction in the risk of distant recurrence or death (HR, 0.74).

Nivolumab was associated with higher rates of grade 3/4 treatment-related adverse events (TRAEs) (13 percent vs 6 percent), serious AEs (8 percent vs 3 percent), and treatment withdrawal owing to TRAEs (9 percent vs 3 percent) vs placebo. Nonetheless, its safety profile correlates with those observed in previous trials on other solid tumours. [Lancet Oncol 2019;20:1506-1517; N Engl J Med 2017;377:1824-1835]

“With [our] positive results … oesophageal/GEJ cancer is the second tumour type, after melanoma, for which nivolumab has provided a benefit as adjuvant treatment,” said the researchers.

Practice-changing

“CheckMate 577 is a practice-changing trial in the treatment of oesophageal cancer,” commented Dr David Ilson from the Memorial Sloan Kettering Cancer Center, New York, US, in a separate editorial. “Although overall survival (OS) data are [immature], the doubling of median DFS will almost certainly translate into an OS benefit. The trial shows the first true advance in the adjuvant therapy of oesophageal cancer in recent years and will become a new [SoC].” [N Engl J Med 2021;384:1269-1271]

However, Ilson noted that, most patients will not obtain benefit from adjuvant nivolumab despite the observed improvements. “[Therefore,] more contemporary biomarkers, including the presence of persistent circulating tumour DNA after surgery, should be explored to better define high-risk populations and potentially monitor patients receiving adjuvant therapy.”

“[Nonetheless, the survival] improvement has been long awaited [in this setting among] those undergoing the arduous journey of CT, radiation, and surgery,” said Ilson. “Because there is no effective screening or early detection, most patients present with locally advanced or overt metastatic disease … CheckMate 577 provides a welcome new therapeutic option for these patients.”

CheckMate 577 is ongoing, and an OS analysis is planned. Further trials are also ongoing to ascertain whether adjuvant checkpoint inhibitor therapy may improve outcomes in patients undergoing definitive CRT without surgery, and peri-operative CT without RT.