Upfront NIVO + chemo maintains survival benefit in advanced oesophagogastric cancer regardless of PD-L1 status

Upfront treatment with nivolumab plus chemotherapy continues to yield significant survival benefit compared with chemotherapy alone in patients with advanced GC/GEJC/EAC* after 24 months, regardless of their PD-L1 combined positive score (CPS), according to long-term data from the CheckMate-649 trial presented at GICS 2022.

“This analysis confirms the previous data by showing clinically meaningful long-term OS and progression-free survival [PFS] benefits, with sustained separation of the survival curves for patients with tumours expressing PDL-1 CPS ≥5,” highlighted invited discussant Dr Stefano Cascinu of the Vita-Salute San Raffaele University in Milan, Italy.

After a minimum follow-up of 24 months, the nivolumab + chemotherapy group saw sustained improvements in OS (HR, 0.79, 95 percent confidence interval [CI], 0.71-0.88) and PFS (HR, 0.79, 95 percent CI, 0.70-0.89) — which the investigators described as “clinically meaningful” compared with the chemotherapy alone group. [GICS 2022, abstract 240]

The long-term clinical benefit persisted even after the initiation of second-line treatment — as indicated by the longer median PFS2** of 12.2 months with the combination therapy vs 10.4 months with chemotherapy alone (HR, 0.75, 95 percent CI, 0.67-0.84).

In prespecified subgroup analyses, OS benefit favouring the combination therapy persisted across key subgroups, including patients with poor prognostic factors such as those with high tumour burden, liver metastases, or low albumin, noted presenting author Dr Kohei Shitara of National Cancer Center Hospital East in Kashiwa, Japan.

“[In addition,] patients with tumours with high microsatellite instability showed remarkable benefit with nivolumab plus chemotherapy, but efficacy was also clearly observed when these patients were excluded from the analysis,” he reported. 

CPS as biomarker?

When the analyses were stratified by CPS for PD-L1, both OS and objective response rate (ORR) were higher in the nivolumab + chemotherapy group than the chemotherapy group alone, regardless of CPS. While OS benefit was seen among patients with PD-L1 CPS ≥5 — which was the population the published primary analysis was based on — the current updated analysis showed that those with CPS <5 also benefited.

The addition of nivolumab to chemotherapy led to more durable and deep responses than chemotherapy alone, regardless of whether patients had CPS ≥5 or <5.

“These results call into question — at least in part — the role of PD-L1 CPS, as well as the choice of 5 as a cutoff [when selecting patients who are likely to benefit from the combination therapy,]” Cascinu pointed out.

He suggested that future study should look into a different biomarker that can potentially be used either alone or in conjunction with PD-L1 CPS for patient selection.

The expanded data

The current updated analysis included 1,581 patients from the global, phase III CheckMate-649 cohort of 2,031 patients. These participants were randomized to nivolumab + chemotherapy (XELOX/FOLFOX; n=789) or chemotherapy alone (n=833), which represented two of the three arms in the CheckMate-649 trial. Patients who had been followed up for a minimum of 24 months were analysed.

There were no new safety signals with the longer follow-up. Most of the treatment-related adverse events (TRAEs) with potential immunologic aetiology were grade 1/2, while grade 3/4 events occurred in ≤5 percent of patients in both groups.

“TRAEs with potential immunologic aetiology resolved in most patients,” said Shitara. “The majority of nonendocrine events resolved with the use of established management algorithms. Some endocrine events were considered unresolved due to continuing need for hormonal replacement therapy.”

“These data further support the use of nivolumab + chemotherapy as standard first-line treatment in patients with advanced oesophagogastric cancer,” he concluded.

*GC/GEJC/EAC: gastric cancer/gastroesophageal junction cancer/oesophageal adenocarcinoma

**defined as the time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever occurred earlier