GI cancer

New standard of care for hard-to-treat upper GI cancers


The addition of nivolumab to chemotherapy improves survival in patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma.

The phase 3 CheckMate 649 trial compared nivolumab plus chemotherapy versus chemotherapy alone as first-line treatment for unresectable non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression.

The study, published in The Lancet, randomised 1,581 patients from 29 countries including Australia.

It found patients in the nivolumab plus chemotherapy group with a PD-L1 combined positive score (CPS) of five or more had a 3·3-month improvement in median overall survival compared with chemotherapy alone (14·4 vs 11·1 months), with a 29% reduction in the risk of death (HR 0·71).

The proportion of patients alive at 12 months was numerically higher with nivolumab plus chemotherapy than with chemotherapy alone (57% v 46%).

“Nivolumab plus chemotherapy also provided superior PFS in patients with a PD-L1 CPS of five or more, with a 32% reduction in the risk of progression or death versus chemotherapy alone (HR 0·68 [98% CI 0·56–0·81]; p<0·0001),” the study said.

“Median PFS was 7·7 months (95% CI 7·0–9·2) with nivolumab plus chemotherapy versus 6·0 months (5·6–6·9) with chemotherapy alone. The 12-month PFS estimate was 36% (95% CI 32–41) with nivolumab plus chemotherapy versus 22% (18–26) with chemotherapy alone.”

The investigators, including Associate Professor Kynan Feeney from St John of God Murdoch Hospital (WA), found the addition of nivolumab also added an overall survival benefit in patients with a PD-L1 CPS of one or more (HR 0.77), all randomised patients (HR 0.80) and a number of prespecified subgroups.

The most common treatment-related adverse events were nausea, diarrhoea, and peripheral neuropathy across both groups.

Grade 3–4 treatment-related adverse events were more common in the nivolumab plus chemotherapy group (59% v 44%), as were any-grade treatment related adverse events leading to discontinuation (36% v 24%).

They reported 16 (2%) treatment related deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group. Causes of death included pneumonitis, febrile neutropenia or neutropenic fever, GI bleeding, GI toxicity, infection, intestinal mucositis, pneumonia, septic shock, and stroke.

“The safety profile of nivolumab plus chemotherapy was consistent with the known safety profiles of the individual treatments and no new safety signals were identified,” the investigators said.

“This is the first global study, to our knowledge, to show superior OS in a randomised controlled trial with a median OS exceeding 1 year in the first-line setting for patients with non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, for which treatment options are limited and no advances have been made in the past decade.”

They said nivolumab plus chemotherapy therefore represented a new standard first-line treatment for this patient group. It has been approved in the US for this indication.

A Comment article in the journal agreed – saying CheckMate 649 was an “important milestone” in the treatment of upper GI cancer.

“This long-awaited progress will create opportunities for biomarker refinement and the development of further combination therapy strategies within the gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma treatment landscape.”

CheckMate 649 was funded by Bristol Myers Squibb.

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