Understanding the Use of Nivolumab in the Current Upper GI Landscape

David Zhen, MD

In an interview with Targeted Oncology, David Zhen, MD, a medical oncologist and associate professor in the clinical research division at the Fred Hutchinson Cancer Center and associate professor in the division of hematology and oncology at the University of Washington School of Medicine in Seattle, Washington, discussed the relevance of nivolumab (Opdivo) in the upper gastrointestinal (GI) cancer population.

Among the general data from the CheckMate 649 trial (NCT02872116) of nivolumab plus chemotherapy, he touched on the continuing debate of using combined positive score (CPS) of PD-L1 as a cut-off, as well as the 5-year updated data from the 2025 American Society of Clinical Oncology (ASCO) GI Cancer Symposium. For these patients with advanced GI cancer, Zhen also noted the manageable toxicity with the combination of immunotherapy and chemotherapy.

Targeted Oncology: What are the options for patients with upper GI cancer?

David Zhen, MD: The treatment of upper GI cancers depends on whether someone has localized disease or advanced disease. I'll be focusing mostly on the patients with advanced disease, and in that setting, usually the foundation is with chemotherapy, usually a combination of fluoropyrimidine, often fluorouracil, and then platinum [chemotherapy]…here in the United States, we often use oxaliplatin. Now with recent data, there's also the use of immunotherapy agents: PD-1 checkpoint inhibitors such as nivolumab.

You mentioned nivolumab as a newer option; can you discuss the design of the trial looking at this drug for upper GI cancers?

CheckMate 649 was a pivotal global phase 3 trial that established the benefit of the use of nivolumab in the first-line treatment setting for advanced upper GI cancers.¹ This was a randomized study that enrolled patients with untreated, unresectable, or metastatic esophagus, gastroesophageal junction, or gastric adenocarcinoma with good performance status. These were all patients with HER2-negative disease, and they were randomly assigned to 1 of 3 arms.

One of the arms I won't talk about, because that was looking at dual checkpoint inhibitors with nivolumab and ipilimumab [Yervoy]. That was not very effective. I'm going to focus on the comparisons of chemotherapy plus immunotherapy vs immunotherapy alone. The chemotherapy [comparator] was either capecitabine plus oxaliplatin or FOLFOX [folinic acid, fluorouracil, and oxaliplatin] vs capecitabine or FOLFOX combined with nivolumab.

The primary end point of this study was trying to restrict to a PD-L1–elevated population, so the dual primary end points were overall survival [OS] and progression-free survival [PFS] in patients who had a PD-L1 CPS of 5 or greater. Secondary end points looked at the OS and PFS in all other populations with PD-L1 [CPS scores of 1 or higher].

What was the efficacy of nivolumab and chemotherapy in the CheckMate 649 trial?

The trial did meet its primary end point of a survival benefit in patients who had a CPS of 5 or above. Specifically, the OS in this group of patients was a median OS of 14.4 months compared with 11.1 months with chemotherapy alone [HR, 0.71; 95% CI, 0.61–0.81], which was impressive since this was the first study that demonstrated an OS benefit beyond a year.

We now have 5-year long-term data that was presented at ASCO GI in January 2025, and this further confirmed the results with now a 5-year survival benefit rate of 16% vs 6% with chemotherapy alone.

How do you usually mitigate any common adverse events [AEs] that come with this combination?

This is a pretty manageable regimen, since most of the toxicities are attributable to the chemotherapy, and so most of the toxicities are usually related to the cytopenias from chemotherapy, as well with the nausea management, diarrhea, and such that we're all aware of with chemotherapy. Very few AEs were related to immune-related events, and even if they occurred, they generally were very mild and very manageable.

What advice would you give a colleague who hasn't used nivolumab often in this setting?

Nivolumab is a very easy-to-use agent in this group of patients. It's also very tolerable and effective based on the results of CheckMate 649. The nice thing about nivolumab…when we're considering our chemotherapy regimens such as FOLFOX, which we've come to use, the dosing strategy makes it easier to align with the infusion. Nivolumab can be given every 2 weeks or every 4 weeks, and then…it doesn't add too much of the toxicities to standard chemotherapy. Definitely, we know from this trial that it can improve OS. Certainly, it's an agent to definitely consider in patients who would be eligible otherwise.

Was there anything else that stood out to you about CheckMate649?

While the primary end point here was looking at patients with PD-L1 of CPS 5 or above, it is noteworthy that in the trial there was noted a survival benefit in all patients, regardless of PD-L1 [HR, 0.79; 95% CI, 0.71–0.88]. There's been a lot of debate about what CPS cutoffs we should be using. In late 2024, the FDA had convened just because of the confusion over the PD-L1 cutoffs.

I think where we may be heading, down the road, is that we may be looking at PD-L1 as more of a positive or negative result, and the reason being is because that's where the confidence lie in pathology reads. But what we're also seeing in studies is that when it's truly negative, we are seeing much less of a benefit. In other words, in terms of clinical practice, even though CPS of 5 and above does confer greater benefit, some patients who are at least still positive might still drive some benefits.

Reference:

1. Janjigian Y, Moehler M, Ajani J, et al. Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up results from CheckMate 649. J Clin Oncol. 2025;43(suppl 4):398. doi:10.1200/JCO.2025.43.4_suppl.398