Updated Nivolumab Data Solidify Use in Advanced Gastric/GEJ/Esophageal Cancers

The authors

A Between the Lines program, filmed during the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, focused on results from the phase 3 CheckMate649 trial (NCT02872116), which assessed nivolumab (Opdivo) plus chemotherapy vs chemotherapy alone.¹ The results noted sustained efficacy for the first-line regimen in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma.

The program was led by David H. Ilson, MD, PhD, an attending physician at Memorial Sloan Kettering Cancer Center. He was joined by Sunnie Kim, MD, associate professor of medicine at the University of Colorado Anschutz Medical Campus, and Raji Shameem, MD, a medical oncologist and hematologist at the Orlando Health Cancer Institute.

To begin, Ilson highlighted that chemotherapy is the “cornerstone treatment of metastatic disease” for those with gastric cancer. Typically, folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are the current treatment options in the US. Other countries may use capecitabine and oxaliplatin but avoid using a third drug because of toxicity concerns.

Kim utilizes biomarker testing to optimize first-line treatment for patients. Specifically, reflexive testing will be recommended for those with mismatch repair disease, PD-L1 with a combined positive score (CPS), HER2 overexpression, and Claudin18.2 (CLDN18.2) overexpression.

Shameem noted some of the recent immunotherapy-based FDA approvals. For patients with PD-L1 status and who are HER2 positive, fam-trastuzumab deruxtecan-nxki (Enhertu) was approved in January 2021.² Additionally, zolbetuximab-clzb (Vyloy) plus chemotherapy was approved for those who are CLDN18.2 positive/HER2 negative.³

CheckMate649 Trial

A total of 2031 patients were randomly assigned 1:1:1 into the nivolumab/chemotherapy group (n = 789), the chemotherapy-alone group (n = 833), or the nivolumab/ipilimumab (Yervoy) group (n = 409). This analysis focused on the nivolumab/chemotherapy vs chemotherapy-alone results. Patients were given either 360 mg of nivolumab plus oxaliplatin every 3 weeks or 240 mg of nivolumab plus FOLFOX every 2 weeks. The chemotherapy group was given oxaliplatin every 3 weeks or FOLFOX every 2 weeks.

A majority of patients were men (68% vs 71%), non-Asian (77% vs 78%), had a primary tumor that was gastric cancer (70% vs 70%), and had metastatic disease (96% vs 95%) between the combination and monotherapy arms, respectively. The data cutoff was May 28, 2024, and the minimum follow-up was 60.1 months.

The median overall survival (OS) in the all-randomized population was 13.7 months (95% CI, 12.4-14.5) in the nivolumab group vs 11.6 months (95% CI, 10.9-12.5) in the chemotherapy group (HR, 0.79; 95% CI, 0.71-0.88). In the group with a PD-L1 CPS of 1 or more, the median OS was 13.8 months (95% CI, 12.4-14.8) vs 11.4 months (95% CI, 10.7-12.3) between both arms (HR, 0.76; 95% CI, 0.67-0.85). For those with a CPS of 5 or more, the median OS was 14.4 months (95% CI, 13.1-15.2) vs 11.1 months (95% CI, 10.1-12.1) between the combination and monotherapy groups (HR, 0.71; 95% CI, 0.61-0.81). For those with a CPS of 10 or more, the median OS was 15.0 months (95% CI, 13.6-16.7) vs 10.9 months (95% CI, 9.9-12.0) between both groups, respectively (HR, 0.68; 95% CI, 0.58-0.79).

“Historically, with chemotherapy alone and metastatic disease, long-term survivals are achieved in less than 5% [of patients] now. To get a long-term survival statistic in the mid-teens is unprecedented and indicates a durable benefit in improving OS with the inclusion of nivolumab as part of first-line treatment. The magnitude of benefit is determined by the positivity rate for CPS, with the greatest benefit in a CPS of 5 or higher,” Ilson said.

The median progression-free survival (PFS) in the all-randomized cohort was 7.8 months (95% CI, 7.1-8.6) in the nivolumab group vs 6.9 months (95% CI, 6.7-7.2) in the chemotherapy group (HR, 0.79; 95% CI, 0.71-0.89). For those with a PD-L1 CPS of 1 or more, the median PFS was 7.5 months (95% CI, 7.0-8.5) vs 6.9 months (95% CI, 6.2-7.1) between both groups (HR, 0.77; 95% CI, 0.68-0.87). For those with a CPS of 5 or more, the median PFS was 8.3 months (95% CI, 7.0-9.4) vs 6.1 months (95% CI, 5.6-6.9) between both groups (HR, 0.71; 95% CI, 0.61-0.82). For those with a CPS of 10 or more, the median PFS was 8.4 months (95% CI, 7.0-9.8) vs 5.8 months (95% CI, 5.5-6.9) between both groups (HR, 0.68; 95% CI, 0.57-0.80).

The overall response rate was 58% (95% CI, 54%-62%) vs 46% (95% CI, 42%-50%) in the all-randomized cohort, 60% (95% CI, 55%-64%) vs 46% (95% CI, 42%-51%) in the cohort with a CPS of 1 or more, 60% (95% CI, 55%-65%) vs 45% (95% CI, 40%-50%) in the cohort with a CPS of 5 or more, and 59% (95% CI, 53%-65%) vs 45% (95% CI, 39%-50%) between the nivolumab combination and chemotherapy-alone groups, respectively.

Ilson asked Kim how these 5-year results impacted the interpretation of the data. Simply put, the findings from CheckMate649 show a positive impact of using nivolumab in the first-line setting for this patient population. For Kim, nivolumab plus chemotherapy should strongly be considered not only in the first-line setting but also in patients who have a CPS between 1 and 4.

CPS scoring became a topic of conversation. Specifically, which patients would be best candidates for nivolumab plus chemotherapy? Shameem backed the data observed in the trial, which showed that those with a CPS of 5 or greater had the best response.

“What about a patient who has a CPS score of 0? I’m not going to recommend immunotherapy because I think that the patient has the least likelihood of having an added response. This is a decision we have in the clinic; we discuss this with the patients. Probably the biggest question is what to do for [CPS] 1 to 5. I always have a discussion with my patient to say the benefits vs the risks, weighing efficacy and toxicity,” Shameem said.

Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 60% of patients in the nivolumab group vs 45% in the chemotherapy group. Serious TRAEs were observed in 17% vs 10%, with TRAEs leading to discontinuation in 19% vs 10%. Between each arm, treatment-related deaths occurred in 2% vs less than 1%. The most common TRAEs between each arm were neutropenia (16% vs 13%), decreased neutrophil count (11% vs 9%), and anemia (6% vs 3%).

To Ilson, the AEs are manageable, and not many new signals were identified with long-term follow-up. He asked Kim how these AEs may impact treatment decisions. “Over the [past] few years, we’ve become quite comfortable managing the AEs from immunotherapy such as nivolumab. The most common AEs we see from this class of drugs are diarrhea, rash, pneumonitis, and thyroid hormone alterations. For the most part, these AEs are lower grade and quite manageable. There’s always the option of pausing therapy. If the AE is severe, giving steroids to dampen the immune system is always an option, as well. Even after these AEs, rechallenge is an option, but that needs to be a discussion with the patient,” Kim said.

Shameem echoed Kim and noted that clinicians are accustomed to seeing many of these AEs. He emphasized continuing to counsel patients and being educated about the rare but possible AEs.

Quality-of-Life Considerations

Ilson believes that the CheckMate649 study achieved quality-of-life management because of the few AEs observed. Kim noted that there has been enough experience with using chemotherapy plus immunotherapy. Finding the right time to stop oxaliplatin can prevent debilitating neuropathy, and Kim explained that when fluoropyrimidine is given during dose reductions, it can also help maintain quality of life.

Testing for PD-L1 is heterogeneous, with different levels and reports. Shameem highlighted the importance of biomarker testing because if it doesn’t occur, how can clinicians know what to treat?

“We always want to offer patients access to tolerable and effective treatments. This is where the debate of the 1% to 5% [CPS] of patients—if you retest, are they going to be 5%? We’re in agreement that if you’re consistently PD-L1 negative, there’s not a clear role for including nivolumab as first-line treatment. [However], there is a key role in educating our pathologists in the community to also do this testing as a reflex so we can make treatment decisions early in the patient’s diagnosis and move treatment forward,” Ilson said.

Emerging Data and Key Takeaways

According to Kim, FGFR2b is a biomarker that is expressed in 30% of patients with gastroesophageal adenocarcinoma, and DKK1 is involved in the Wnt signaling pathway. Currently, clinical trials are underway looking at how these genes are expressed and affect treatment options for this population.

Shameem noted that the 5-year follow-up results from CheckMate649 reaffirm what he does in his clinic. Specifically, he is seeing patients with durable responses that have not been seen before in this population.

Kim said it’s nice to see a role created for immunotherapy in advanced disease, but there is still room to improve. She hopes that the optimization of immunotherapy treatments and understanding which subset of patients benefit most from combined approaches will be investigated further.

“Right now, PD-L1 remains our main biomarker. The small subset of patients who are [microsatellite instability] high has the greatest benefit from checkpoint inhibitors. The ongoing refinement of optimal biomarker detection and selecting the best treatment for the first line—and now we see the hope of maybe combining these new targeted agents, checkpoint inhibitors, FGFR2b inhibitors, and CLDN18.2 inhibitors—is going to be the next wave,” Ilson said.

References

1. Janjigian YY, Moehler MH, Ajani JA, 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(4):398. doi:10.1200/JCO.2025.43.4_suppl.398
2. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed February 4, 2025. https://shorturl.at/68NYQ
3. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed February 4, 2025. https://shorturl.at/qFv0H