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Immunotherapy in Upper GI Cancers
Emerging Immunotherapy Combinations in Upper GI Cancers

Released: December 31, 2025

Samuel J. Klempner
Samuel J. Klempner, MD, FASCO
Elizabeth Smyth
Elizabeth Smyth, MD, FRCP
Raghav Sundar
Raghav Sundar, MD, PhD
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Key Takeaways
  • Although biomarker-driven immunotherapy has improved outcomes for select patients with advanced upper GI cancers, most do not achieve long-term benefit, underscoring the need for better first-line strategies.
  • Next-generation treatment strategies include anti-TIGIT agents, particularly in combination with PD-1/PD-L1 blockade, which have demonstrated encouraging early efficacy.

In a recent webinar, Elizabeth Smyth, MD, FRCP; Samuel J. Klempner, MD, FASCO; and Raghav Sundar, MD, PhD, discussed emerging opportunities for novel immunotherapy combinations in upper gastrointestinal (GI) cancers, highlighting how current biomarker-driven strategies guide first-line treatment while leaving substantial unmet need. The panel also discussed promising next-generation approaches, such as TIGIT inhibition and other tumor microenvironment–targeted strategies, that may improve durability of benefit. 

How is immunotherapy used to treat patients with upper GI cancers? 

Elizabeth Smyth, MD, FRCP:
In advanced gastric and gastroesophageal adenocarcinoma, excluding squamous cancer, the use of immunotherapy is guided by a biomarker-driven approach per the European Society for Medical Oncology guidelines. Patients are first stratified by HER2 status. In those with HER2-positive disease, treatment decisions are further informed by PD-L1 expression. Patients whose tumors are both HER2 positive and PD-L1 positive should receive chemotherapy combined with trastuzumab and an anti–PD-1 immune checkpoint inhibitor (ICI). The recommended treatment regimen for patients with HER2-positive but PD-L1–negative tumors is chemotherapy and trastuzumab alone; immunotherapy is not recommended in this group because of insufficient evidence of benefit.

Patients with HER2-negative disease are subdivided according to claudin 18.2 status, mismatch repair (MMR) status, and PD-L1 status. Patients with claudin 18.2–positive tumors, defined as IHC 2+ or 3+ staining in more than 75% of tumor cells, can be treated with chemotherapy combined with zolbetuximab. Patients with MMR-deficient tumors should receive an ICI added to chemotherapy. Among patients with HER2-negative, MMR-proficient tumors, PD-L1 expression again further refines treatment decisions, but the strength of evidence depends on the combined positive score (CPS). For those with a CPS of 1-4, the addition of an ICI may be considered. However, for patients with a CPS of 5 or 10, strong evidence supports the addition of an ICI to chemotherapy. Finally, a small subset of patients lacks actionable biomarkers. In these patients, treatment consists of chemotherapy alone, with the choice between a doublet or triplet regimen. 

Do you believe there is a need to improve first-line immunotherapy combinations for advanced gastroesophageal adenocarcinoma?  

Samuel J. Klempner, MD, FASCO:
Yes. In short, there is always a need to do better for our patients. Most of the therapies currently used provide only a modest survival benefit, often on the order of a few months, and neither patients nor oncologists find that level of improvement satisfactory. Although it is encouraging that some biomarker-enriched subgroups experience better outcomes, this does not diminish the broader need to improve first-line immunotherapy and targeted treatment strategies.

Elizabeth Smyth, MD, FRCP:
I agree. Although these treatments have been transformative for a small proportion of patients, the overall long-term benefit remains limited. For example, in the phase III CheckMate 649 study, only 16% of patients with HER2-negative, PD-L1–positive (CPS ≥5) disease treated with the recommended regimen of nivolumab plus chemotherapy were alive at 5 years. This means that most patients do not achieve durable benefit, reinforcing the need to develop better therapies for those who are not helped sufficiently by current first-line options.

Raghav Sundar, MD, PhD:
When comparing progress made in upper GI cancers with that in other diseases such as breast and lung cancers, it is clear that we are still behind. There remains a need to push forward with novel approaches beyond standard chemoimmunotherapy to meaningfully improve outcomes for our patients.

What are some recent novel immunotherapy approaches for upper GI cancers? 

Raghav Sundar, MD, PhD:
Beyond PD-1/PD-L1 and CTLA-4 inhibition, novel immunotherapy approaches are focused on targeting other components of the tumor microenvironment. One of the most promising strategies involves second-generation ICIs targeting TIGIT. There is strong biological rationale for combining TIGIT inhibition with PD-1/PD-L1 blockade and dual inhibition may synergistically enhance the antitumor immune response.

Recently, tiragolumab, an Fc-active anti-TIGIT antibody, had shown promise in phase II studies in solid tumors, particularly when combined with atezolizumab. However, at the ESMO 2025 meeting, reports from randomized studies in NSCLC, HCC, and esophageal cancer showed negative efficacy findings.

One important and ongoing debate is whether the Fc domain of anti-TIGIT antibodies influences efficacy, particularly through potential depletion of intratumoral regulatory T-cells. The phase II EDGE-Gastric study of the Fc-silent anti-TIGIT antibody domvanalimab combined with the anti–PD-1 monoclonal antibody zimberelimab and chemotherapy in adults with previously untreated advanced HER2-negative upper GI cancers showed encouraging data, with high response rates and prolonged median progression-free survival (PFS), especially in participants with a tumor area positivity (TAP) score ≥5%, without significant immune-related toxicities.

Building on these results, the phase III STAR-221 trial was initiated, comparing domvanalimab plus zimberelimab plus chemotherapy with the proper control of chemotherapy plus nivolumab in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma, making it a well-designed and clinically relevant study. Unfortunately, in December 2025, a press release indicated that this trial would be discontinued based on a recommendation from an IDMC after review of data from a prespecified interim analysis indicated that domvanalimab plus zimberelimab and chemotherapy did not improve overall survival (OS) relative to nivolumab plus chemotherapy.

Rilvegostomig, a bispecific antibody targeting TIGIT/PD-1, has also shown activity in HER2-negative advanced gastric cancer in the phase II GEMINI-Gastric study. It is currently being assessed in the phase III ARTEMIDE-Gastric-01 study in combination with trastuzumab deruxtecan and a fluoropyrimidine for patients with previously untreated advanced gastric or GEJ adenocarcinoma that is HER2 positive and has PD-L1 CPS ≥1; this regimen will be compared with trastuzumab plus FP or CAPOX and either rilvegostomig or pembrolizumab. 

Samuel J. Klempner, MD, FASCO:
We have known for many years that there is activity of antiangiogenic therapies in gastric cancer. Unfortunately, several recent negative phase III studies have been disappointing in this space. INTEGRATE IIb was a randomized phase III study of regorafenib plus nivolumab vs chemotherapy for patients with advanced/recurrent gastric/GEJ adenocarcinoma with progression/intolerance to ≥2 prior lines of therapy. Unfortunately, OS and PFS were not statistically different between the 2 treatment arms. This was humbling, I think, for all of us who take care of this disease. It is a stark reminder of the expectations we get with chemotherapy. Similarly, the phase III LEAP-015 study of pembrolizumab plus lenvatinib plus chemotherapy for previously untreated HER2-negative advanced gastroesophageal cancer did not meet the prespecified criteria for significance in OS (CPS ≥1) but was significant for PFS. Novel approaches to targeting VEGF include RC148, a bispecific antibody targeting PD-1 and VEGF. This agent has shown activity when combined with RC118, a CLDN18.2-directed ADC, for previously treated CLDN18.2-positive advanced gastric/GEJ adenocarcinoma. 

Your Thoughts
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