Expert Point of View: Elizabeth Smyth, MD

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ASCO discussant Elizabeth Smyth, MD, a consultant medical oncologist at Oxford University Hospitals National Health Service Foundation Trust in the United Kingdom, commented on the EDGE-Gastric trial. This regimen, which evaluated dual checkpoint blockade with next-generation agents, aims to further boost the benefits achieved with checkpoint inhibitors in advanced gastroesophageal cancer, she said.

“Immune checkpoint inhibitors have changed the face of gastroesophageal cancer in the first-line setting. We have three international phase III randomized trials, each showing a consistent benefit of adding anti–PD-1 to chemotherapy, mostly for patients with high PD-L1 expression,” noted Dr. Smyth, but more benefit is needed, she added, since the median gain in overall survival is around 3 months in key trials. “There might be a 20% long-term benefit, based on the tail on the curves,” she said, “but it’s too early to say…. We need to improve the efficacy of checkpoint inhibitors in advanced gastroesophageal cancer.”

Elizabeth Smyth, MD

Elizabeth Smyth, MD

Other Previous Efforts

Efforts to do so, to date, have been somewhat disappointing, especially in nonbiomarker-selected patients. The addition of ipilimumab to nivolumab and chemotherapy did not improve outcomes, though some responders did achieve long-term benefits in CheckMate 649.1 Ipilimumab plus nivolumab and chemotherapy increased toxicity—but not efficacy—in unselected patients in MOONLIGHT,2 showing that more checkpoint inhibition is not necessarily better. As an alternative to anti–PD-1, the targeting of LAG-3 with relatlimab and nivolumab—which is effective in melanoma—looked promising in gastroesophageal cancer, but it did not boost response rates.3

“The efficacy of a specific immune checkpoint inhibitor may depend on the immune context, which may be disease-specific,” Dr. Smyth suggested. “We need translational work to tell us why this might occur, or else we are going to repeat the same mistakes.”

Enter Monoclonal Antibodies Targeting TIGIT

Now comes TIGIT, an immune receptor on some T cells and natural killer cells. In preclinical research, it synergizes with PD-1 to rescue antigen-specific T cells. “The rationale of the EDGE-Gastric trial is sound. TIGIT is one pathway among many in the second generation of immune checkpoint inhibition,” Dr. Smyth explained.

She emphasized that the study findings are very early, and many patients remain on study. To put the initial findings into context, according to Dr. Smyth, “we would expect a response rate from chemotherapy plus anti–PD-1 (the standard of care) to be in the range of 60%, and that’s exactly what we see overall in this study with domvanalimab and zimberelimab (59%). There may be a hint of increased efficacy in patients with PD-L1–high tumors (80%), with the reverse in PD-L1–low tumors (46%). However, these numbers are so small that it’s difficult to make definitive comments.”

“Progression-free survival is literally still on the first quarter of the survival curve,” noted Dr. Smyth. “But the results seem to be in line with what we might expect from earlier trials of chemotherapy plus anti–PD-1, and they are encouraging in the PD-L1–high patients—but it’s a small data set,” she cautioned.

The toxicity is as expected for chemotherapy plus an anti–PD-1 doublet, with a low rate of infusion reactions, “as predicted, because of the Fc silenced anti-TIGIT antibody,” she added. “However, numbers treated are too small to comment on the overall safety profile vs standard treatment. The regimen of domvanalimab and zimberelimab plus FOLFOX appears to be safe, and there may be additional benefit in PD-L1–positive patients. That said, we need a lot more research to understand the disease-specific context of TIGIT before this will become a standard of care.”

DISCLOSURE: Dr. Smyth reported financial relationships with Amal Therapeutics, Aptitude Health, Amgen, Astellas, AstraZeneca, BeiGene, BMS, Celgene, Daiichi Sankyo, Elsevier, Everest Clinical Research, First Word Group, Five Prime Therapeutics, Gritstone Oncology, Imedex, Merck, My Personal Therapeutics, Novartis, Pfizer, Roche, SAI MedPartners, Servier, Touch Oncology, Turning Point Therapeutics, Viracta Therapeutics, and Zymeworks.


1. Shitara K, Ajani JA, Moehler M, et al: Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature 603:942-948, 2022.

2. Lorenzen S, Goetze TO, Hofheinz RD, et al: FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase 2 IKF-S628/AIO-STO-0417 (Moonlight) trial of the AIO. 2023 ASCO Annual Meeting. Abstract 4045.

3. Feeney K, Kelly R, Lipton LR, et al: CA224-060: A randomized, open label, phase II trial of relatlimab (anti-LAG-3) and nivolumab with chemotherapy versus nivolumab with chemotherapy as first-line treatment in patients with gastric or gastroesophageal junction adenocarcinoma. 2019 ASCO Annual Meeting. Abstract TPS4143.


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