Dr Janjigian on the FDA Approval of Zolbetuximab for CLDN18.2+ Gastric/GEJ Adenocarcinoma

“Testing should be done routinely in the first-line setting, and using targeted agents in the first-line setting, even for this previously non-targetable population, is important.”

Yelena Y. Janjigian, MD, chief, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, discusses the significance of the FDA approval of zolbetuximab-clzb (Vyloy) plus chemotherapy for the treatment of patients with HER2-negative, claudin 18.2 (CLDN18.2)–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

On October 18, 2024, the FDA approved zolbetuximab in combination with platinum- and fluoropyrimidine-containing chemotherapy for the treatment of adult patients with previously untreated, locally advanced, unresectable or metastatic, HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma. This regulatory decision was supported by findings from the phase 3 SPOTLIGHT trial (NCT03504397), which evaluated zolbetuximab in combination with mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin), as well as data from the phase 3 GLOW trial (NCT03653507), which assessed the agent in combination with CAPOX (capecitabine and oxaliplatin).

In gastric cancer, a significant unmet need exists for patients with disease that is PD-L1–low and HER2-negative, as there have been limited data on strategies to improve outcomes in this patient subgroup, Janjigian begins. Although immune checkpoint blockade combined with chemotherapy has improved survival and disease control in PD-L1–high populations, historically, no targeted therapies have been available for patients with PD-L1–low disease, she explains. The introduction of zolbetuximab, a claudin inhibitor, to the gastric cancer treatment paradigm is a key advancement in addressing this gap, she emphasizes.

Zolbetuximab is a monoclonal antibody targeting CLDN18.2, a protein that can be screened for in tumor biopsies, she says. Patients eligible for treatment with zolbetuximab must have CLDN18.2-positive disease, defined as having immunohistochemistry 3+ expression of the protein in at least 25% of their tumor sample, according to Janjigian. For patients who meet these criteria and have PD-L1–low or –negative disease, zolbetuximab combined with chemotherapy has become the standard of care in the frontline treatment setting, she reports. Routine testing for CLDN18.2 in the first-line setting is crucial, as this biomarker allows for the use of targeted agents in populations previously considered to have non-targetable disease, Janjigian concludes.

Disclosures: Dr Janjigian reported receiving consulting fees and travel funding from AbbVie, Amerisource Bergen, Arcus Biosciences, Ask-Gene Pharma Inc., Astellas, AstraZeneca, Basilea Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, eChinaHealth, Ed Med Resources (OncInfo), Eisai Inc., Eli Lilly, Geneos Therpeutics, GlaxoSmithKline, Guardant Health Inc., H. C. Wainwright & Co. LLC, Imedex, Imugene, Inspirna, Lynx Health, Master Clinician Alliance, Merck, Merck Serono, Mersana Therapeutics, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Physicians’ Education Resource LLC, Research to Practice, Sanofi Genzyme, Seagen, Silverback Therapeutics, Suzhou Liang Yihui Network Science and Technology Company, Talem Health, TotalCME, WebMD LLC, and Zymeworks Inc; receiving funds for research support from Arcus Biosciences, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Inspirna, Merck, NCI, Stand Up 2 Cancer, and Transcenta; and owning stock options in Inspirna.

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