CLDN18.2-Targeted Triplet Therapy in First-Line Gastric Cancer: Kohei Shitara, MD

Emerging phase 2 data are helping refine first-line treatment strategies for CLDN18.2–positive gastric and gastroesophageal cancers, highlighting the growing role of biomarker-driven selection and combination immunotherapy approaches.

In this interview with The American Journal of Managed Care^® (AJMC^®), Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Japan, discusses how high CLDN18.2 expression may guide patient selection, the rationale for adding nivolumab to zolbetuximab-based therapy, practical considerations for managing toxicity, and how findings from the ILUSTRO (NCT03505320) study informed the phase 3 LUCERNA (NCT06901531) trial.

The findings were presented at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium.

This interview has been lightly edited for clarity.

AJMC: How do the stronger progression-free survival (PFS) results in patients with high CLDN18.2 expression influence your approach to patient selection in the first-line setting?

Shitara: The encouraging PFS results observed in patients with high CLDN18.2 expression reinforce the importance of biomarker-driven patient selection in the first-line setting. As treatment intensity increases, it becomes increasingly important to identify patients most likely to derive meaningful benefit. Of note, median PFS also favored a combined positive score (CPS) of 1 or greater vs CPS less than 1. These findings support prioritizing patients with high CLDN18.2 expression when considering zolbetuximab-based regimens.

AJMC: What was the rationale for adding nivolumab to zolbetuximab plus chemotherapy, and do the data suggest added benefit from this triplet approach?

Shitara: The rationale for adding nivolumab was based on the complementary mechanisms of action, as zolbetuximab can induce immune-mediated tumor cell killing and potentially modulate the tumor microenvironment to enhance antitumor immunity. In ILUSTRO, the triplet regimen demonstrated encouraging antitumor activity and durable responses. Although the phase 2 design does not allow isolation of nivolumab’s individual contribution, the data support further evaluation in randomized trials.

AJMC: With high rates of treatment-related adverse events, what were the key challenges in managing toxicity, and how feasible is this regimen in routine practice?

Shitara: The study did not show unexpected toxicities. The main challenges of zolbetuximab were gastrointestinal toxicities, particularly nausea and vomiting, which are known adverse effects of zolbetuximab. Proactive antiemetic prophylaxis, early intervention, and dose modifications were essential to maintain treatment adherence. FOLFOX [folinic acid, fluorouracil, and oxaliplatin] and nivolumab-related toxicities could be managed well according to established guidance. With appropriate supportive care and experience, the regimen appears feasible in routine clinical practice, particularly in well-selected patients.

AJMC: How did these phase 2 findings shape the design and goals of the phase 3 LUCERNA trial?

Shitara: The ILUSTRO results provided proof of concept for combining zolbetuximab with chemotherapy and immunotherapy in the first-line setting. These findings informed the biomarker-enriched design of the phase 3 LUCERNA trial and reinforced the importance of optimized toxicity management. LUCERNA aims to determine whether this strategy can deliver clinically meaningful survival benefits in a randomized, global population.