Episode 4: Zolbetuximab: a new opportunity in the treatment of CLDN18.2 positive metastatic gastric cancer patients

Presented by Prof Eric Van Cutsem (University Hospitals Leuven) and Prof Marc Van den Eynde (Cliniques Universitaires Saint-Luc)

In metastatic gastric cancer patients, approximately one-third exhibit positivity for CLDN18.2, an antigen also identified in other malignancies such as pancreatic cancer. Zolbetuximab, a novel monoclonal antibody drug, selectively targets CLDN18.2. Two concurrent studies were conducted to investigate this agent’s efficacy in the initial treatment of metastatic gastric or gastroesophageal cancer patients. Both trials involved comparing the addition of zolbetuximab to a first-line chemotherapy regimen against a placebo.

The SPOTLIGHT trial demonstrated a significant extension in PFS and OS when zolbetuximab was combined with mFOLFFOX6, in contrast to a placebo plus mFOLFOX6. The GLOW trial, conducted across diverse countries and multiple centres, revealed that adding zolbetuximab to CAPOX significantly prolonged PFS. Additionally, patients treated with zolbetuximab exhibited a significantly extended OS as a secondary endpoint. Safety assessments indicated that zolbetuximab usage, particularly at the treatment onset, resulted in higher incidences of nausea and vomiting as all-grade TEAEs compared to the placebo. Experts speculate that this may be attributed to improved antiemetic management or patient adaptation.

The consistent positive outcomes from these parallel studies strongly suggest the benefits of incorporating zolbetuximab into first-line treatment. While current ESMO guidelines recommend HER2 and PD-L1 biomarkers, and MSI-H is clinically utilized, CLDN18.2 status is not currently considered a biomarker. This is anticipated to change upon regulatory approval of zolbetuximab for treatment.

Experts foresee the need for exploring potential biomarker overlap in the future. Both discussed studies involved HER2-negative tumours, with some overlap observed in PD-L1/CPS positivity. Clarifying the relevance of these biomarkers will guide future treatment sequencing and potential combination therapies. The absence of such clarity underscores the importance of further investigation.

Moreover, these studies highlight the significance of CLDN18.2, paving the way for a new generation of drugs. This insight may extend to other cancer types, such as CLDN18.2-positive pancreatic cancer, where targeted monoclonal antibody therapy, like zolbetuximab, could prove beneficial.

References:

Shah MA. et al. (2023) Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nature Medicine 29: 2133-2141

Shitara K. et al. (2023) Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated,locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. The Lancet vol. 401 (10389): 1655-1668