SPOTLIGHT on new targets in immunotherapy: claudin 18.2

Chemotherapy in combination with zolbetuximab could be a potential first-line therapy for gastric or gastroesophageal junction (G/GEJ) adenocarcinomas. Along similar lines, antibody-drug conjugates targeting claudin 18.2 are being investigated, and while CAR-T cells have shown activity in a phase 1 study, there may be substantial obstacles for practical implementation in the clinic.

In an in-depth overview of new targets in immunotherapy beyond checkpoint inhibitors, Prof. Kohei Shitara (National Cancer Center Hospital East, Japan) focused on new data from clinical trials looking at tight-junction protein claudin 18.2 as a target in G/GEJ cancers [1]. The rationale is that most G/GEJ tumours overexpress claudin 18.2, and as a consequence of disrupted polarity in neoplastic growth, the tight junctions including claudin 18.2 are exposed to the lumen/cell surface. Zolbetuximab recognises an epitope on the first extracellular loop of claudin 18.2, which in healthy tissue would be inaccessible.

Notably, the randomised, double-blind, phase 3 GLOW trial (NCT03653507) showed that zolbetuximab combined with capecitabine and oxaliplatin improved outcomes compared with placebo and chemotherapy as first-line treatment in claudin 18.2-positive, HER2-negative G/GEJ adenocarcinomas [2]. Updated data from the phase 3 SPOTLIGHT trial (NCT03504397) continued to demonstrate significant improvement in overall survival at 36 months of follow-up with the addition of zolbetuximab to the mFOLFOX6 regimen versus placebo (21% vs 9%; HR 0.75; 95% CI 0.60–0.94; P=0.0053) as well as median progression-free survival (PFS 10.61 months in the zolbetuximab group vs 8.67 months in the placebo group) for patients with claudin-positive, HER2-negative locally advanced unresectable or metastatic G/GEJ adenocarcinoma [3].

Prof. Shitara shared key practice considerations for this new potential standard-of-care first-line treatment for these patients, including toxicity concerns, since zolbetuximab is already approved in Japan [1]. He also shared data from a phase 1 trial (n=59) developing a claudin 18.2-targeted CAR T-cell therapy, which offered an objective response rate of 55% and a median PFS of 5.9 months in gastric cancer patients [4]. However, toxicity and production concerns are considerable barriers to clinical implementation, he concluded.

1. Shitara K. Cellular therapies in the treatment of GI cancer. Session: New targets in immunotherapy beyond CTL4 and PD(L)1. ESMO Gastrointestinal Cancers Congress 2024, 26–29 June, Munich, Germany.
2. Shah MA, et al. Nat Med. 2023;29(8):2133-2141.
3. Shitara K, et al. Lancet. 2023;401(10389):1655-1668.

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Posted on 21 August 2024