Positive results reported by Astellas Pharma regarding its novel Claudin 18.2-targeting antibody, zolbetuximab, suggest that an approval in front-line gastric and gastroesophageal junction (GEJ) adenocarcinoma is not far off. Two Phase III studies, SPOTLIGHT (NCT03504397) and GLOW (NCT03653507), examined the efficacy of monoclonal antibody zolbetuximab in patients deemed to have high expression of Claudin 18.2 (characterised as more than 75% of tumour cells with moderate to high expression, as measured by immunohistochemical assay) versus traditional chemotherapy (FOLFOX6 in SPOTLIGHT and CAPOX in GLOW).

In results presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium 2023, zolbetuximab was shown to significantly increase both progression-free and overall survival compared to chemotherapy alone in the SPOTLIGHT trial (10.61 months versus 8.67 months, hazard ratio [HR]: 0.751, and 18.23 months versus 15.54 months, HR: 0.750, respectively). Latterly, Astellas has indicated that the GLOW trial has also met its primary endpoint. Altogether, these positive results could herald the approval of the first targeted therapy in gastric and GEJ adenocarcinoma since Roche’s HER2-targeting Herceptin (trastuzumab) entered the market in 2010.

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Herceptin’s approval transformed patient outcomes in HER2-positive patients, but only approximately 10–20% of patients are HER2-positive. By comparison, in the SPOTLIGHT study, 38% of patients tested positive for Claudin 18.2, meaning this therapy could see substantial uptake. Some challenges are anticipated, though. First, Claudin 18.2 testing is not currently done as standard, and will need to be rolled out to maximise uptake. Secondly, since the inception of the SPOTLIGHT and GLOW trials, Bristol Myers Squibb’s (BMS) PD-1 inhibitor Opdivo has become standard of care in the front-line setting for HER2-negative patients. It will be important to understand how this patient sub-group fares on PD-1 inhibitors since the availability of Opdivo, with which physicians will be highly familiar, may see this therapy used instead of zolbetuximab in eligible patients. Consequently, the results of the ILLUSTRO trial (NCT03505320), which is examining the efficacy of zolbetuximab in combination with PD-1 inhibitors, will be highly anticipated.

While zolbetuximab is expected to see a first approval in gastric and GEJ adenocarcinoma, Claudin 18.2 is also aberrantly expressed in several other cancers, including breast, pancreatic, lung and oesophagal cancers, potentially opening the door to expansions into these markets. Indeed, Astellas is running a Phase II trial examining zolbetuximab in pancreatic cancer. More generally, there are several other Claudin 18.2-targeting therapies in earlier stages of development being investigated in multiple cancer types, including antibody-drug conjugates, bispecific antibodies, and cell therapies such as CAR-Ts.

One feature that makes Claudin 18.2 a particularly interesting target is that the surface expression of this protein increases as cancer progresses. This could present the possibility that patients may be effectively re-treated with a Claudin 18.2-targeting therapy, even if treatment had previously been unsuccessful. Altogether, how best to utilise novel Claudin 18.2 therapies still needs to be resolved. This exciting target is, however, expected to offer hope to a substantial sub-group of patients with gastric and GEJ adenocarcinoma – patients who, until recently, had very few options at all.

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