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Phase 3 SPOTLIGHT trial: investigational zolbetuximab shows survival benefit in CLDN18.2-positive gastric cancer

In patients with CLDN18.2-positive, HER2-negative advanced gastric or gastro-oesophageal junction adenocarcinoma, adding investigational zolbetuximab to chemotherapy prolonged progression-free and overall survival versus chemotherapy alone, with more nausea and vomiting leading to discontinuation.

  • Kohei Shitara, MD; Florian Lordick, MD; Yung-Jue Bang, MD; Peter Enzinger, MD; David Ilson, MD; Manish A Shah, MD; et al.

  • April 14, 2023

  • The Lancet
  • The Lancet, Volume 401, Issue 10389, Pages 1655–1668
  • 10.1016/S0140-6736(23)00620-7

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Evidence before this study

At the time of publication of this study, to our knowledge, there were no non-immunotherapy, biomarker-based therapies approved for the first-line treatment of patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. We used Ovid to search Embase on Feb 3, 2023, using the terms (“claudin 18” OR “CLDN18”) AND (“stomach cancer” OR “gastroesophageal junction”) AND (“phase 2 clinical trial” OR “phase 3 clinical trial”), with no language or time restrictions. We filtered the results by articles with no time restrictions, and conference abstracts published within the past 3 years. We removed results related to the current study, conference abstracts reporting the same study or later published as articles, reviews, editorials, a phase 1 study, and a study in patients with locally advanced resectable gastric cancer. Our search yielded four studies with efficacy and safety data. Three studies evaluated zolbetuximab: the phase 2a MONO study of zolbetuximab monotherapy showed restricted antitumour efficacy, with a manageable safety profile in patients with claudin-18 isoform 2 (CLDN18.2)-positive tumours; the phase 2b FAST study of zolbetuximab plus chemotherapy showed improved progression-free survival and overall survival versus chemotherapy, with a manageable safety profile in patients with CLDN18.2-positive tumours; and the phase 2 ILUSTRO study (cohort 2) of zolbetuximab plus chemotherapy showed a median progression-free survival of 13·7 months and an objective response in 63% of patients, with a manageable safety profile in patients with CLDN18.2-positive, HER2-negative tumours. A phase 1b–2 study evaluated a CLDN18.2-specific chimeric antigen receptor T-cell therapy and showed promising anti-tumour efficacy with a manageable safety profile in patients with CLDN18.2-positive tumours.

Added value of this study

With over 550 patients randomly assigned in the SPOTLIGHT trial, first-line zolbetuximab plus chemotherapy showed improved progression-free survival and overall survival versus placebo plus chemotherapy in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. To our knowledge, SPOTLIGHT is the first global, phase 3 study to examine the efficacy and safety of the addition of CLDN18.2-targeted therapy (ie, zolbetuximab) to standard chemotherapy (ie, mFOLFOX6 [modified folinic acid, fluorouracil, and oxaliplatin regimen]) in gastric or gastro-oesophageal junction adenocarcinoma and to show prolonged survival with a CLDN18.2-targeted therapy. Nearly 40% of screened patients had tumours that met the definition of CLDN18.2 positivity used in this study. Although nausea and vomiting leading to discontinuation were more frequent with zolbetuximab plus chemotherapy versus placebo plus chemotherapy, the safety profile was manageable in the context of the significant benefits for both progression-free and overall survival.

Implications of all the available evidence

The SPOTLIGHT trial addresses a high unmet need for additional biomarker-targeted therapies to improve survival outcomes in patients with previously untreated, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma for whom, other than immunotherapy, no advances have been reported in over a decade. The results of SPOTLIGHT suggest that CLDN18.2 tumour positivity defines a large population of patients whose survival is prolonged by targeted therapy with zolbetuximab plus chemotherapy, and that zolbetuximab could represent a new potential first-line therapy in combination with chemotherapy in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma.

Source: The Lancet

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