Zolbetuximab plus mFOLFOX6 successful in CLDN18.2-positive subgroup of gastric cancer

Zolbetuximab added to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improved the progression-free survival (PFS) and overall survival (OS) of patients with claudin-18.2-positive (CLDN18.2-positive)/HER2−negative, locally advanced, unresectable or metastatic, gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma, primary results of the SPOTLIGHT study revealed.

Zolbetuximab is a first-in-class chimeric, IgG1 monoclonal antibody targeting CLDN18.2 and inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [1,2]. In a phase 2b trial, this agent, in combination with epirubicin + oxaliplatin + capecitabine (EOX), improved the survival in patients with increased expression of CLDN18.2 in their tumour cells [3]. This result led to the development of the SPOTLIGHT study.

SPOTLIGHT (NCT03504397) is a global phase 3 trial randomising newly diagnosed patients with CLDN18.2-positive/HER2-negative, locally advanced, mG/GEJ adenocarcinoma (n=565) 1:1 to mFOLFOX6 plus zolbetuximab or to mFOLFOX6 plus placebo [4]. Over 38.5% of assessable patients were CLDN18.2 positive, defined as moderate to strong CLDN18.2 staining in ≥75% of tumour cells. PFS was the primary endpoint of the study and Dr Kohei Shitara (National Cancer Center Hospital East, Japan) presented the primary findings.

After a median follow-up of 12.9 months, the median PFS was significantly higher if patients were treated with zolbetuximab compared with mFOLFOX6 only (10.61 months vs 8.67 months; HR 0.75; 95% CI 0.59‒0.94; P=0.0066, see Figure). The corresponding 24-month PFS rates were 24% and 15%, respectively. The OS results confirmed the benefit of the addition of zolbetuximab to mFOLFOX6 with a median OS of 18.2 months compared with 15.5 months for patients who received mFOLFOX6 only (HR 0.75; 95% CI 0.60‒0.94; P=0.0053).

Figure: Higher PFS for patients on zolbetuximab compared with mFOLFOX6 only [4]



PFS, progression-free survival; mFOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin.

According to the authors, the safety profile of zolbetuximab and mFOLFOX6 was acceptable. The incidence of treatment-emergent adverse events was comparable for the 2 treatment arms, but grade 3 or higher nausea (16.1% vs 6.5%) and vomiting (16.1% vs 5.8%) were more common in the zolbetuximab arm. Dr Shitara commented that these events mostly occurred in the first cycle of zolbetuximab and that they were manageable with treatment adjustments. In total, 13.6% of the patients discontinued zolbetuximab due to treatment-related adverse events compared with 2.2% of the patients in the placebo arm.

In conclusion, zolbetuximab plus mFOLFOX6 candidates as a new standard-of-care therapy for patients with CLDN18.2-positive/HER2-negative, locally advanced, mG/GEJ adenocarcinoma. It is the first moleculary targeted therapy to show a statistically significant survival benefit since trastuzumab.

1. Sahin U, et al. Eur J Cancer. 2018;100:17–26.
2. Rohde C, et al. Jpn J Clin Oncol. 2019;49:870–876.
3. Sahin U, et al. Ann Oncol. 2021;32:609–619.
4. Shitara K, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Late-breaking abstract 292, ASCO GI, 19–21 January, San Francisco, CA, USA.

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Posted on 17 March 202321 May 2024