As reported in The Lancet by Kohei Shitara, MD, and colleagues, the phase III SPOTLIGHT trial has shown significantly prolonged progression-free and overall survival with the addition of the anti–claudin-18 isoform 2 (CLDN18.2) antibody zolbetuximab to mFOLFOX6 (modified leucovorin [or levoleucovorin], fluorouracil, and oxaliplatin) in previously untreated patients with locally advanced, inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma.

Kohei Shitara, MD

Study Details

In the double-blind trial, 565 patients from sites in 20 countries were randomly assigned between June 2018 and April 2022 to receive zolbetuximab as an 800 mg/m² loading dose followed by 600 mg/m² every 3 weeks (n = 283) or placebo (n = 282) plus mFOLFOX6 every 2 weeks for four 42-day cycles. CLDN18.2-positive status was defined as ≥ 75% of tumor cells showing moderate-to-strong membranous CLDN18 staining. The primary endpoint of the study was progression-free survival assessed by independent review committee in the intent-to-treat population.

Progression-Free Survival

Median follow-up for progression-free survival was 12.94 months in the zolbetuximab group vs 12.65 months in the control group. Median progression-free survival was 10.61 months (95% confidence interval [CI] = 8.90–12.48 months) in the zolbetuximab group vs 8.67 months (95% CI = 8.21–10.28 months) in the control group (hazard ratio [HR] = 0.75, 95% CI = 0.60–0.94, P = .0066). Rates at 12 and 24 months were 49% vs 35% and 24% vs 15%, respectively.

Subsequent anticancer therapies were received by 48% of those in the zolbetuximab group vs 53% of the control group; types of therapies received were similar in the two groups.

At interim analysis, median follow-up for overall survival was 22.14 months in the zolbetuximab group vs 20.93 months in the control group. Median overall survival was 18.23 months (95% CI = 16.43–22.90 months) in the zolbetuximab group vs 15.54 months (95% CI = 13.47–16.53 months) in the control group (HR = 0.75, 95% CI = 0.60–0.94, P = .0053). Rates at 12 and 24 months were 68% vs 60% and 39% vs 28%, respectively.

Adverse Events

Among 279 patients in the zolbetuximab group and 278 in the control group who received at least one dose of study medication, grade ≥ 3 adverse events occurred in 87% vs 78%; the most common in the zolbetuximab group were neutropenia (28% vs 23% in control group), decreased neutrophils (25% vs 25%), nausea (16% vs 6%), and vomiting (16% vs 6%). Serious adverse events occurred in 45% vs 44% of patients.

Adverse events led to discontinuation of any study drug in 38% vs 29% (zolbetuximab in 20%, placebo in 11%). Treatment-related deaths occurred in five patients (2%) in the zolbetuximab group vs four patients (1%) in the control group.

The investigators concluded, “Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 vs placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients.”

Jaffer A. Ajani, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Astellas Pharma, Inc. For full disclosures of the study authors, visit thelancet.com.