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
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.
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.
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.