Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-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

Abstract

LBA292 Background: 1L treatment for pts with HER2−, mG/GEJ adenocarcinoma is typically chemotherapy and immunotherapy; an unmet need still exists. CLDN18.2 is expressed in normal gastric mucosa cells and retained in mG/GEJ tumor cells. In the FAST study, zolbetuximab, which targets CLDN18.2, prolonged survival of pts with LA unresectable or mG/GEJ adenocarcinoma when combined with chemotherapy. SPOTLIGHT (NCT03504397) is a phase 3 global, double-blind study comparing zolbetuximab + folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) vs placebo + mFOLFOX6 as 1L treatment for pts with CLDN18.2+/ HER2−, LA unresectable or mG/GEJ adenocarcinoma. Methods: Previously untreated pts with CLDN18.2+ (moderate-to-strong membrane staining in ≥75% tumor cells by IHC)/HER2− LA unresectable or mG/GEJ adenocarcinoma were randomized 1:1 to zolbetuximab IV 800 mg/m2 (cycle [C] 1, day [D] 1) followed by 600 mg/m2 (C1D22, and every 3 weeks in later cycles) + mFOLFOX6 IV (D1, 15, 29) for four 42-day cycles vs placebo + mFOLFOX6; pts without PD continued for >4 cycles with zolbetuximab or placebo, + folinic acid and 5-FU at investigator’s discretion until PD or discontinuation criteria were met. The primary endpoint (EP) was PFS per RECIST v1.1 by IRC. Secondary EPs included OS, ORR, and safety. Differences in efficacy between treatment arms were tested by stratified log rank tests; OS was tested if PFS was significant. Results: Among 2735 pts screened, 565 pts were randomized 1:1 to zolbetuximab + mFOLFOX6 (N = 283) or placebo + mFOLFOX6 (N = 282). PFS was statistically significantly improved with zolbetuximab + mFOLFOX6 (median 10.61 vs 8.67 mo, HR 0.751, P=0.0066; Table). OS was also significantly improved (median 18.23 vs 15.54 mo, HR 0.750, P=0.0053, < 0.0135 as boundary; Table). ORR was similar between treatment arms. Most common TEAEs with zolbetuximab + mFOLFOX6 were nausea (82.4% vs 60.8% in zolbetuximab vs placebo arms), vomiting (67.4% vs 35.6%), and decreased appetite (47.0% vs 33.5%); the incidences of serious TEAEs were similar between both arms (44.8% vs 43.5%). Conclusions: Targeting CLDN18.2 with 1L zolbetuximab combined with mFOLFOX6 statistically significantly prolonged PFS and OS in pts with CLDN18.2+/ HER2−, LA unresectable or mG/GEJ adenocarcinoma. TEAEs were consistent with previous studies. Zolbetuximab + mFOLFOX6 may be a new option for these pts. Funding source: This study was funded by Astellas Pharma Inc. Medical writing support, conducted in accordance with Good Publication Practice (GPP 2022) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Ann Ferguson, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and funded by Astellas Pharma Inc. Clinical trial information: NCT03504397 . [Table: see text]

Recent Advances in the Systemic Treatment of Localized Gastroesophageal Cancer

“…The SPOTLIGHT and the GLOW trial randomized patients when ≥75% of tumor cells showed moderate to strong membranous immunohistochemical staining [ 51 , 52 ]. First results of the SPOTLIGHT trial were presented at the 2023 ASCO GI Cancers Symposium and showed superior PFS (10.61 vs. 8.67 months; HR 0.751; 95% CI 0.589–0.942; p = 0.0066) as well as superior OS (18.23 vs. 15.54 months; HR 0.75; 95% CI 0.601–0.936); p = 0.0053) for FOLFOX + zolbetuximab in comparison to FOLFOX + placebo in advanced and metastatic patients [ 53 ]. These results represent a major breakthrough in targeted therapies for gastroesophageal cancer and may lead to further trials in resectable settings.…”

Recent Advances in Immunotherapy and Molecular Targeted Therapy for Gastric Cancer

“…In the phase IIb FAST study, zolbetuximab + chemotherapy significantly improved survival compared with chemotherapy alone in AGC patients expressing CLDN18.2 [ 62 ]. The phase III SPOTLIGHT placebo-controlled trial of zolbetuximab + chemotherapy in 565 patients with CLDN18.2-positive, HER2-negative AGC showed that the combination was superior to chemotherapy + placebo for PFS and OS in all randomized patients (median PFS 10.61 vs 8.67 months, HR: 0.751; 95% CI: 0.589–0.942, p = 0.0066; median OS 18.23 vs 15.54 months, HR: 0.75; 95% CI: 0.601–0.936, p = 0.0053) [ 63 ]. Zolbetuximab is being investigated in combination with immunotherapeutic agents in the ILUSTRO trial in patients with CLDN18.2 positive AGC (NCT03505320).…”

Advances in the treatment of gastric cancer: 2022–2023

“…Results were recently reported from the SPOTLIGHT trial, a double-blind placebo-controlled trial evaluating the addition of zolbetuximab to first-line chemotherapy with modified FOLFOX6 in advanced HER2-negative gastric and esophageal adenocarcinoma [13 ▪▪ ]. Patients had to test positive by immunohistochemistry for overexpression of CLDN 18.2, and high expression was detected in 42% of screened HER2-negative patients.…”