Zolbetuximab Plus mFOLFOX6 Extends Survival for Patients with CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma

For patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, treatment with zolbetuximab/mFOLFOX6 yielded a progression-free survival (PFS) of 10.61 months whereas placebo/mFOLFOX6 resulted in a PFS of 8.67 months.

In a primary analysis of the phase 3 SPOTLIGHT trial (NCT03504397), frontline treatment with zolbetuximab plus mFOLFOX6 garnered superior progression-free and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma, compared with placebo plus mFOLFOX6.1

Results presented during the 2023 Gastrointestinal Cancers Symposium showed that the median progression-free survival (PFS) by independent review committee was 10.61 months (95% CI, 8.90-12.48) with zolbetuximab/mFOLFOX6 vs 8.67 months (95% CI, 8.21-10.28) with placebo/mFOLFOX6, leading to a 25% reduction in the risk of disease progression or death (HR, 0.751; 95% CI, 0.589-0.942; P = .0066).

“Zolbetuximab plus mFOLFOX6 is a new potential standard-of-care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma,” Kohei Shitara, MD, the lead study author of the trial and a medical oncologist at National Cancer Center Hospital East in Kashiwa, Japan, said in a presentation during the meeting.

Standard treatment for patients with HER2-negative, metastatic gastric/GEJ adenocarcinoma is chemotherapy with mFOLFOX6, but there is still an unmet need in terms of targeted therapies for this population.2 Currently, the median OS is approximately 1 year.

CLDN18.2 is a tight junction protein that is expressed in normal gastric mucosa cells and is retained in advanced gastric/GEJ tumor cells. As CLDN18.2 may become exposed on the surface of gastric/GEJ cells, Shitara noted that it makes a promising target.

Zolbetuximab, which is a first-in-class CLDN18.2-targeting chimeric IgG1 monoclonal antibody that induces antibody-dependent cellular cytotoxicity/complement dependent cytotoxicity, resulted in a prolongation of survival in patients with higher expression of CLDN18.2 in the phase 2b FAST trial (NCT01630083).3 Here, the median PFS was 9.0 months with zolbetuximab and epirubicin, oxaliplatin, and capecitabine (EOX) vs 5.7 months with EOX alone; the median OS was 16.5 months and 8.9 months, respectively.

The international, double-blind, placebo-controlled SPOTLIGHT trial enrolled patients with previously untreated locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma and CLDN18.2 positivity. To be eligible for enrollment, patients must have had moderate-to-strong CLDN18 staining in at least 75% of tumor cells, have HER2-negative disease, and an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1 to receive the combination of zolbetuximab and mFOLFOX6 (n = 283) or placebo and mFOLFOX6 (n = 282).

Zolbetuximab was given intravenously (IV), at 800 mg/m2 on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1 and days 1 and 22 of subsequent cycles, every 3 weeks and mFOLFOX6 was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, zolbetuximab was given at the same dosing schedule in combination with 5-fluorouracil (5-FU) and folinic acid IV every 2 weeks. Patients in the placebo arm were given placebo at the every-3-week schedule and chemotherapy was administered at the same dosing schedule.

Patients were stratified by region (Asian vs non-Asian), number of organs with metastases (0-2 vs ≥ 3), and prior gastrectomy (yes vs no).

The primary end point was PFS. Key secondary end points were OS, time to confirmed deterioration in global health status/quality of life, physical functioning, and OG25-Pain. Additional outcome measures included objective response rate (ORR), duration of response (DOR), safety, and patient-reported outcomes (PROs).

As part of the study design, OS was only tested if the PFS benefit with zolbetuximab was found to be significant. Shitara noted that the interim OS analysis was planned at the primary PFS analysis, with a cutoff date of September 9, 2022, for both analyses. In the interim OS analysis, the 1-sided P value threshold for significance was .0135.

Regarding baseline characteristics, the median age was 61.0 years (range, 20-86), 62.2% of patients were male, and 31.4% of patients were from Asia. Most patients had 2 or less organs with metastases (77.6%), and 29.4% of patients had prior gastrectomy. The primary disease site was stomach in 76.0% of patients and was GEJ in 24.1%.

The Lauren classification of disease was diffuse (35.6%), intestinal (24.3%), or mixed/others (39.8%). More than half of patients had an ECOG performance status of 1 (56.7%). A total 13.2% of patients had tumors with a PD-L1 combined positive score of at least 5, which was part of an ad-hoc analysis.

Forty-eight percent of patients in the zolbetuximab arm received subsequent anticancer therapies vs 53% in the placebo arm.

Additional data showed that the 12- and 24-month PFS rates were 49% and 24%, respectively, in the zolbetuximab arm and 35% and 15%, respectively, in the placebo arm. The PFS benefit with zolbetuximab/mFOLFOX6 was observed across most prespecified subgroups, except for those whose primary site of disease was GEJ (HR, 1.015; 95% CI, 0.649-1.586) and with mixed/other classification (HR, 0.929; 95% CI, 0.601-1.434).

The median OS was 18.23 months (95% CI, 16.43-22.90) with zolbetuximab/mFOLFOX6 and 15.54 months (95% CI, 13.47-16.53) with placebo/mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; P = .0053).

At 12, 24, and 36 months, the OS rates in the zolbetuximab and placebo arms, respectively, were 68% vs 60%, 39% vs 28%, and 21% vs 9%, respectively. Similar to the PFS analysis, the OS benefit was seen in most patient subgroups, except for those with GEJ as the primary site of disease (HR, 1.072; 95% CI, 0.690-1.666) and others with mixed/other classification (HR, 0.992; 95% CI, 0.638-1.543).

The ORR with zolbetuximab was 60.7% (95% CI, 53.72%-67.30%) and 62.1% (95% CI, 55.17%-68.66%). The best overall response was a complete response in 5.7% and 3.3% of zolbetuximab- and placebo-treated patients, respectively; a partial response in 55.0% and 58.8% of patients, stable disease in 21.3% and 24.6% of patients, and progressive disease in 6.6% of patients on both arms. The median DOR was 8.51 months (95% CI, 6.80-10.25) on the zolbetuximab arm and 8.11 months (95% CI, 6.47-11.37) on the placebo arm.

Shitara noted that the formal PROs analysis is pending, but an initial descriptive analysis did not indicate differences between treatment arms.

Regarding safety, the incidence of treatment-emergent adverse effects (TEAEs) was similar between arms, at 99.6% in both treatment groups. Grade 3 or higher TEAEs were reported in 86.7% and 77.7% of those on the zolbetuximab and placebo arms, respectively; serious TEAEs occurred in 44.8% and 43.5%. Treatment-related adverse effects (TRAEs) that led to treatment discontinuation of zolbetuximab or placebo occurred in 13.6% and 2.2% of patients, respectively. Moreover, 1.8% and 1.4% of TRAEs, respectively, led to death.

The most common TEAEs associated with zolbetuximab/mFOLFOX6 were nausea (all-grade, 81.0%; grade ≥ 3, 16.1%), vomiting (all-grade, 64.5%; grade ≥ 3, 16.1%), and decreased appetite (all-grade, 47.0%; grade ≥ 3, 5.7%). Shitara added that the first occurrence of nausea and vomiting took place in the first or second treatment cycles.

Editor’s Note: Dr. Shitara has received honoraria from Bristol-Myers Squibb; Janssen; Taked; consulting or advisory roles with Abbvie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Health Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda; and research funding from Amgen (Inst); Astellas Pharma (Inst); Chugai Pharma (Inst); Daiichi Sankyo (Inst); Eisai (Inst); MSD (Inst); Ono Pharmaceutical (Inst); Taiho Pharmaceutical (Inst).


  1. Shitara K, Lordick F, Bang Y-J, et al. 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. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292
  2. Van Cutsem, Sagaert X, Topal B, et al. Gastric cancer. Lancet. 2016;388(10060):2654-2664. doi:10.1016/S0140-6736(16)30354-3
  3. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32:609-619. doi:10.1016/j.annonc.2021.02.005