First-line zolbetuximab plus mFOLFOX6 in claudin-18 isoform 2-positive gastric and gastroesophageal junction adenocarcinoma: positioning SPOTLIGHT in the immunotherapy era

The phase III SPOTLIGHT trial of zolbetuximab plus mFOLFOX6 in claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma is an important milestone in biomarker-directed therapy for this disease (1). Shitara et al. showed that adding zolbetuximab, a first-in-class anti-CLDN18.2 monoclonal antibody, to an oxaliplatin-fluoropyrimidine backbone significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone in a biomarker-selected population defined by high CLDN18.2 expression (1). In an era when first-line immunotherapy is largely restricted to tumors with higher programmed death-ligand 1 (PD-L1) expression, SPOTLIGHT directly addresses the sizeable group of HER2-negative, PD-L1-low patients who have had limited options beyond cytotoxic chemotherapy.

SPOTLIGHT enrolled patients with previously untreated, unresectable or metastatic gastric or GEJ adenocarcinoma that was centrally confirmed to be HER2-negative and CLDN18.2-positive using the VENTANA CLDN18 (43-14A) immunohistochemistry (IHC) assay (1). High CLDN18.2 expression was stringently defined as moderate-to-strong membranous staining in at least 75% of tumor cells. Patients were randomized to receive mFOLFOX6 plus either zolbetuximab or placebo. Both PFS and OS were key primary endpoints. The addition of zolbetuximab significantly reduced the risk of disease progression or death and the risk of death alone, with early and sustained separation of the Kaplan-Meier curves (1). Median PFS and OS were prolonged by several months despite the control arm performing well, reflecting contemporary standards of care and supportive therapy in high-volume centers.

Of note, objective response rates were similar between the two arms, but responses in the zolbetuximab group tended to be more durable, and disease control metrics favored the experimental regimen (1). This pattern suggests that zolbetuximab’s benefit manifests primarily as deeper and more sustained tumor control rather than a dramatic increase in initial response. The toxicity profile was dominated by gastrointestinal adverse events—nausea, vomiting and decreased appetite—which were more frequent and sometimes more severe with zolbetuximab, particularly during the first cycles (1). These events are biologically plausible given CLDN18.2 expression in normal gastric mucosa and the antibody’s effector mechanisms. Importantly, they were generally manageable with aggressive antiemetic prophylaxis, infusion-rate modifications and supportive care, although treatment discontinuation due to gastrointestinal toxicity was not negligible. No new or unexpected safety signals were identified (1). The robustness of these findings is further supported by a recent meta-analysis restricted to randomized clinical trials, which confirmed that the addition of zolbetuximab to chemotherapy significantly improves both PFS and OS in patients with advanced CLDN18.2-positive gastric or GEJ adenocarcinoma (2). This analysis also demonstrated a consistent safety profile characterized predominantly by gastrointestinal adverse events, reinforcing the reproducibility of the SPOTLIGHT and GLOW results across randomized settings (2).

Beyond its established role as a predictive biomarker for zolbetuximab, the prognostic significance of CLDN18.2 expression in gastric cancer warrants careful consideration. A recent systematic review and meta-analysis by Moraes et al. suggested that CLDN18.2 expression may be associated with poorer survival outcomes, indicating its potential relevance as a prognostic biomarker (3). However, the included studies showed substantial heterogeneity, with considerable variability in IHC assays and scoring thresholds. These limitations preclude definitive conclusions regarding CLDN18.2 as an independent prognostic determinant. In this context, the clinical importance of CLDN18.2 is currently most robust as a predictive biomarker and therapeutic target, particularly in the setting of CLDN18.2-directed antibody therapy.

CLDN18.2 is a tight-junction protein physiologically restricted to differentiated gastric epithelial cells. During malignant transformation, disruption of cell polarity exposes CLDN18.2 on the luminal tumor cell surface, rendering it accessible to circulating antibodies. Zolbetuximab binds to CLDN18.2 and induces tumor cell death primarily through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (4). Early-phase studies, such as the FAST trial combining zolbetuximab with epirubicin, oxaliplatin, and capecitabine (EOX) chemotherapy and the ILUSTRO multicohort phase II program, provided proof of concept that targeting CLDN18.2 can translate into clinical benefit in patients with high CLDN18.2 expression, especially when stringent expression cutoffs are used (5,6). SPOTLIGHT confirms in a global phase III setting that CLDN18.2 is not merely a lineage marker but a therapeutically actionable target that defines a population deriving meaningful survival benefit from antibody-based therapy (1). Importantly, CLDN18.2 protein overexpression should be distinguished from CLDN18-ARHGAP fusion genes, which represent a distinct molecular alteration in gastric cancer. A systematic review and meta-analysis by Zhang et al. reported that CLDN18-ARHGAP fusions are associated with aggressive tumor biology and poorer clinical outcomes (7). At present, there is no evidence that fusion-positive tumors derive benefit from CLDN18.2-targeted antibodies such as zolbetuximab. Accurate molecular discrimination between membranous CLDN18.2 expression and CLDN18 fusion events will therefore be essential in future biomarker-driven treatment algorithms.

From a practical standpoint, several implementation questions arise. First, assays for immunohistochemical testing of CLDN18.2 expression will be critical. Recent international recommendations and global ring studies have highlighted the importance of standardized pre-analytic conditions, validated antibody clones, and reproducible scoring criteria for CLDN18.2 IHC (8-10). Large inter-laboratory studies have demonstrated acceptable analytical performance and concordance across clinically relevant testing platforms, supporting the feasibility of broader implementation of CLDN18.2 assessment in routine pathology practice (9,10). SPOTLIGHT and GLOW relied on central testing with a rigorously validated companion diagnostic and strict pre-analytic conditions (1,11,12). As zolbetuximab enters routine practice, pathology laboratories will need clear guidance on tissue handling, staining protocols, scoring criteria and reporting, as emphasized in recent pathology-focused reviews and expert recommendations (8,13). Second, sampling error due to intratumoral and inter-lesional heterogeneity may lead to misclassification, particularly if only small biopsies from a single site are available; where feasible, larger or multiple biopsies and assessment of both primary and metastatic sites may mitigate this risk. Third, CLDN18.2 expression only partially segregates from other established biomarkers. In a large Japanese cohort of advanced gastric and GEJ adenocarcinomas, CLDN18.2 positivity (moderate–strong membranous staining in ≥75% of tumor cells) was observed in about one quarter of patients and was almost evenly distributed across microsatellite instability-high/mismatch repair (MSI-H/MMR)-deficient, Epstein-Barr virus (EBV)-positive, HER2-positive and “other” molecular subtypes, as well as across PD-L1 combined positive score (CPS) categories, indicating that double- and even triple-positive tumors are not uncommon (14). Consequently, CLDN18.2 should not be viewed in isolation but as one component of an integrated biomarker panel. Recent Japanese guidance (Japanese Gastric Cancer Association/Japanese Society of Pathology) therefore recommends parallel testing for HER2, PD-L1 CPS, MSI/MMR and CLDN18.2 before initiation of first-line systemic therapy, to enable more refined, biomarker-driven treatment selection and optimal sequencing of HER2-targeted therapy, immune checkpoint inhibitors and CLDN18.2-directed agents.

For HER2-negative advanced gastric and GEJ adenocarcinoma, first-line therapy has been transformed by combination regimens that pair platinum–fluoropyrimidine chemotherapy with a programmed cell death protein 1 (PD-1) inhibitor, particularly in tumors with PD-L1 CPS of 5 or higher, as in CheckMate 649 and KEYNOTE-859 (15,16). In PD-L1-low disease, the benefit from adding immunotherapy is attenuated and sometimes uncertain in exploratory subgroup analyses (15,16). SPOTLIGHT and the companion phase III GLOW trial, which evaluated zolbetuximab plus CAPOX, were designed before immunotherapy became firmly entrenched as a first-line standard and therefore did not formally compare zolbetuximab-based therapy with chemo-immunotherapy (1,12). However, the biomarker profile of the enrolled population is revealing: in SPOTLIGHT, only a minority of patients had PD-L1 CPS ≥5, and the trial clearly demonstrated benefit from zolbetuximab in a cohort enriched for PD-L1-low tumors (1).

How should clinicians integrate these data into practice? For patients with CLDN18.2-positive, HER2-negative tumors and low PD-L1 expression, zolbetuximab plus chemotherapy is a compelling first-line option, supported by robust phase III evidence (1,12). For CLDN18.2-positive tumors with high PD-L1 expression, both chemo-immunotherapy and zolbetuximab-based combinations are biologically rational choices, but direct comparative data are lacking. Emerging triplet regimens that combine a PD-1 inhibitor, zolbetuximab and chemotherapy may, in the future, offer the possibility of simultaneous targeting of CLDN18.2 and the immune checkpoint axis, particularly in dual-positive tumors (6,16). Until such data mature, treatment decisions in CLDN18.2-positive, PD-L1-high disease will require careful shared decision-making that considers regional approvals, toxicity profiles, comorbidities and patient preferences. Conversely, for CLDN18.2-negative, PD-L1-high tumors, PD-1 inhibitor plus chemotherapy remains the obvious first-line standard (15,16). For “double-negative” tumors (CLDN18.2-negative and PD-L1-low), conventional chemotherapy remains the backbone, and clinical trial enrollment should be actively pursued. SPOTLIGHT, together with GLOW and earlier phase II studies, thus helps to stratify HER2-negative advanced gastric cancer into biologically and therapeutically distinct subsets defined by CLDN18.2 and PD-L1 status (1,5,12).

The price of on-target CLDN18.2 inhibition is gastrointestinal toxicity. Nausea, vomiting and decreased appetite were significantly more common with zolbetuximab than with placebo, particularly during early cycles when tumor burden and normal mucosal CLDN18.2 expression are highest (1). In clinical practice, proactive strategies will be essential: treating zolbetuximab-containing regimens as highly emetogenic, adopting aggressive prophylactic antiemetic regimens aligned with contemporary guidelines, considering slower initial infusion rates or prolonged infusion times, and having clear protocols for temporary interruptions and supportive care (17,18). Inadequate anticipatory management could jeopardize adherence, whereas thoughtful supportive care can maintain dose intensity and preserve quality of life. Health-related quality of life analyses from SPOTLIGHT and GLOW suggest that the survival gains achieved with zolbetuximab are not offset by sustained deterioration in patient-reported outcomes, despite the higher early incidence of nausea and vomiting (12,19).

SPOTLIGHT should be viewed as the beginning rather than the end of the CLDN18.2 story. Key priorities for future research include establishing the role of CLDN18.2 within an integrated biomarker framework that incorporates HER2, mismatch repair status, and PD-L1, rather than considering it as a stand-alone determinant of treatment selection. In this context, further optimization of diagnostic algorithms for CLDN18.2 testing, together with refinement of scoring cutoffs, will be essential to ensure reproducible and clinically meaningful patient selection. Importantly, it remains unclear whether patients with intermediate or heterogeneous CLDN18.2 expression might benefit from treatment intensification or rational combination strategies, particularly given the intratumoral heterogeneity observed in routine biopsy specimens (14). These challenges are further compounded by emerging biological insights into primary and acquired resistance to CLDN18.2-directed therapy. A recent translational study has suggested that dynamic modulation of CLDN18.2 expression, alterations in antibody-dependent effector-cell function, and remodeling of the tumor microenvironment may contribute to treatment resistance (20), underscoring the need for longitudinal biomarker assessment beyond baseline testing. In this context, combination approaches that pair zolbetuximab with PD-1 blockade, other targeted agents or novel immunomodulators are particularly attractive and are being explored in ongoing trials such as ILUSTRO (NCT03505320) and LUCERNA (NCT06901531). In parallel, next-generation CLDN18.2-targeted modalities—including antibody-drug conjugates (e.g., CMG901, IBI343), CD3-engaging bispecific antibodies and CLDN18.2-directed chimeric antigen receptor T (CAR-T) cells—are entering clinical development (21-23) and may ultimately allow CLDN18.2-directed strategies to be tested in earlier disease settings and across a broader spectrum of CLDN18.2-expressing malignancies.

The SPOTLIGHT trial establishes CLDN18.2 as a clinically relevant biomarker and zolbetuximab plus mFOLFOX6 as a new therapeutic option for patients with CLDN18.2-positive, HER2-negative, advanced gastric or GEJ adenocarcinoma (1). For a substantial subset of patients—many of whom have low PD-L1 expression—this regimen delivers reproducible survival gains at the cost of manageable, predominantly gastrointestinal toxicities (1,12). In the broader landscape, CLDN18.2 now stands alongside HER2 and PD-L1 as a major determinant of first-line treatment strategy. The practical challenge for clinicians is to build testing pathways and toxicity-management protocols that allow zolbetuximab-based combinations to be deployed safely and effectively (17,18). The scientific challenge for the field is to integrate CLDN18.2 into rational triplet regimens and composite biomarker frameworks that capture the multidimensional biology of gastric and GEJ cancer. SPOTLIGHT does not close the discussion on CLDN18.2; it opens a new chapter in biomarker-driven, first-line therapy for this disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-167/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-167/coif). S.K. has received grants from Ono Pharmaceutical Co., Ltd., MSD Co., Ltd. Nobelpharma, Janssen Pharmaceutical K.K., Eli Lilly Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., AstraZeneca Co., Ltd., Abbvie, Kyowa Kirin, Astellas Pharmaceutical Co., Ltd., Novartis Co., Ltd., and Bayer; has received honoraria from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD Co., Ltd., Daiichi-Sankyo Co., Ltd., Merck Biopharma Co., Ltd., Bristol-Myers Squibb Co., Ltd., Eli Lilly Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bayer, Eisai, Novartis Co., Ltd., and Astellas Pharmaceutical Co., Ltd. The author has no other conflicts of interest to declare.

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