Zolbetuximab on the SPOTLIGHT—a light spot?

Gastric cancer (GC) represents a world health concern, constituting one of the foremost contributors to cancer-related mortality worldwide. According to estimates for the year 2020, GC resulted in approximately 768,793 deaths and an incidence exceeding 1.1 million cases (1). Regrettably, a considerable portion of patients receive diagnoses at advanced disease stages, contributing to a notably low 5-year survival rate of less than 10% (2,3). Moreover, a substantial proportion of patients diagnosed with non-metastatic GC and subjected to curative-intent treatment strategies, encompassing both surgical intervention and chemotherapy, inevitably experience disease recurrence (2,3).

Until 2010, significant breakthroughs in the therapeutic management of metastatic GC proved elusive. The utilization of a combined regimen involving a fluoropyrimidine alongside a platinum agent has persisted as the primary treatment approach for the majority of patients with metastatic GC throughout decades, characterized by a median overall survival (OS) period of less than one year (4).

The introduction of human epidermal growth factor receptor 2 (HER-2) as a biomarker marked a pivotal advancement in overcoming this barrier. The incorporation of trastuzumab into chemotherapy as a first-line treatment demonstrated efficacy particularly in GC patients exhibiting HER2-positive tumors [identified through immunohistochemistry (IHC) scoring of 3+ or fluorescence in situ hybridization (FISH) positivity combined with an IHC score of 2+] (5). Subsequently, the integration of an anti-programmed cell death 1 (anti-PD-1) agent for individuals with either PD-ligand 1 (PD-L1) positivity or microsatellite instability high (MSI-H) tumors has emerged as a significant development in clinical practice, yielding improvements in OS (6,7).

Claudin 18.2 (CLDN18.2), a recently identified biomarker and member of the tight junction protein family, has garnered significant attention in the field. Throughout the progression of carcinogenesis, it has been observed that there is a heightened surface expression of CLDN18.2 on cancer cells. Consequently, this upregulation renders CLDN18.2 an auspicious target for potential therapeutic interventions. Zolbetuximab, a chimeric immunoglobulin G1 antibody targeting CLDN18.2, has shown therapeutic promise when combined with oxaliplatin-based chemotherapy for metastatic GC patients positive for CLDN18.2 (8,9). Since 2019, multiple phase II trials have scrutinized the clinical effectiveness of zolbetuximab in advanced GC, suggesting enhanced benefits with zolbetuximab-chemotherapy combinations and in instances of high CLDN18.2 tumor expression (10-12). Both the FAST and ILUSTRO phase II trials have showcased promising efficacy of zolbetuximab alongside chemotherapy as first-line option for CLDN18.2 positive GC, especially among individuals with highly positive CLDN18.2, defined as ≥75% of cancer cells exhibiting moderate to high levels of CLDN18.2 expression in IHC (11,12). This subgroup of patients exhibiting high expression levels of CLDN18.2 constitutes approximately 40% of individuals diagnosed with metastatic HER-2 negative GC.

At the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, investigators reported findings from the phase III SPOTLIGHT trial (8), which was a global, multicenter, randomized clinical trial evaluating zolbetuximab or placebo plus mFOLFOX6 in terms of efficacy and safety as first-line option for patients with CLDN18.2-positive, HER2-negative, advanced gastric/gastroesophageal junction (GEJ) cancer. The trial enrolled 565 patients at 215 centers worldwide. The primary endpoint was progression-free survival (PFS) and secondary endpoints included OS, overall response rate (ORR), duration of response, safety and tolerability, and quality-of-life.

The median age of participants was 62 years, with 62% being men, and 69% non-Asian. The primary site of tumors was the stomach in 77% of participants, and 22.6% had metastases in ≥3 organs. The study revealed statistically significant improvements in both PFS and OS with zolbetuximab plus mFOLFOX6 compared to placebo plus mFOLFOX6. Specifically, the zolbetuximab arm presented a 24.9% reduction of risk of progression or death [n=565; hazard ratio (HR) =0.751; 95% confidence interval (CI): 0.598–0.942; P=0.0066] and prolonged median PFS to 10.61 (95% CI: 8.90–12.48) months compared to 8.67 (95% CI: 8.21–10.28) months with placebo. Additionally, the zolbetuximab arm extended OS, reducing the risk of death by 25.0% (HR =0.750; 95% CI: 0.601–0.936; P=0.0053), with median OS of 18.23 (95% CI: 16.43–22.90) versus 15.54 (95% CI: 13.47–16.53) months in the placebo arm (8). The noteworthy observation was the unexpected superior performance demonstrated by both study arms, surpassing initial expectations, which could partially be explained by 31% of the participants deriving from Japan or Korean, where GC exhibits a comparative more favorable prognosis.

Despite interesting OS and PFS benefits, the absence of a notable increase in the ORR with the incorporation of zolbetuximab compared to the control arm, showcasing rates of 55% and 58.8% respectively, was indeed disappointing. In addition, although the incidence of serious treatment-emergent adverse events (TEAEs) was comparable between zolbetuximab and placebo groups (44.8% versus 43.5%, respectively), the experimental arm experienced more nausea (82.4% versus 60.8%), and vomiting (67.4% versus 35.6%). Those adverse events occurred mostly in the first and second zolbetuximab cycles, and are considered on-target CLDN18.2 effects (8). The effective management of nausea and vomiting in clinical practice holds paramount significance, with the determination of the most suitable antiemetic regimen remaining an unresolved matter.

The subsequent GLOW trial (9), presented at the March ASCO Plenary Series in 2023, was also a phase III randomized clinical trial encompassing 507 CLDN18.2-positive, HER2-negative, advanced gastric/GEJ adenocarcinoma patients. The main difference between the SPOTLIGHT and the GLOW trial was the selection of chemotherapy regimen. Participants in the GLOW trial were randomly assigned to receive zolbetuximab or placebo plus CAPOX (capecitabine + oxaliplatin) as first-line setting. Similar to the SPOTLIGHT trial, this study unveiled that adding zolbetuximab to chemotherapy bolstered median PFS (8.21 versus 6.80 months; HR =0.68; 95% CI: 0.54–0.86; P=0.0007) and OS (14.39 versus 12.16 months; HR =0.77; 95% CI: 0.61–0.96; P=0.011). Nevertheless, the OS attained by the control arm in the GLOW trial aligns more closely with the outcomes observed in various first-line studies concerning metastatic GC.

Once more, no significant discrepancy in ORR was observed between the two treatment arms, with rates of 42.5% versus 40.3% in the zolbetuximab and placebo arm, respectively (9). Additionally, it is noteworthy that nausea and vomiting were more prevalent in the zolbetuximab arm, necessitating heightened clinical attention. Interestingly, in both studies, patients submitted to gastrectomy proportionally experienced lower vomiting compared to patients who had not undergone that surgery.

A meta-analysis of three randomized clinical trials (FAST, SPOTLIGHT, and GLOW) involving 1,233 patients revealed significant extensions in PFS (HR =0.64; 95% CI: 0.49–0.84; P<0.01; I²=59%) and OS (HR =0.72; 95% CI: 0.62–0.83; P<0.01; I²=31%) among patients assigned to zolbetuximab combined with chemotherapy compared to those receiving chemotherapy alone. While no notable improvement was observed in ORR (P=0.34), disease control rate (P=0.68), partial response (P=0.95), and stable disease (P=0.09) for the zolbetuximab group, the addition of zolbetuximab to chemotherapy notably elevated complete response [odds ratio (OR) =2.09; 95% CI: 1.17–3.73; P=0.01; I²=0%] and decreased disease progression (OR =0.52; 95% CI: 0.28–0.96; P=0.04; I²=40%). Furthermore, zolbetuximab plus chemotherapy led to a significant increase in grade ≥3 TEAEs (OR =1.44; 95% CI: 1.09–1.90; P=0.01; I²=8%) (13).

These randomized trials advocate for the utilization of zolbetuximab in conjunction with existing chemotherapy regimens as a novel and efficacious treatment approach for CLDN18.2-positive advanced GC. However, neither the SPOTLIGHT trial nor the GLOW trial compares zolbetuximab combination with the current standard treatment of chemotherapy associated with immunotherapy agents, prompting doubts about the optimal selection for initial treatment. Alongside HER2, microsatellite instability status, and PD-1, CLDN18.2 biomarker testing should be routinely evaluated as an additional predictive marker in the frontline management of advanced GC. Nevertheless, numerous inquiries remain unresolved, including the potential synergistic effects of combining zolbetuximab with checkpoint inhibitors or with anti-HER-2 agents, once expression of CLDN18.2 may overlap with the expression of HER2, MSI and PD-L1. So far there is no established standard treatment for subjects with overlapping expression of PD-L1 and CLDN18.2. Additionally, the long-term performance of zolbetuximab and its associated costs necessitate further investigation.

Acknowledgments

Funding: None.

Footnote

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

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