Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). In normal tissues, the CLDN18.2 epitope within the tissue adhesion complex is completely inaccessible; however, on malignant transformation, cell adhesion is disrupted, and the CLDN18.2 epitope is exposed on the gastric and GEJ (G/GEJ) adenocarcinoma cell surface, making it a promising target.
Figure 1. Claudin 18.2 structure, function and expression patterns. [3]
FDA Approved Vyloy (Zolbetuximab)
On October 18, 2024, the Food and Drug Administration (FDA) approved zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. VYLOY is the first and only CLDN18.2-targeted treatment approved by FDA.
The approval is based on results from the Phase 3 SPOTLIGHT and GLOW clinical trials. Both trials met their primary endpoint, progression-free survival (PFS), as well as a key secondary endpoint, overall survival (OS), in patients treated with VYLOY plus chemotherapy compared to placebo plus chemotherapy.
In January 2023, Astellas announced that the SPOTLIGHT trial demonstrated a 24.9% reduction in the risk of disease progression or death for patients receiving Vyloy in combination with mFOLFOX6 compared to the placebo group, achieving the trial's primary endpoint. The median PFS for the Vyloy group was 10.61 months (vs. 8.67 months), and the median OS was 18.23 months (vs. 15.54 months). The rates of severe treatment-related adverse events (TEAEs) were similar in both groups, at 44.8% and 43.5%, consistent with previous trial results.
In March 2023, the GLOW trial results showed that Vyloy with CAPOX reduced the risk of disease progression or death by 31.3% compared to the placebo group. The median PFS for the Vyloy group was 8.21 months (vs. 6.80 months). Additionally, the Vyloy combination therapy lowered the risk of death by 22.9%, with a median OS of 14.39 months (vs. 12.16 months). The rates of severe treatment-related adverse events were comparable between the two groups, consistent with previous findings.
Figure 2. PFS in phase 3 GLOW trial [2]
Figure 3. OS in phase 3 GLOW trial [2]
Other Claudin-18.2 Targeted Therapies
The FDA approval is not only a long-awaited victory for Astellas but also for the Claudin 18.2. Currently, there are other targeted therapies against Claudin 18.2 under development, including bispecific antibodies (BsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell therapies (CAR-T).
Figure 4. Various classes of developmental claudin 18.2-targeted therapies. [3]
Bispecific Antibodies
Gresonitamab, ASP2138, AZD5863, and QLS31905 are designed to bind Claudin 18.2 and CD3. Gresonitamab has been evaluated in an international multicenter Phase I study involving patients with AGC or PDAC (NCT04260191). QLS31905 was evaluated in a Phase I trial with heavily pretreated patients who had advanced solid tumors. Among 27 patients receiving doses of ≥200 μg/kg, the overall response rate (ORR) was 11.1%, and the disease control rate (DCR) was 63.0%, with no responses observed in patients with gastric or GEJ cancers. Phase I trials for ASP2138 (NCT05365581) and AZD5863 (NCT06005493) are currently underway.
Q-1802, a humanized bispecific antibody targeting Claudin 18.2 and PD-L1, is being assessed in an open-label, single-arm Phase I trial (NCT04856150). The dose-escalation phase has been completed with no dose-limiting toxicities observed, reaching a maximum dose of 20 mg/kg. Common adverse events included nausea (62.1%), vomiting (62.1%), and abdominal pain (27.6%). Two of nine patients in the dose-expansion cohort achieved partial responses, and four had stable disease.
PT886 is a novel bispecific antibody targeting Claudin 18.2 and CD47, currently undergoing testing in an open-label Phase I trial involving patients with advanced gastric cancer, GEJ adenocarcinoma, or PDAC.
Givastomig (TJ-CD4B/ABL111) is an innovative bispecific antibody targeting Claudin 18.2 and 4-1BB. It is currently in Phase I trials at sites in the U.S. and China (NCT04900818). Preliminary results indicate that three patients (16.6%) experienced partial responses. Common toxicities included grade 1-2 nausea (22%), fatigue (14%), and vomiting (12%), with a total of seven grade 3 adverse events reported.
Antibody-Drug Conjugates (ADCs)
CMG901 (AZD0901) is an ADC comprising a humanized anti-CLDN18.2 IgG1 antibody conjugated via a protease-cleavable linker to MMAE, with a DAR of about 4. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392). In April 2022, the FDA granted a fast-track designation to CMG901 for use as a monotherapy in patients with unresectable or metastatic gastric or GEJ cancer that is relapsed or refractory to approved therapies.
EO-3021 (SYSA1801) is a differentiated, clinical-stage ADC with best-in-class potential comprised of an immunoglobulin G1 (IgG1) mAb that targets Claudin 18.2. It is site-specifically conjugated to the monomethyl auristatin E (MMAE) payload via a cleavable linker with a drug-to-antibody ratio (DAR) of 2. In an ongoing Phase I trial, 33 patients with advanced, heavily pretreated Claudin 18.2-positive gastric or pancreatic cancer received monotherapy with EO-3021. Among the 21 patients evaluable for efficacy, the ORR was 38.1%, and the disease control rate (DCR) was 57.1%. In patients with AGC, the ORR and DCR increased to 47.1% and 64.7%, respectively. Most patients experienced nausea and vomiting, with grade ≥3 reactions reported at 42.9% and 28.6%. Additionally, 7 out of 33 patients (21.2%) reported dry eye, which was considered treatment-related.
Furthermore, several other ADCs are still in early clinical testing, including TPX-4589/LM-302 (NCT05001516, NCT05934331), RC118 (NCT04914117, NCT05205850), SKB315 (NCT05367635), SOT102 (NCT05525286), TORL-2-307-ADC (NCT05156866), and JS107 (NCT05502393).
CAR-T Cell Therapies
CT041 is a second-generation CAR-T cell product consisting of an anti-CLDN18.2 scFv with a CD28 costimulatory domain and a CD3ζ signaling domain, which are linked with a CD8α hinge region and CD28 transmembrane region. Preclinical data demonstrate strong anti-tumor activity in mouse xenograft models, with minimal damage to non-malignant gastric tissues or other organs. In a Phase I study, CT041 showed significant potential in patients with metastatic Claudin 18.2-positive gastric adenocarcinoma or pancreatic cancer, achieving an ORR of 33.3% and a median PFS of 130 days. In a subsequent Phase II trial, the ORR across all cancer patients reached 48.6%, with gastric cancer patients showing an ORR of 57.1%. The DCR was 73.0% for all cancers and 75.0% specifically for gastric cancer.
Several other Claudin 18.2-targeting CAR-T therapies are currently being tested in early studies. These include LB1908, a second-generation CAR equipped with a 4-1BB co-stimulatory domain, and two fourth-generation CAR-T cell products designed to secrete specific cytokines and chemokines: RD07 (NCT05284968) and CT048 (NCT05393986).
The Future of CLDN18.2 Targeted Therapy
CLDN18.2 is emerging as the second most important target for gastric cancer, following HER-2. In populations with high expression levels, it may even surpass HER-2. The FAST trial demonstrated overall survival (OS) outcomes comparable to those of HER-2 therapies. More research is needed to determine the ideal CLDN18.2 levels for maximizing patient benefit.
Combination therapies are another area of promise. The success of Zolbetuximab in combination with chemotherapy suggests that it may also be effective when paired with other targeted drugs. Notably, combining Zolbetuximab with immunotherapy could enhance T cell infiltration, working synergistically with immune checkpoint inhibitors.
Additionally, there is a need for further investigation into prognostic indicators. Molecular subtypes, such as the CLDN18-ARHGAP26/6 fusion, may help guide more precise treatments, especially since they indicate poorer survival and chemotherapy resistance. Identifying and validating additional predictive factors for CLDN18.2 could benefit specific patient groups.
Overall, CLDN18.2 holds great promise in HER-2-negative gastric cancer due to its high selectivity and prevalence. The novel antibody Zolbetuximab has shown significant efficacy and safety, whether used alone or in combination with chemotherapy. Recently, CLDN18.2 CAR-T cell therapy has also demonstrated impressive potential, with plans to advance to Phase III trials, possibly increasing effectiveness when combined with other therapies. As we continue to refine molecular structures and conduct clinical trials, anti-CLDN18.2 therapies are well-positioned to answer critical questions and deliver exciting advancements in the future.
References:
[1] Astellas’ VYLOYTM (zolbetuximab-clzb) Approved by U.S. FDA for Treatment of Advanced Gastric and GEJ Cancer https://www.astellas.com/en/news/29291
[2] Shah, M.A., Shitara, K., Ajani, J.A. et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 29, 2133–2141 (2023). https://doi.org/10.1038/s41591-023-02465-7
[3] Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol. 2024 Mar 19
[4] Evaluation and reflection on claudin 18.2 targeting therapy in advanced gastric cancer. Chin J Cancer Res. 2020 Apr; 32(2): 263–270.