Advancements in CLDN18.2 Targeted Therapy for the Management of Gastric Cancers

The pursuit of effective treatments for gastrointestinal cancers (GICs), particularly GC, has gained significant momentum with the discovery of CLDN18.2 as a promising therapeutic target. This protein shows limited expression in healthy tissues but exhibits abnormal expression in various digestive malignancies, including but not limited to GC and gastroesophageal junction (GEJ) cancer. Ongoing clinical trials and recent advancements investigating CLDN18.2-targeted therapies, such as monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, have yielded favorable initial results, though more research is necesssary.¹ This progress in the advent of treatment modalities aligns with the urgent need to overcome the challenges posed by GICs and marks a crucial step toward integrating CLDN18.2-targeted therapies into the clinical care of GICs.
 
Heemali Kamdar, DO, is a GI Fellow at Nemours Children’s Hospital in Wilmington, Delaware. At Nemours Children’s Hospital, Dr Kamdar provides comprehensive patient care regarding GI disorders and has a keen interest in research regarding GCs. In this article, Dr Kamdar provides valuable insights into the latest advancements in CLDN18.2 targeted therapy for the management of GCs.

Can you explain the significance of CLDN18.2 in the context of normal gastric mucosa and how it becomes relevant in malignant transformation?

CLDN18.2 is a protein that plays a crucial role in the formation of tight junctions between epithelial cells. Tight junctions are essential for maintaining the integrity of the epithelial barrier in various tissues, including the gastric mucosa. In the context of normal gastric mucosa, CLDN18.2 contributes to the tight junctions between gastric epithelial cells, helping to prevent the leakage of substances across the epithelial layer.¹
 
The transformation of gastric epithelial tissue into a malignant state results in the disturbance of cell polarity, leading to the presentation of CLDN18.2 epitopes on the cell surface. Abnormal levels of CLDN18.2 expression can be linked to cancer, especially in cases involving malignancies of the digestive system.¹ Therefore, the significance of CLDN18.2 in GC lies in its potential as a diagnostic biomarker and therapeutic target. Researchers have explored the use of CLDN18.2 as a biomarker for GC, and it continues to be investigated as a target for various antibody-based therapies such as bispecific antibodies, ADCs, and CAR T-cell therapies.

Can you explain the significance of CLDN18.2 as a potential target in the treatment of GIC and the rationale behind why it may be a promising target from a mechanistic point of view?

The rationale behind considering CLDN18.2 as a therapeutic target is rooted in its unique expression pattern. For example, targeted monoclonal antibodies often encounter challenges in accessing CLDN18.2 within tightly-bound supramolecular complexes in healthy tissue, but the disturbed cell polarity associated with carcinogenesis leads to exposure of CLDN18.2 epitopes, making them available for binding of target monoclonal antibodies and, therefore, an attractive target for selective therapeutic interventions. This selectivity is crucial to minimize off-target effects on healthy tissues.¹

How do CLDN18.2 targeted therapies such as zolbetuximab, a chimeric monoclonal antibody, differ from traditional chemotherapy or other standard treatment approaches in managing GIC? How does zolbetuximab specifically target and kill CLDN18.2-positive cells in patients with GIC?

CLDN18.2 targeted therapies, such as zolbetuximab, represent a novel approach in the management of GIC; these targeted therapies primarily differ from more traditional treatment agents, such as chemotherapy, in their mechanism of action and specificity. Conventional chemotherapy and standard treatment practices often lack precision in targeting malignant cells, inadvertently causing harm to healthy tissue and increasing the likelihood of treatment-emergent adverse effects.²
 
Zolbetuximab is a “first-in-class” chimeric immunoglobulin G1 (IgG1) monoclonal antibody, which targets and binds to CLDN18.2, a tight junction protein typically present in gastric mucosa cells. As gastric malignancies progress, CLDN18.2 may become more exposed on the surface of cancer cells, making it an attractive target. Zolbetuximab works by binding to CLDN18, triggering apoptosis through both the antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity pathways.³ While systemic chemotherapy remains the primary treatment strategy for patients with recurrent or metastatic GC, its clinical efficacy is constrained in cases of diffuse-type GC.⁴

How does CLDN18.2 targeted therapy fit into the broader treatment strategies for GIC, including its role in combination with other modalities like chemotherapy, immunotherapy, or radiation therapy? Are there specific patient populations within GIC that may benefit more from CLDN18.2 targeted therapy?

Patients diagnosed with diffuse-type GC usually undergo systemic chemotherapy as the primary treatment, but the clinical benefits of systemic chemotherapy are limited for these patients.⁴
 
CLDN18.2 targeted therapy can be combined with systemic chemotherapy regimens to enhance treatment efficacy. This combination approach aims to capitalize on the specificity of targeted therapy while leveraging the broader cytotoxic effects of chemotherapy. In the SPOTLIGHT trial (ClinicalTrial.gov identifier: NCT03504397), the inclusion of zolbetuximab alongside chemotherapy demonstrated a survival advantage compared with a standard first-line chemotherapy regimen; patients who received zolbetuximab plus chemotherapy exhibited a median PFS of 10.61 months, while those who received placebo plus chemotherapy had a PFS of 8.67 months.⁵
 
The expression of CLDN18.2 varies among different GICs and even within subtypes of more specific cancers.⁶ CLDN18.2 targeted therapy may be particularly relevant in cases where the expression of this protein is high, and identifying patients with CLDN18.2-positive tumors can help tailor personalized treatment strategies for better outcomes.

Can you discuss the median PFS times and OS for the zolbetuximab and placebo groups from the SPOTLIGHT phase 3 study? How do these findings compare to PFS and OS within the scope of existing treatment strategies for patients with GIC?

In the SPOTLIGHT trial, a total of 565 participants diagnosed with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic GC or GEJ cancer were randomized to receive either zolbetuximab (n=283) or placebo (n=282) in combination with mFOLFOX. These participants were followed for a median duration of roughly 13 months and the primary endpoint reported on PFS of treated patients compared with patients receiving placebo. Patients treated with zolbetuximab in combination with mFOLFOX6 achieved a median PFS of 10.61 months (95% CI, 8.90-12.48), surpassing the 8.67 months (95% CI, 8.21-10.28) observed in those who received placebo in combination with mFOLFOX6. Furthermore, the zolbetuximab group exhibited a longer median OS of 18.23 months, demonstrating a significant decrease in mortality risk, compared with 15.54 months in the placebo in combination with the mFOLFOX6 group. These results are of great significance as they emphasize the advantages of combining zolbetuximab with mFOLFOX6 and represent the first phase 3 results that demonstrate the benefits of targeting CLDN18.2.⁵ This highlights the potential of this approach in improving treatment outcomes.
 
In the GLOW Trial (ClinicalTrials.gov identifier: NCT03653507), a total of 507 participants diagnosed with CLDN18.2-positive tumors were randomized 1:1 to receive either zolbetuximab in combination with CAPOX (n=254) or placebo in combination with CAPOX (n=253). These participants were followed for a median duration of roughly 12 months when assessing the primary endpoint of PFS. Patients treated with zolbetuximab in combination with CAPOX achieved a median PFS of 8.21 months, surpassing the 6.80 months observed in those who received placebo in combination with CAPOX. Additionally, the zolbetuximab group exhibited a longer median OS of 14.39 months, demonstrating a decrease in mortality, compared with 12.16 months in the placebo in combination with the CAPOX group.⁷

Overall, the findings from both the SPOTLIGHT and GLOW trials showcase the clinical benefits associated with zolbetuximab in combination with mFOLFOX6 or CAPOX. These results represent a significant advancement in demonstrating the efficacy of targeting CLDN18.2 across various tumor types, which instills hope for the treatment of GICs.

Can you discuss the safety profile of CLDN18.2 targeted therapies, including common adverse effects and how they may be managed in clinical practice?

Treatment-related adverse events (TRAEs) remain a real concern; as seen in the SPOTLIGHT trial, TRAEs of all grades were observed in over 99% of participants, while grade ≥3 TRAEs were reported in 87% of patients treated with zolbetuximab and 78% of participants treated with placebo, respectively. Nausea, vomiting, and decreased appetite were the most commonly reported adverse events.⁵ However, there have been no observed instances of therapeutic resistance linked to zolbetuximab.¹
 
In clinical practice, these effects can often be effectively managed with supportive care measures, dose modifications, or pre-medications to minimize infusion-related reactions as well as co-administering single or combination antiemetic treatment. Regular monitoring and proactive management of adverse events are essential to ensure the overall well-being of patients undergoing CLDN18.2-targeted therapies.
 
This Q&A was edited for clarity and length.

References

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2. Chua CYX, Ho J, Demaria S, Ferrari M, Grattoni A. Emerging technologies for local cancer treatment. Adv Ther (Weinh). 2020;3(9):2000027. doi:10.1002/adtp.202000027
 
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(5):609-619. doi:10.1016/j.annonc.2021.02.005
 
4. Ooki A, Yamaguchi K. The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol. 2022;14. doi:10.1177/17588359221083049
 
5. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668. doi: 10.1016/S0140-6736(23)00620-7
 
6. Dottermusch M, Krüger S, Behrens HM, Halske C, Röcken C. Expression of the potential therapeutic target claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch. 2019;475(5):563-571. doi:10.1007/s00428-019-02624-7
 
7. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7
 
 
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