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Claudin18.2 in Gastric Cancer
Considering a Claudin18.2-Targeted Agent in the Current Treatment Landscape for HER2-Negative Gastric Cancers

Released: June 14, 2023

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Key Takeaways
  • Treatment options remain limited for patients with advanced gastric cancer whose tumors are HER2 negative, mismatch repair proficient, and PD-L1 negative.
  • Claudin18.2 is a promising therapeutic target that is highly expressed in gastric tumors but not in any normal tissue outside the gastric mucosa.
  • Survival benefits have been observed with the claudin18.2-targeted antibody zolbetuximab in combination with chemotherapy for the first-line treatment of patients with gastric cancer.

Claudin18.2 is a major structural component of tight junctions in the gastric epithelia expressed by differentiated cells. Several tumor types—including pancreatic, esophageal, biliary, and gastric cancer—broadly express claudin18.2, making it an important tumor target. Because claudin18.2 is expressed only by differentiated cells and not in healthy tissue outside the gastric mucosa, antibodies targeting it cause few off-target toxicities and do not interfere with the replenishment of the gastric mucosa.

In this commentary, I will discuss the current standard of care in advanced gastric cancer, recent reports from the SPOTLIGHT and GLOW clinical trials evaluating the claudin18.2-targeted monoclonal antibody zolbetuximab, and how zolbetuximab may fit into modern gastric cancer practice.

Current Approach to Systemic Therapy for Advanced Gastric Cancer
Our current therapeutic approach for treatment of advanced gastric adenocarcinoma is based on HER2 overexpression, PD‑L1 overexpression, and mismatch repair. In the first-line setting, patients with HER2-positive gastric tumors should receive fluoropyrimidine plus trastuzumab and chemotherapy. In addition, KEYNOTE‑811 showed patients benefit from the addition of pembrolizumab to this regimen, with HER2 increasing the efficacy of the immunotherapy.

In patients whose tumors do not express HER2, treatment is based on PD-L1 expression as measured by combined positive score (CPS). Patients with a PD-L1 CPS of 0‑4 usually receive fluoropyrimidine with chemotherapy, but the addition of nivolumab can be considered. For patients with a PD-L1 CPS ≥5, nivolumab is given with fluoropyrimidine and chemotherapy.

A New Biomarker-Directed Approach for Gastric Cancer
Because chemotherapy alone provides a median overall survival of <1 year, there is a high unmet need among patients whose tumors are HER2 negative and have a PD-L1 CPS <5. The identification of more molecular targets is needed to improve care for these patients.

At ESMO 2018, Moran and colleagues reported their findings from an evaluation of claudin18.2, HER2, and PD‑L1 expression in patients with gastric cancer, which I found very helpful. Of the samples with high claudin18.2 expression, only 12% expressed HER2. By contrast, 37% of the samples expressed both HER2 and PD‑L1. Based on these data, there is limited overlap in claudin18.2 and HER2, and the two can be considered mutually exclusive.

Emerging Data With Therapies Targeting Claudin18.2
Several ongoing clinical trials are evaluating claudin18.2-targeting agents for previously untreated advanced gastric/gastroesophageal junction adenocarcinomas. The 2 main ongoing phase III trials with available data are the SPOTLIGHT and GLOW trials evaluating the monoclonal antibody zolbetuximab. The strength of immunohistochemistry (IHC) staining defining positive claudin18.2 expression varies across clinical trials, but SPOTLIGHT and GLOW used cutoffs of ≥75%.

SPOTLIGHT enrolled 565 patients with high claudin18.2 expression and absent HER2 expression. The addition of zolbetuximab to modified folinic acid/fluorouracil/oxaliplatin (mFOLFOX) followed by 5-fluorouracil (5-FU) and folinic acid led to benefits in progression-free survival (PFS) and overall survival (OS) compared with mFOLFOX followed by 5-FU and folinic acid alone in an interim analysis.

GLOW enrolled 507 patients with claudin18.2-positive, HER2-negative tumors to receive zolbetuximab plus capecitabine/oxaliplatin (CAPOX) followed by capecitabine vs placebo plus CAPOX followed by capecitabine. Again, interim data show improvements in PFS and OS with the addition of zolbetuximab.

Other therapies targeting claudin18.2 are in earlier stages of evaluation. In particular, my research group is involved in a phase I/II trial of CT041, a claudin18.2-targeted CAR T-cell therapy that has shown encouraging results in patients with gastrointestinal cancers, including gastric and pancreatic. At ASCO 2023, we presented data showing that 5 of 8 patients had loss of detectable claudin18.2 circulating tumor DNA (ctDNA) shortly after CT041 therapy, and these patients had longer PFS and OS compared with patients who were treated who did not achieve ctDNA-negative status. 

Zolbetuximab in Clinical Practice
Where will zolbetuximab and other claudin18.2‑directed therapies fit into the treatment paradigm if they are approved? Based on the data, I believe there will be a place for zolbetuximab monotherapy for patients who are ineligible for chemotherapy and in combination with chemotherapy for patients with higher performance status. I continue to assess HER2 and PD‑L1 expression and mismatch repair status in all my patients, and if/when zolbetuximab receives FDA approval and becomes available, I also will evaluate claudin18.2 expression by IHC. Laboratories, either academic or commercial, will need to be prepared to test for claudin18.2.

In the frontline setting, patients who are HER2 positive will continue receiving HER2-targeted therapy in combination with chemotherapy plus immunotherapy, even if they also express claudin18.2. I think patients with HER2-negative and claudin18.2-positive gastric tumors, however, will receive zolbetuximab with chemotherapy.

One area that remains to be explored is the combination of zolbetuximab chemotherapy plus immunotherapy. We await the results of other clinical trials to learn the efficacy and adverse event profile of these combinations and which chemotherapy backbone to use.

Your Thoughts?
Have you enrolled any of your patients with advanced gastric cancer in a clinical trial evaluating a claudin18.2-targeted therapy? Please answer the polling question and join the conversation by posting a comment.

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