Zolbetuximab Plus Gemcitabine and Nab-Paclitaxel Under Investigation in Claudin 18.2+ Metastatic Pancreatic Cancer

The first-in-class chimeric monoclonal antibody zolbetuximab (IMAB362) is being investigated in combination with gemcitabine and nab-paclitaxel (Abraxane) vs gemcitabine and nab-paclitaxel alone as a frontline treatment for patients with Claudin 18.2 (CLDN18.2)–positive metastatic pancreatic cancer in a phase 2 trial (NCT03816163).

With this trial, investigators hope to further explore the benefits of targeting CLDN18.2 in patients with metastatic pancreatic cancer, according to lead study author Wungki Park, MD.

“CLDN18.2 is a target of interest in many ongoing clinical trials. Currently, this trial of zolbetuximab is open across 85 centers in 9 countries, and the safety lead-in [portion of the research] has already occurred,” said Park, who is an assistant attending physician and a medical oncologist at Memorial Sloan Kettering Cancer Center. “We are excited about this study, and we are hoping to share insightful data in the near future.”

In an interview with OncLive^®, Park discussed the rationale of targeting CLDN18.2 in patients with pancreatic cancer, preclinical data supporting the use of zolbetuximab in this patient population, and the key objectives of the ongoing phase 2 trial.

OncLive^®: What is known about CLDN18.2 as a potential target in pancreatic cancer?

Park: Fluorouracil, oxaliplatin, and irinotecan [FOLFIRINOX] with nab-paclitaxel and gemcitabine is the current first-line standard-of-care [SOC] combination chemotherapy used in metastatic pancreatic cancer. Despite the advance of treatment options, the 5-year overall survival [OS] rate remains less than 3% for patients with [metastatic pancreatic cancer]. We are in dire need of new therapeutic options.

CLDN18.2 is a good target to utilize; this is a protein located in a cell-to-cell junction. [CLDN18.2] is usually not exposed to the surface; it is in between cells, but during the transformation into cancer cells, [CLDN18.2] is exposed, and the epitope of this protein can be utilized as a tropism for the targeting of therapeutic agents. Zolbetuximab is an IgG1 monoclonal antibody that specifically binds to this protein.

What preclinical data support further exploration of zolbetuximab in combination with gemcitabine and nab-paclitaxel in this patient population?

Our poster showed dissected tumor staining that shows the positivity of CLDN18.2 from a tumor site. It is relatively common with heterogeneous levels of expression, and [patients with high expression of CLDN18.2 can have expression levels of] up to 68% [and higher]. Approximately, 1 in 4 patients will have a high expression of CLDN18.2, [and the trial is designed to enroll these patients].

Zolbetuximab is an IgG1 monoclonal antibody that induces cytotoxicity through antibody dependency, or through complement-mediated cytotoxicity. The preclinical data suggest [zolbetuximab] may improve cytotoxicity if it is combined with chemotherapy, such as gemcitabine. CLDN18.2 expression level also increases [cytotoxicity of zolbetuximab] in the preclinical data.

This is a trial that is designed to test SOC gemcitabine and nab-paclitaxel with or without zolbetuximab.

What is the design of the phase 2 trial evaluating this approach?

This was initially designed as a phase 2 randomized, international trial, and the initial accrual goal was 129 patients with [metastatic pancreatic cancer who had] a high expression of a CLDN18.2. Enrollment was successful, and [investigators] revised the plan and amended the protocol to expand to 369 patients. This was to have a better look at the overall outcome of this [combination regimen].

We currently do not have outcome data, but we do have a plan of looking at the interim report [after 212 OS] events [occur]. The final OS analysis will occur after [283] OS events.

Could you expand on eligibility criteria for the trial? What should be known about the patient population?

[Those who are eligible for the trial] have [CLDN18.2-positive] metastatic pancreatic cancer and an ECOG performance status of 0 or 1 at baseline. Patients should have cytologically or a pathologically confirmed adenocarcinoma of the pancreas and measurable disease by RECIST v1.1 criteria.

The randomization happens in a 2:1 ratio, and patients are stratified based on ECOG performance status of 0 vs 1, and whether they have liver metastases.

Our poster presentation [shared during the 2022 ASCO Annual Meeting] summarized the design of the trial and our ongoing efforts. Hopefully we can share exciting results in the near future.

Reference

1. Park W, O’Reilly EM, Furuse J, et al. Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in first-line treatment of Claudin 18.2-positive metastatic pancreatic cancer (mPC): Phase 2, open-label, randomized study. J Clin Oncol. 2022;40(suppl 16):4186. doi:10.1200/JCO.2022.40.16_suppl.TPS4186