Anti-CLDN18.2 ADC Receives FDA Fast Track Designation in Advanced PDAC

The recombinant human anti-CLDN18.2 agent is designed to bind to tumor cells that express CLDN18.2. When the ADC undergoes lysosomal processing, TOPO1i is liberated and consequently damages tumor cell DNA and yields apoptosis.

The FDA has granted fast track designation to the investigational TOPO1i anti-Claudin 18.2 (CLDN18.2) antibody drug conjugate (ADC) IBI343 as a treatment for patients with advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC), according to a press release from the developers, Innovent Biologics Inc.¹

Specifically, IBI343 is intended for use in patients with relapsed/refractory disease following 1 prior line of therapy.

The recombinant human anti-CLDN18.2 agent is designed to bind to tumor cells that express CLDN18.2. When the ADC undergoes lysosomal processing, TOPO1i is liberated and consequently damages tumor cell DNA and yields apoptosis.

“Pancreatic cancer is highly malignant and difficult to diagnose early. At present, the treatment of advanced pancreatic cancer is still based on systemic chemotherapy,” Hui Zhou, PhD, senior vice president at Innovent, said in the press release.1 “As the world's first CLDN18.2 ADC to obtain [fast track designation] certification in this difficult-to-treat cancer, IBI343 single-agent therapy shows encouraging efficacy and tolerable safety in the late-line treatment of patients with advanced pancreatic cancer. We will continue to confirm its efficacy and safety in this disease in subsequent clinical trials, and also explore IBI343 in combination therapy and other solid tumors including gastric cancer.”

Investigators previously presented data from a phase 1 trial (NCT05458219) evaluating the efficacy and safety of IBI343 among patients with advanced PDAC or biliary tract cancer at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Among 25 evaluable patients who received IBI343 at 6 mg/kg or 8 mg/kg and had CLDN18.2 expression of at least 40%, the unconfirmed objective response rate (ORR) was 28.0% (95% CI, 12.1%-49.4%), the confirmed ORR was 8.0% (95% CI, 1.0%-26.0%), and the disease control rate (DCR) was 80.0% (95% CI, 59.3%-93.2%).² For patients who received the agent at 6 mg/kg and had CLDN18.2 expression of at least 60% (n = 13), the corresponding values were 38.5% (95% CI, 13.9%-68.4%), 15.4% (95% CI, 1.9%-45.4%), and 84.6% (95% CI, 54.6%-98.1%). Additionally, the respective rates for 10 patients with PDAC and CLDN18.2 expression of at least 60% who received 6 mg/kg were 40.0% (95% CI, 12.2%-73.8%), 20.0% (95% CI, 2.5%-55.6%), and 90.0% (95% CI, 55.5%-99.7%).

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 91.4% of patients, and 37.1% had grade 3 or higher TEAEs. Any-grade and grade 3 or higher treatment-related AEs (TRAEs) affected 80.0% and 25.7% of patients, respectively. Additionally, 31.4% and 20.0% of patients had dose interruptions due to TEAEs and TRAEs, respectively, and 2.9% and 2.9% discontinued treatment.

“We are excited to share the latest clinical development updates on IBI343 at ASCO. As an innovative TOPO1i ADC, IBI343 showed a positive clinical signal in [patients] with advanced pancreatic cancer, and the incidence of grade 3 or above gastrointestinal [AEs was] low,” Zhou said in a press release on these findings.³

In this phase 1 trial, patients were assigned to receive IBI343 intravenously at 6 mg/kg or 9 mg/kg every 3 weeks.

The trial’s primary end point was safety. Secondary end points included ORR, DCR, duration of response (DOR), and progression-free survival (PFS) based on investigator assessment. At the time of the analysis, the data for DOR and PFS were not yet mature.

Those with locally advanced unresectable or metastatic PDAC or biliary tract cancer and progression on or intolerance of standard therapy were eligible for enrollment on the trial. Other eligibility criteria included having 1 or more measurable lesions per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, and CLDN18.2 expression of at least 40% during the dose expansion phase.

References

1. Innovent receives fast track designation from the U.S. FDA for IBI343 (TOPO1i anti-CLDN18.2 ADC) as monotherapy for advanced pancreatic cancer. News release. Innovent Biologics, Inc. June 12, 2024. Accessed June 13, 2024. https://tinyurl.com/332f9z56
2. Yu X, Zhang J, Tazbirkova A, et al. Safety and efficacy of IBI343 (anti-claudin18.2 antibody-drug conjugate) in patients with advanced pancreatic ductal adenocarcinoma or biliary tract cancer: preliminary results from a phase 1 study. J Clin Oncol. 2024;42(suppl 16):3037. doi:10.1200/JCO.2024.42.16_suppl.3037
3. Innovent presents at the 2024 ASCO Annual Meeting on clinical data of anti-CLDN18.2 ADC (IBI343) in patients with advanced pancreatic cancer or biliary tract cancer. News release. Innovent Biologics, Inc. June 2, 2024. Accessed June 13, 2024. https://tinyurl.com/3ascn57d