Innovent Biologics announced that its IBI343, a novel antibody-drug conjugate (ADC), has received Breakthrough Therapy Designation (BTD) from China's National Medical Products Administration (NMPA) for the treatment of CLDN18.2-positive advanced pancreatic ductal adenocarcinoma (PDAC). This designation applies to patients who have experienced disease progression after at least one prior systemic treatment. The decision is supported by data from an ongoing Phase 1 trial conducted across the US, Australia, and China, which demonstrated a favorable safety profile and promising antitumor activity of IBI343 as a monotherapy in this patient population.
The Phase 1 study (NCT05458219) evaluated IBI343 in patients with CLDN18.2-positive advanced PDAC, defined as ≥60% tumor cells with membranous staining intensity ≥1+ by immunohistochemistry (IHC). A total of 43 patients received IBI343 at 6 mg/kg every three weeks. All participants had previously received at least one line of prior therapy, with 60.5% having received two or more lines of anticancer treatment.
Clinical Efficacy and Safety
The study reported a confirmed overall objective response rate (ORR) of 23.3%. Progression-free survival (PFS) events occurred in 26 patients, with a median progression-free survival (mPFS) of 5.3 months (4.1-7.4) as of the data cutoff date. These results suggest that IBI343 could offer a clinically meaningful benefit in a patient population with limited treatment options.
Dr. Hui Zhou, Senior Vice President of Innovent, commented on the BTD, stating, "As the world's first CLDN18.2 ADC to receive BTD in this difficult-to-treat cancer, IBI343 monotherapy has shown encouraging efficacy and tolerable safety in late-line treatment of patients with advanced pancreatic cancer. Subject to PoC data readout, we plan to initiate pivotal MRCT studies to further confirm its efficacy and safety in this indication. Additionally, we will also explore the potential of IBI343 in combination therapy for pancreatic cancer and other solid tumors, including gastric cancer."
Pancreatic Cancer: An Unmet Need
Pancreatic cancer remains one of the most aggressive malignancies, with a five-year survival rate of approximately 10%. Early detection rates are low, and treatment options for advanced disease are limited, typically involving systemic chemotherapy regimens such as fluorouracil (5-FU) or gemcitabine-based combinations. Second-line treatment options offer a chemotherapy response rate of only 6-16%, a median progression-free survival of 2 to 5 months, and a median overall survival of approximately 6 to 9 months, underscoring the urgent need for novel therapeutic approaches.
Mechanism of Action
IBI343 is an antibody-drug conjugate (ADC) composed of an anti-CLDN18.2 antibody conjugated to the cytotoxic drug exatecan. CLDN18.2, a member of the claudin family of tight junction molecules, is normally restricted to the gastric mucosa but is exposed on the surface of tumor cells in 50% to 70% of pancreatic cancer cases. Upon binding to CLDN18.2-expressing tumor cells, IBI343 undergoes internalization, followed by degradation of the cleavable linker, releasing exatecan. This results in DNA damage and apoptosis of the tumor cells. The released drug can also diffuse across the plasma membrane, killing neighboring tumor cells, resulting in a "bystander killing effect."
Regulatory Status and Future Directions
In addition to the recent BTD from China's NMPA for advanced PDAC, IBI343 received its first BTD in May 2024 for monotherapy in CLDN18.2-positive advanced gastric/gastro-esophageal junction adenocarcinoma (GC) patients who progressed after two prior lines of systemic treatment. Furthermore, the U.S. Food and Drug Administration (FDA) granted IBI343 Fast Track Designation in June 2024 for advanced, unresectable or metastatic PDAC that has relapsed and/or is refractory to one prior line of therapy. Innovent plans to initiate pivotal multi-regional clinical trials to further evaluate the efficacy and safety of IBI343 in pancreatic cancer and other solid tumors.
