OnCusp Therapeutics announced encouraging initial Phase 1a results for CUSP06, a cadherin-6 (CDH6)-directed antibody-drug conjugate, demonstrating promising efficacy in heavily pretreated platinum-resistant high-grade serous ovarian cancer (HGSOC) patients. The data were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Phase 1a Study Design and Patient Population
The ongoing Phase 1 trial is an open-label, multicenter, first-in-human study evaluating CUSP06's safety, tolerability, pharmacokinetics, and preliminary efficacy in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors. As of May 13, 2025, data were available for 37 patients who received CUSP06 once every three weeks at doses ranging from 1.6 to 5.6 mg/kg.
The patient population was heavily pretreated, with a median of 4 prior lines of therapy, representing a challenging treatment scenario for platinum-resistant ovarian cancer patients.
Efficacy Results in Ovarian Cancer
CUSP06 demonstrated notable efficacy in platinum-resistant HGSOC patients without requiring CDH6 biomarker pre-selection. The overall response rate (ORR) was 36% in HGSOC patients (9/25), including 5 confirmed partial responses and 4 unconfirmed partial responses. Notably, 2 of the confirmed responders had previously received mirvetuximab treatment, suggesting activity even in patients who had progressed on other targeted therapies.
The response rates were particularly impressive at higher dose levels with prophylactic granulocyte colony-stimulating factor (G-CSF) support, reaching 50% at both the 4.0 mg/kg + G-CSF and 4.4 mg/kg + G-CSF cohorts. All patients with unconfirmed partial responses and all responders remain on treatment, indicating durable responses.
The clinical benefit rate was remarkably high at 92% (23/25 patients). Additionally, CA-125 responses occurred in 45% of Gynecologic Cancer InterGroup (GCIG)-evaluable HGSOC patients, providing further evidence of clinical activity. Responses were observed in both low and high-CDH6-expressing tumors, suggesting broad applicability across different expression levels.
Safety Profile
CUSP06 demonstrated a manageable safety profile consistent with other topoisomerase-1 inhibitor ADCs. Hematologic toxicities were the most common treatment-related adverse events, which is expected for this class of agents and manageable with appropriate supportive care measures.
CUSP06 Mechanism and Design
CUSP06 is composed of a proprietary antibody with high CDH6 binding affinity, a protease-cleavable linker, and an exatecan payload, which is a potent and clinically validated topoisomerase-1 inhibitor. The linker is specifically designed to complement the exatecan payload, enabling a stable and homogeneous ADC with a drug-to-antibody ratio of eight.
The payload is engineered as a weak substrate for BCRP/P-gp drug efflux pumps, which drive chemoresistance to many therapies. Preclinical data showed this linker-payload combination has an increased "bystander effect" compared with competitor ADCs, potentially contributing to its clinical activity.
Regulatory Status and Development Plans
CUSP06 recently received Fast Track designation from the U.S. Food and Drug Administration for the treatment of patients with platinum-resistant ovarian cancer, recognizing its potential to address an unmet medical need.
"We are excited by the early results, especially in platinum-resistant HGSOC, which demonstrated promising activity in a heavily pretreated population without requiring CDH6 biomarker selection," said Dr. Bing Yuan, Co-Founder and CEO of OnCusp Therapeutics. "These data, together with previously presented preclinical findings, underscore the best-in-class potential of CUSP06."
The Phase 1a results support continued evaluation of CUSP06 in platinum-resistant HGSOC and other CDH6-positive tumors in Phase 1b expansion cohorts. The Phase 1b portion will focus on further characterizing safety and efficacy in select tumor types.
OnCusp obtained exclusive global rights outside of China to develop and commercialize CUSP06 from Multitude Therapeutics in 2022. The company raised an oversubscribed $100 million Series A financing round in January 2024, co-led by Novo Holdings, OrbiMed, and F-Prime Capital.
