Corbus Pharmaceuticals' CRB-701 (SYS6002), a next-generation antibody-drug conjugate (ADC) targeting Nectin-4, has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory metastatic cervical cancer. This designation aims to accelerate the development and review process for CRB-701, addressing a significant unmet need in patients with limited treatment options. The FDA's Fast Track program is designed to facilitate the development and expedite the review of drugs intended to treat serious conditions that demonstrate the potential to fill an unmet medical need.
Mechanism of Action and Clinical Development
CRB-701 is designed to improve upon existing Nectin-4-targeted therapies like enfortumab vedotin by utilizing a site-specific, cleavable linker and a homogenous drug-antibody ratio of 2, with MMAE as the payload. This design aims to enhance targeted delivery of the cytotoxic payload while improving tolerability and reducing cumulative toxic effects. Nectin-4 is a clinically validated, tumor-associated antigen frequently overexpressed in urothelial and cervical cancers, as well as other solid tumors.
Corbus Pharmaceuticals has recently completed enrollment of the dose escalation portion of its Phase 1 clinical trial (NCT06265727) evaluating CRB-701 in the U.S. and Europe. This three-part trial is assessing the safety, pharmacokinetics, and efficacy of CRB-701 in patients with advanced solid tumors known to be associated with high Nectin-4 expression. The company anticipates reporting initial data from the dose escalation study in Q1 2025.
Early Clinical Data
Updated results from the phase 1 portion of the study were presented at the 2024 ASCO Annual Meeting and showed that the agent was generally well tolerated and produced antitumor responses across multiple dose levels. Early pharmacokinetic data also showed consistently lower levels of free monomethyl auristatin E across all dose levels compared with enfortumab vedotin.
As of a May 2024 data cutoff, the overall response rate (ORR) with CRB-701 across all tumor types at dose levels of 2.7 mg/kg or higher was 40%, including 6 partial responses (PRs) and 2 unconfirmed responses. The disease control rate (DCR) in the overall population was 73%.
In patients with metastatic urothelial cancer (n = 9), the ORR was 44%, including 4 PRs and 1 unconfirmed response. Among patients with cervical cancer (n = 7), the emerging ORR was 43%, comprising 3 PRs and 1 unconfirmed response. The respective DCRs were 78% and 86%.
Safety and Tolerability
In the dose-escalation portion of the trial, CRB-701 was primarily associated with grade 1/2 adverse effects (AEs), and no grade 4/5 AEs or dose-limiting toxicities have been observed to date. The most common treatment-emergent AEs were anemia and eye-related events. A single case of grade 1 peripheral neuropathy was observed and associated with grade 3 hypokalemia, both of which resolved within 10 days with potassium replacement therapy. Two grade 3 corneal disorders occurred at doses of 2.7 mg/kg and 3.6 mg/kg, prompting the introduction of preventive eye measures. No corneal events have been observed at the 4.5-mg/kg dose. Over 50% of patients enrolled presented with corneal disorders or dry eye at baseline.
Future Directions
With the dose escalation portion of the Phase 1 trial now complete, Corbus is proceeding with dose expansion at the 2.7-mg/kg and 3.6-mg/kg dose levels to further assess the pharmacology and safety of CRB-701. The anticipated data release in Q1 2025 will provide further insights into the potential of CRB-701 as a novel treatment option for Nectin-4-positive advanced solid tumors.
