FDA Grants Fast Track Designation to CRB-701 in Relapsed/Refractory Cervical Cancer

The FDA has granted fast track designation to the Nectin-4–directed antibody-drug conjugate (ADC) CRB-701 (SYS6002) for the treatment of adult patients with relapsed/refractory metastatic cervical cancer.1

CRB-701 is a next-generation ADC comprising a site-specific, cleavable linker; a homogenous and precise drug-antibody ratio of 2; and a novel monoclonal antibody targeting Nectin-4.1,2 The agent was designed to overcome dose-limiting toxicities associated with the linker-payload used by enfortumab vedotin-efjv (Padcev).2

The agent is currently under investigation in a phase 1/2 trial (NCT06265727) of patients in the United States and Europe with solid tumors that are known to be associated with high Nectin-4 expression.1 Enrollment in the dose-escalation portion of the trial is now complete, and the company expects to report the first data from this portion in early 2025.

Phase 1/2 Trial Overview

This 3-part open-label trial was designed to evaluate the safety, pharmacokinetics, and efficacy of CRB-701 among patients at least 18 years of age with advanced urothelial carcinoma or Nectin-4–positive advanced solid tumors.2 Other eligibility criteria include an ECOG performance status of 0 or 1, adequate organ function, no uncontrolled diabetes, and no active central nervous system metastases. The dose-escalation portion of the study is guided by a Bayesian Optimal Interval design, with accelerated titration at dose level 1.

Patients receive 1 of 7 escalating doses of CRB-701, ranging from 0.2 mg/kg to 4.5 mg/kg. Treatment is administered intravenously every 3 days over a 21-day cycle.

The study’s primary objectives are to assess the safety and tolerability of CRB-701 and determine the maximum tolerated dose and/or the phase 2 dose of the agent. Pharmacokinetics and antitumor activity serve as additional end points.

Patients in the dose-escalation portion spanned 5 tumor types, with ages ranging from 35 to 76 years. Most patients were female (70.3%).

Emerging Safety and Efficacy Data With CRB-701

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.2,3

At the data cutoff of May 2024, the overall response rate (ORR) with CRB-701 across all tumor types and at dose levels of 2.7 mg/kg or higher was 40%, including 6 partial responses (PRs) and 2 unconfirmed responses.3 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%.

As of the data cutoff, the agent generated the first confirmed stable disease at the 0.6-mg/kg dose level and the first confirmed PR in the metastatic urothelial cancer cohort at the 1.2-mg/kg dose level.

Regarding safety, in the dose-escalation portion, CRB-701 was primarily associated with grade 1/2 adverse effects (AEs); no grade 4/5 AEs or dose-limiting toxicities have been observed to date.2 The most common treatment-emergent AEs were anemia and eye-related events. One patient treated at the 2.7-mg/kg dose level experienced a grade 3 rash lasting 8 days without requiring dose modification or interruption. Two additional cases of skin rash (grade 1 and grade 2) resolved without intervention. Since the January 2024 update, no new treatment-related serious AEs have been reported.

A single case of grade 1 peripheral neuropathy was observed and associated with grade 3 hypokalemia. Both AEs 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.3

Based on these results, dose escalation is ongoing at the 4.5-mg/kg dose level.2 Dose expansion is also being conducted at the 2.7-mg/kg and 3.6-mg/kg dose levels to further assess pharmacology and safety.

References

1. FDA grants fast track designation to CRB-701 for the treatment of relapsed or refractory metastatic cervical cancer. News Release. Corbus Pharmaceuticals. December 3, 2024. Accessed December 4, 2024. https://ir.corbuspharma.com/press-releases/detail/429/fda-grants-fast-track-designation-to-crb-701-for-the
2. Ye DW, Zhang J, Yang H, et al. Clinical update on the first-in-human trial of SYS6002 (CRB-701), a next-generation, Nectin-4 targeting, MMAE bearing, antibody drug conjugate. J Clin Onc. 2024;42(suppl 16):3151. doi:10.1200/JCO.2024.42.16_suppl.3151
3. SYS6002 (CRB-701) a next-generation Nectin-4 targeting antibody drug conjugate continues to demonstrate encouraging safety and efficacy observed in patients with Nectin-4 positive tumors in a clinical update presented at ASCO 2024. News Release. Corbus Pharmaceuticals. June 1, 2024. Accessed December 4, 2024. https://www.corbuspharma.com/press-releases/detail/417/sys6002-crb-701-a-next-generation-nectin-4-targeting