FDA Grants CRB-701 Fast Track Status in R/R Cervical Cancer

• The FDA granted fast track designation to CRB-701 (SYS6002) in relapsed/refractory (R/R) metastatic cervical cancer.
• CRB-701 is a Nectin-4–directed antibody-drug conjugate (ADC).
• A phase 1/2 trial (NCT06265727) is currently evaluating the agent in patients with solid tumors that are known to be associated with high Nectin-4 expression.

The FDA granted fast track designation to CRB-701, a Nectin-4–directed ADC for the potential treatment of adult patients with R/R metastatic cervical cancer.¹

CRB-701, a next-generation ADC, features a site-specific, cleavable linker; a homogenous,consistent drug-antibody ratio of 2, and a novel monoclonal antibody targeting Nectin-4.^1,2This agent was developed to address dose-limiting toxicities (DLTs) that are linked to the linker-payload system used in enfortumab vedotin-efjv (Padcev).²

Currently, a 3-part, phase 1/2 trial (NCT06265727) is evaluating the agent’s safety, pharmacokinetics (PK), and efficacy in patients with solid tumors that are known to be associated with high Nectin-4 expression. The trial is ongoing in the US and Europe. With enrollment in the dose-escalation portion of the study now complete, first data from this portion is expected to be released in early 2025.¹

Patients aged 18 years of age with advanced urothelial carcinoma or Nectin-4–positive advanced solid tumors are eligible for enrollment in the study if they have no uncontrolled diabetes, an ECOG performance status of 0-1, adequate organ function, and no active central nervous system metastases.^2,3

Concept of gynecologic cancer: © tom - stock.adobe.com

The dose-escalation phase of the study employs a Bayesian Optimal Interval design, incorporating accelerated titration at the initial dose level. Those included in the study are receiving 1 of 7 escalating doses of CRB-701 given via intravenous infusion every 3 days over a 21-day cycle. These doses range from 0.2 mg/kg to 4.5 mg/kg.

The primary end points include assessing the safety and tolerability of CRB-701 in part A evaluating the disease control rate (DCR) and objective response rate (ORR) in parts B and C. Secondary end points include PK, safety, and antitumor activity.

Patients enrolled in the dose-escalation phase represented 5 different tumor types, with ages ranging from 35 to 76 years. The majority were female (70.3%).³

Findings From the Phase 1 Trial of CRB-701

According to updated findings from the phase 1 portion of the study presented at the 2024 American Society of Clinical Oncology Annual Meeting, CRB-701 showed promising antitumor responses across multiple dose levels. The agent was also generally well tolerated.^3,4

At a data cutoff of May 2024, the agent induced responses across tumor types. Specifically at dose levels of 2.7 mg/kg or higher, the ORR was 40%. This included 6 partial responses (PRs) and 2 unconfirmed responses.⁴ The DCR in these patients was 73%.

Among those with metastatic urothelial cancer (n = 9), the ORR was 44%, and included 4 PRs and 1 unconfirmed response. The DCR was 78%. Those with cervical cancer (n = 7) had an ORR of 43%, including 3 PRs and 1 unconfirmed response, and the DCR was 86%.

As of the data cutoff, CRB-701 demonstrated its first confirmed case of 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. Early PK analysis revealed consistently lower levels of free monomethyl auristatin E across all dose levels compared with enfortumab vedotin.^3,4

In terms of safety, the dose-escalation phase primarily involved grade 1/2 adverse events (AEs), with no grade 4/5 AEs or DLTs reported to date.² The most common treatment-emergent AEs were anemia and eye-related events. One patient treated with the 2.7 mg/kg dose had a grade 3 rash lasting 8 days, which did not require dose modification or interruption. Further, there were 2 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.

One case of grade 1 peripheral neuropathy occurred alongside grade 3 hypokalemia, both resolving within 10 days after potassium replacement therapy. There were 2 grade 3 corneal disorders seen at the 2.7 mg/kg and 3.6 mg/kg dose levels, leading to the implementation of preventive eye care measures. No corneal events have been noted at the 4.5 mg/kg dose level. Over 50% of patients presented with corneal disorders or dry eye symptoms at baseline.⁴

The dose-escalation phase of the trial is progressing at the 4.5 mg/kg dose level, while dose expansion cohorts at the 2.7 mg/kg and 3.6 mg/kg levels are further evaluating pharmacology and safety.³

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 5, 2024. https://tinyurl.com/3r38fyyc

2. A phase 1/​2 study to investigate CRB-701 in solid tumors. ClinicalTrials.gov. Updated August 20, 2024. Accessed December 5, 2024. https://www.clinicaltrials.gov/study/NCT06265727?term=CRB-701&rank=1

3. 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

4. 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 5, 2024. https://tinyurl.com/38zppxxs