BT8009 Receives Fast Track Designation for Advanced Urothelial Cancer


A Nectin-4–directed drug received FDA Fast Track Designation based on preclinical and clinical data showing potential efficacy and safety in patients with locally advanced or metastatic urothelial cancer.

BT8009, a Bicycle Toxin Conjugate (BTC), received Fast Track Designation (FTD) as monotherapy for adults with previously treated locally advanced or metastatic urothelial carcinoma, according to the drug’s developer Bicycle Therapeutics.1

The Nectin-4–targeted agent has shown antitumor activity and was well tolerated in preclinical studies. It also demonstrated clinical activity in the phase 1/2 BT8009-100 trial (NCT04561362) for advanced solid tumors including urothelial cancer and other disease types.2

“FTD represents another positive step in the development of BT8009 and reflects the pressing need for a clinically meaningful, differentiated therapy compared to what is available for patients.” Kevin Lee, PhD, MBA, the CEO of Bicycle Therapeutics, said in a statement.1

Nectin-4 is a protein that is overexpressed in on the cell surface of multiple tumor types including urothelial carcinoma but is otherwise uncommon in healthy adults. The antibody-drug conjugate (ADC) enfortumab vedotin (Padcev), which also targets Nectin-4, has been approved for use in patients with previously treated metastatic urothelial cancer following the phase 3 EV-301 trial (NCT03474107).3

ADCs combine an antibody with a cytotoxic payload, but their large molecular size can result in poor tumor penetration.4 BTCs, which use a bicyclic peptide conjugated to a toxin with a cleavable linkage, have a significantly smaller molecular size. Investigators hypothesized that a higher dose of BTCs with a reduced toxic payload in each would lead to better tumor penetration than ADCs.

BT8009 consists of a Nectin-4-binding bicyclic peptide, a cleavable linker system, and the cell penetrant toxin mono-methylauristatin E (MMAE). When used in xenograft models, BT8009 showed tumor regression and penetration by MMAE that lasted after the BTC was cleared from systemic circulation.

The ongoing BT8009-100 trial is evaluating safety and tolerability of BT8009 given weekly and every other week, as monotherapy and in combination with the anti­–PD-L1 agent pembrolizumab (Keytruda) every 3 weeks. The tumor types in the trial include urothelial, breast, ovarian, lung, and other solid tumors. Patients in this trial must have exhausted available standard of care treatment for their cancer.

As of September 2022, the phase 1 dose escalation cohorts of the trial consisting of 49 patients are completed and results will be presented at a conference in the first half of 2023.2 Results of the phase 1 portion were consistent with preclinical data and included clinical responses in patients with urothelial cancer. Additionally, 1 patient with non–small cell lung cancer who had received 4 prior lines of therapy had a confirmed RECIST partial response and was continuing to receive BT8009 after 7 cycles. The phase 2 dose expansion cohorts have begun enrolling patients to receive the recommended phase 2 doses of 5 mg/m2 weekly and 7.5 mg/m2 given once a week in the first 2 weeks of a 21-day cycle.

The company also stated that it plans to initiate a phase 2 trial of BT8009 for patients with untreated cisplatin-ineligible urothelial cancer in combination with an immune checkpoint inhibitor.2 This trial would start in 2023 and enroll over 100 patients.

A FTD is intended to enable faster development and review of drugs that fill unmet needs in disease settings that lack treatment options. The drug may qualify for accelerated approval and priority review from the FDA.1

“We believe this designation is a valuable component of our future clinical and regulatory strategy as we work to align with the FDA to address the pressing unmet needs of people living with urothelial cancer,” Lee stated in a press release.


1. Bicycle Therapeutics announces FDA fast track designation granted to BT8009 for the treatment of adult patients with previously treated locally advanced or metastatic urothelial cancer. Bicycle Therapeutics. January 4, 2023. Accessed January 5, 2023.

2. Bicycle Therapeutics announces first patient dosed in BT8009 Phase II expansion cohorts and provides program update. Bicycle Therapeutics. November 8, 2022. Accessed January 5, 2023.

3. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed January 5, 2023.

4. Rigby M, Bennett G, Chen L, et al. BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors. Mol Cancer Ther. 2022;21(12):1747-1756. doi:10.1158/1535-7163.MCT-21-0875

Related Videos
Related Content