BT8009

Overview

Zelenectide pevedotin (BT8009; BCY8245) is an investigational Bicycle Toxin Conjugate targeting Nectin‑4, a cell-adhesion molecule overexpressed in several epithelial cancers, notably urothelial carcinoma. Early-phase clinical data show antitumor activity as monotherapy in metastatic urothelial cancer (mUC) pretreated with platinum and PD‑(L)1 therapy and in combination with pembrolizumab in cisplatin‑ineligible, treatment‑naive mUC. A randomized phase 2/3 program (Duravelo‑2) is ongoing. (aacrjournals.org)

Mechanism of action

• Drug class: Bicycle Toxin Conjugate (a small, fully synthetic bicyclic peptide conjugated to a cytotoxin). (aacrjournals.org)
• Target: Nectin‑4. (aacrjournals.org)
• Payload/linker: monomethyl auristatin E (MMAE) coupled via a protease‑cleavable valine‑citrulline–PABC linker. The design enables payload release in the tumor microenvironment and may not require cellular internalization, supporting bystander killing. (aacrjournals.org)
• Pharmacology (preclinical): short plasma half‑life, low circulating free MMAE, and robust tumor regression in Nectin‑4–expressing xenografts. (aacrjournals.org)

Clinical development

• First‑in‑human phase 1/2 trial (Duravelo‑1; NCT04561362) evaluated monotherapy and combinations; the recommended phase 2 dose (RP2D) for monotherapy is 5 mg/m² weekly. (mycancergenome.org)
• A global randomized, adaptive phase 2/3 trial in mUC (Duravelo‑2; NCT06225596) is enrolling to study zelenectide pevedotin as monotherapy and with pembrolizumab versus chemotherapy. (ascopubs.org)

Efficacy

Monotherapy (EV‑naive, previously treated mUC; RP2D 5 mg/m² weekly)
- ESMO 2024 update (Duravelo‑1): among 38 efficacy‑evaluable patients, ORR 45% (1 CR, 16 PR; 13 confirmed), disease control included durable stable disease ≥16 weeks in 9 patients; median duration of response 11.1 months (95% CI 3.9, not reached). (oncologypro.esmo.org)

Combination with pembrolizumab (first‑line, cisplatin‑ineligible mUC)
- ASCO 2025 presentation/topline update (Duravelo‑1): among 20 efficacy‑evaluable patients, ORR 65% with 25% CR; confirmed responses in 50% (10/20); median DOR not yet mature at the January 3, 2025 cutoff. (onclive.com)

Note: These are early, non-comparative cohorts; confirmatory randomized data are pending from Duravelo‑2. (ascopubs.org)

Safety

Monotherapy at RP2D in EV‑naive mUC (N=45):
- Any‑grade treatment‑emergent AEs 93%; grade ≥3 TEAEs 53%. Common treatment‑related AEs (≥15%): nausea (33%), asthenia (22%), fatigue (20%), pyrexia (20%), diarrhea (18%), appetite decreased (16%), alopecia (16%). Notably, no grade ≥3 treatment‑related neuropathy, skin reactions, or eye disorders were reported. Dose reductions 27%; interruptions 53%; discontinuations 4%. (oncologypro.esmo.org)

Phase 1 dose‑escalation experience across tumor types:
- Generally gastrointestinal AEs and fatigue predominated; low incidence of skin/ocular events and peripheral neuropathy relative to antibody‑drug conjugates; most common grade ≥3 TRAE was neutropenia (14% across all doses), with serious drug‑related AEs in 6% and none in the 5 mg/m² cohort. (investors.bicycletherapeutics.com)

Combination with pembrolizumab (first‑line cisplatin‑ineligible mUC):
- Topline update described a safety/tolerability profile consistent with monotherapy; peripheral neuropathy, skin reactions, and eye disorders were primarily low grade; grade 3 TRAEs of clinical interest were reversible; no grade 4–5 TRAEs reported. (biospace.com)

Further reading

• Preclinical MOA and pharmacology (Molecular Cancer Therapeutics, 2022). (aacrjournals.org)
• Medicinal chemistry/discovery (Journal of Medicinal Chemistry, 2022). (pubs.acs.org)
• Duravelo‑1 monotherapy update in EV‑naive mUC (ESMO 2024 abstract 652P). (oncologypro.esmo.org)
• Duravelo‑1 combo with pembrolizumab in 1L cisplatin‑ineligible mUC (ASCO 2025 coverage/topline update). (onclive.com)
• Duravelo‑2 randomized phase 2/3 trial overview (ASCO 2024 TPS4619). (ascopubs.org)

ClinicalTrials.gov entries
- Duravelo‑1 (NCT04561362). (mycancergenome.org)
- Duravelo‑2 (NCT06225596). (yalemedicine.org)

Abbreviations: ADC, antibody‑drug conjugate; AE, adverse event; CR, complete response; DOR, duration of response; EV, enfortumab vedotin; mUC, metastatic urothelial carcinoma; ORR, objective response rate; PR, partial response; RP2D, recommended phase 2 dose; TEAE/TRAE, treatment‑emergent/treatment‑related adverse event.

Last updated: Oct 2025