Investigational Drug
BT8009
HealthScout AI Analysis
Show HealthScout AI Analysis
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
Active trials using BT8009
Found 4 active trials using this drug:
HealthScout AI summary: Adults with advanced/metastatic NSCLC harboring centrally confirmed NECTIN4 gene amplification (non-squamous and squamous cohorts), previously treated with up to 3 prior lines (including prior platinum/IO or appropriate targeted therapy for actionable drivers), receive zelenectide pevedotin (BT8009) monotherapy. BT8009 is a Nectin-4–targeted Bicycle Toxin Conjugate delivering MMAE; key exclusions include prior MMAE, active/untreated CNS mets, significant ocular disease, and active ILD/pneumonitis.
ClinicalTrials.gov ID: NCT06933329
HealthScout AI summary: This trial enrolls adults with measurable, recurrent, unresectable, or metastatic NECTIN4-amplified breast cancer (either HR+/HER2-negative or triple-negative) who have received up to three prior lines of therapy. All participants receive zelenectide pevedotin (BT8009), a NECTIN4-targeting Bicycle Toxin Conjugate delivering MMAE.
ClinicalTrials.gov ID: NCT06840483
HealthScout AI summary: Adults with unresectable locally advanced or metastatic urothelial carcinoma (bladder, ureter, renal pelvis, or urethra) are randomized to BT8009, a Nectin‑4–targeted Bicycle Toxin Conjugate delivering MMAE, as monotherapy (post‑platinum, no prior MMAE) or BT8009 plus pembrolizumab in the first-line setting, versus standard platinum-based chemotherapy with optional avelumab maintenance. Key cohorts include first-line, platinum-eligible patients and previously treated patients with progression after ≥1 systemic regimen.
ClinicalTrials.gov ID: NCT06225596
HealthScout AI summary: This trial assesses BT8009, a Bicycle Toxin Conjugate targeting Nectin-4, both as monotherapy and combined with pembrolizumab, in patients with advanced Nectin-4 expressing solid tumors such as urothelial carcinoma, breast, NSCLC, and ovarian cancers, who have progressed after prior treatment or lack standard therapy options. The study evaluates safety, pharmacokinetics, and preliminary efficacy, with previously reported promising response rates in treated urothelial cancer patients.
ClinicalTrials.gov ID: NCT04561362
