Investigational Drug
BT8009
TrialFetch AI Analysis
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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 3 active trials using this drug:
TrialFetch 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
TrialFetch 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
TrialFetch 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
