Urothelial carcinoma — bladder, ureteral, and upper-tract — accounts for roughly 80,000 new US diagnoses and 17,000 deaths per year. The treatment landscape shifted significantly between 2019 and 2023 with FDA approval of enfortumab vedotin (Padcev) — a Nectin-4-targeting antibody-drug conjugate — for advanced and frontline metastatic disease. Peptide-based programs are now competing for share against that ADC-based standard of care.
Bicycle Therapeutics' zelenectide pevedotin (BT8009) is the most-advanced peptide candidate in urothelial cancer. The drug targets the same Nectin-4 antigen as enfortumab vedotin but as a small bicyclic peptide-MMAE conjugate, which Bicycle argues gives a different tissue-distribution and toxicity profile. The Phase 2/3 Duravelo-2 trial is testing the drug plus pembrolizumab in first-line locally advanced or metastatic urothelial cancer, with interim data released at ASCO 2026 (May 21 embargo lift, Monday June 1 oral presentation). The Phase 1 Duravelo-1 expansion in cisplatin-ineligible 1L patients hit 65% ORR with the pembrolizumab combination.
Stories here cover Duravelo trial data, the broader Bicycle pipeline, ImPact Biotech's padeliporfin VTP in upper-tract disease, and the competitive context with enfortumab vedotin and other ADC programs. See #bicycle-therapeutics, #nectin-4, and #peptide-drug-conjugate for adjacent threads.
In the June 1 rapid oral session (Abstract 4516, Yohann Loriot), the dose-optimization stage of the randomized Phase 2 Duravelo-2 trial showed the optimal dose of the bicyclic peptide-drug conjugate zelenectide pevedotin (BT8009) plus pembrolizumab produced response rates comparable to published standard-of-care data in previously untreated locally advanced or metastatic urothelial carcinoma, with roughly four-fold lower skin reactions and about half the peripheral neuropathy. The separate Duravelo-1 Phase 1 trial showed median progression-free survival comparable to standard of care in cisplatin-ineligible patients.
Bicycle Therapeutics' formal post-ASCO 2026 press release Friday morning specified the headline Phase 2 numbers from yesterday's abstract release. In the Duravelo-2 combination cohort, the optimal zelenectide dose plus pembrolizumab 200 mg every three weeks produced 65% ORR (17/26 evaluable patients) regardless of confirmation, with 58% BICR-confirmed ORR (15/26) at the 27-week cutoff in previously untreated locally advanced or metastatic urothelial cancer. An additional confirmed BICR response observed after the cutoff would bring the rate to 62%. The trial tested two dose schedules: 5 mg/m² weekly and 6 mg/m² two-weeks-on-one-week-off; the optimal dose moves forward in the Phase 3 expansion. Treatment retention was high and dose-limiting adverse events limited. The 65% Phase 2 ORR matches the 65% Phase 1 Duravelo-1 ORR (13/20) — pharmacology consistency across two different patient populations, an unusual durability signal for a peptide-drug conjugate.
Bicycle Therapeutics released Duravelo-2 Phase 2/3 interim analysis data at ASCO 2026 — zelenectide pevedotin (BT8009, a Nectin-4-targeting bicyclic peptide-MMAE conjugate) plus pembrolizumab in previously untreated locally advanced or metastatic urothelial cancer. The full data presentation is scheduled for Monday June 1, 8:30-8:36 AM CT in the GU Cancers oral session (Abstract 4516). The Duravelo-1 monotherapy comparator anchor — 65% ORR (13/20) in cisplatin-ineligible 1L mUC at 5 mg/m² + pembrolizumab combination, with median DOR 11.1 months in the monotherapy expansion — sets the bar for what the Duravelo-2 combination interim must clear. Bicycle's five-abstract ASCO package includes the oral Duravelo-2 piece plus four posters covering Duravelo-1 monotherapy update, BT5528 EphA2 monotherapy and combination cohorts, and BT8009 second-line urothelial data.
Bicycle Therapeutics confirmed the Duravelo-2 oral abstract presentation slot at the ASCO 2026 Annual Meeting on Monday, June 1, 8:30–8:36 a.m. CT. The abstract reports interim analysis results from Duravelo-2, a Phase 2/3 trial of zelenectide pevedotin (BT8009) plus pembrolizumab as first-line treatment for previously untreated locally advanced or metastatic urothelial carcinoma. Zelenectide pevedotin is Bicycle's Nectin-4-targeting bicyclic peptide-drug conjugate, a separate program from the EphA2-targeting nuzefatide pevedotin (BT5528) covered earlier on this site. The Q1 2026 print (April 30) reaffirmed $559.5M cash and runway to 2030 supporting the Phase 3 expansion of the platform.
Bicycle's EphA2-targeting bicyclic peptide-drug conjugate nuzefatide pevedotin (BT8009) at 6.5 mg/m² Q2W plus nivolumab achieved 40% confirmed ORR (4/10) in metastatic urothelial patients who had progressed on checkpoint inhibitors, and 100% (3/3) in MMAE-naive EphA2+ patients. No Grade ≥3 treatment-related adverse events of clinical interest. Presented at AACR 2026 on April 20.