zelenectide pevedotin (BT8009) / Bicycle Therap - LARVOL DELTA

Interim analysis results from Duravelo-2: Zelenectide pevedotin (zele; BT8009) + pembrolizumab in patients (pts) with previously untreated locally advanced/metastatic urothelial carcinoma (la/mUC). (ASCO 2026) - P2 | "Pts in Co1 were randomized 1:1:1 to: zele 5 mg/m2 on Days [D]1/8/15 + pembro 200 mg on D1; or zele 6 mg/m2 on D1/8 + pembro 200 mg on D1; or gemcitabine + cisplatin/carboplatin ± avelumab on a 21-D cycle. Zele at 5 mg/m2 on D1/8/15 + pembro and 6 mg/m2 on D1/8 + pembro on a 21-D cycle demonstrate encouraging response rates and safety profiles with the potential to differentiate from ADCs in previously untx pts. The 6 mg/m2 D1/8 regimen demonstrated a more favorable benefit-risk profile to meet the need for safer and more tolerable treatments, with substantially reduced toxicity, better tolerability, improved potential for combinability, and enhanced convenience, leading to fewer discontinuations. Zele-related AECIs in pts with previously untx la/mUC treated with zele 6 mg/m2 on D1/8 + pembro (N=30)."

Clinical • Metastases • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Urothelial Cancer

First-in-Human, Phase I/II Dose Escalation and Expansion Study of Zelenectide Pevedotin in Patients With Advanced Solid Tumors: Results From Monotherapy Dose Escalation. (PubMed, J Clin Oncol) - P1/2 | "Zelenectide pevedotin monotherapy demonstrated a generally well-tolerated safety profile and preliminary efficacy, particularly in UC, supporting investigation of UC and non-UC populations in the expansion phase."

First-in-human • Journal • Monotherapy • P1/2 data • Fatigue • Hematological Disorders • Neutropenia • Oncology • Pain • Solid Tumor • Urothelial Cancer • NECTIN4

Phase 1/2 Duravelo-1 study: Preliminary results of nectin-4–targeting zelenectide pevedotin (BT8009) plus pembrolizumab in previously untreated, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. (ASCO 2025) - P1/2, P2/3 | "Zelenectide pevedotin (zele, previously BT8009) is a highly selective Bicycle Toxin Conjugate (BTC) targeting Nectin-4 and conjugated to MMAE, and has shown an objective response rate (ORR) of 45% and a generally tolerable safety profile as monotherapy in previously treated, enfortumab vedotin-naïve pts with mUC in the ongoing Phase 1/2 study (NCT04561362, Duravelo-1; Reig et al., 2024)... Zelenectide pevedotin + pembro shows promising anti-tumor activity as a first-line treatment in a cohort of cisplatin-ineligible pts with la/mUC including a large proportion of pts with PS = 2. The combination of zele + pembro was generally tolerable and broadly consistent with the existing safety profiles of each respective agent. No new safety signals were observed with the combination."

Clinical • Metastases • P1/2 data • Diabetes • Genito-urinary Cancer • Infectious Disease • Neutropenia • Oncology • Ophthalmology • Pain • Pneumonia • Respiratory Diseases • Solid Tumor • Urothelial Cancer • NECTIN4

BT8009-100 phase I/II study of novel bi-cyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies associated with nectin-4 expression (AACR 2022) - P1/2 | "Here, we describe the preliminary monotherapy dose escalation results of the ongoing multicenter Phase I/II clinical trial (NCT04561362) that assesses the safety and tolerability of BT8009 administration in patients with advanced solid tumors associated with Nectin-4 expression, not exposed to enfortumab vedotin. BT8009 exhibits a promising preliminary tolerability profile and preliminary antitumor activity. The molecule will continue to be explored in the current dose-escalation/dose-expansion study of BT8009 monotherapy and in combination with nivolumab."

Clinical • P1/2 data • Oncology • Solid Tumor • Urothelial Cancer • NECTIN4

Enhanced anti-tumor activity of zelenectide pevedotin in triple negative breast cancer (TNBC) patients (pts) with NECTIN4 gene amplification (amp) (SABCS 2024) - P1/2 | "Background: Zelenectide pevedotin (zele, formerly BT8009) is a highly selective Bicycle® Toxin Conjugate (BTC) comprised of a bicyclic peptide targeting Nectin-4 conjugated to monomethyl auristatin E. BTC® molecules have lower molecular weight and shorter plasma half-life than antibody-drug conjugates, with distinct pharmacokinetics/dynamics, i.e., potential for rapid tumor penetration and minimal healthy tissue exposure...All 3 NECTIN4 amp responders were previously treated with sacituzumab govitecan... NECTIN4 amplification appears to show predictive clinical utility in identifying pretreated TNBC pts with enhanced response to zelenectide pevedotin, with an ORR of 57.1% in NECTIN4 gene amp positive pts including polysomy versus an ORR of 13.3% in biomarker unselected TNBC. Despite the limited sample size, this post-hoc analysis underscores the promising anti-tumor activity of zelenectide pevedotin in pts with NECTIN4 amp TNBC, who continue to have..."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • NECTIN4

Interim analysis results from Duravelo-2: Zelenectide pevedotin (zele; BT8009) in patients (pts) with previously treated locally advanced/metastatic urothelial carcinoma (la/mUC). (ASCO 2026) - P2 | "Zele monotherapy at 5 mg/m2 on D1/8/15 and 6 mg/m2 on D1/8 on a 21-D cycle demonstrate encouraging response rates and safety profiles with the potential to differentiate from ADCs in previously treated pts. The 6 mg/m2 D1/8 regimen provides a more favorable benefit-risk profile to meet the need for safer and more tolerable treatments, with enhanced potential for combinability and convenience, leading to fewer discontinuations. Zele-related AECIs in pts with previously treated la/mUC treated with zele 6 mg/m2 on D1/8 (N=30)."

Clinical • Metastases • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Urothelial Cancer

NECTIN4 amplification (amp) as an actionable alteration in non-small cell lung cancer (NSCLC) (ESMO 2025) - P1/2, P2 | "Combined with the enhanced efficacy of zelenectide pevedotin in NECTIN4 -amp NSCLC in Duravelo-1, these findings support NECTIN4 amp as a promising predictive biomarker for precision oncology in NSCLC. Legal entity responsible for the study The authors."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • CTLA4 • ERBB3 • HER-2 • KRAS • NECTIN4 • PD-1

NECTIN4-amplified breast cancer targeted by Zelenectide Pevedotin: Amplification and expression are frequent, concordant, and stable (AACR 2026) - P1/2, P2 | "Nectin-4 can be effectively engaged by the BDC zelenectide pevedotin with high affinity. The frequency and stability of NECTIN4 amplification across breast cancer subtypes supports its evaluation as a biomarker for patient selection in Nectin-4-targeted trials."

Discordant • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • HER-2 • NECTIN4

Bicycle Continued Access Protocol (BiCAP) for Participants Receiving a Bicycle Investigational Product (clinicaltrials.gov) - P2 | N=16 | Not yet recruiting | Sponsor: BicycleTx Limited

New P2 trial • Oncology • Solid Tumor

Zelenectide pevedotin (BT8009) monotherapy in previously treated metastatic urothelial carcinoma (mUC): Update on Duravelo-1. (ASCO 2026) - P1/2, P2 | "Here, we present updated safety and efficacy results of zele monotherapy in enfortumab vedotin (EV)–naïve patients with mUC from the Phase 1/2 Duravelo-1 study (NCT04561362). Zele monotherapy at 5 mg/m2 once weekly continues to demonstrate an encouraging efficacy profile and a promising safety profile with the potential to differentiate from ADCs in EV-naïve patients with mUC. Antitumor activity was preserved in patients with exposure to taxanes. Treatment withdrawal resulting from zele-related AECIs was uncommon."

Metastases • Monotherapy • Diabetes • Oncology • Ophthalmology • Solid Tumor • Urothelial Cancer

Identifying optimized dosage for zelenectide pevedotin in locally advanced/metastatic urothelial carcinoma (la/mUC) using quantitative analyses. (ASCO 2026) - P1/2, P2 | "Zele is being evaluated in a randomized Phase 2/3 study at 2 dosages, 5 mg/m2 on Days (D)1/8/15 and 6 mg/m2 on D1/8 of a 21-D cycle, each as monotherapy or combined with pembrolizumab (P) in pts with la/mUC (NCT06225596, Duravelo-2) [Loriot, 2025]. 6 mg/m2 D1/8 was identified as the optimized zele dosage for monotherapy and in combination with P based on the overall benefit-risk informed by the comprehensive quantitative analyses."

Metastases • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Urothelial Cancer

Zelenectide Pevedotin Plus Pembrolizumab Shows Promise in First-Line Urothelial Carcinoma (Cancer Network) - "Yohann Loriot...presented the data at the 2026 ASCO Annual Meeting....As of the July 23, 2025 data cutoff, 30 patients were evaluable in each investigational arm, with a median follow-up of 7.0 months....Efficacy findings revealed strong antitumor activity in the optimized 6 mg/m² cohort (n = 26 evaluable), which achieved a confirmed ORR of 57.7% (95% CI, 36.9%-76.6%), including a 30.8% complete response (CR) rate and a 26.9% partial response (PR) rate. Stable disease was observed in 19.2% of patients, while 15.4% experienced progressive disease. By comparison, the 5 mg/m² cohort (n = 29 evaluable) achieved an ORR of 55.2% (95% CI, 35.7%-73.6%), with a 24.1% CR rate and a 31.0% PR rate."

P2/3 data • Urothelial Cancer

The journey of targeted drug conjugates in solid tumors: moving beyond antibody drug conjugates. (PubMed, Expert Opin Investig Drugs) - "We expect promising preclinical and clinical data emerging for SMDCs, PDCs, and BDC molecules will translate into approvals, such as BDC molecules that are under pivotal randomized phase II clinical investigation. These novel treatments will increase survival and quality of life for patients with solid tumors."

Journal • Review • Oncology • Solid Tumor

A phase 2 study of zelenectide pevedotin, a bicycle drug conjugate, in patients with NECTIN4 amplified advanced breast cancer (Duravelo-3) (ESMO 2025) - P1/2, P2 | "Pharmacokinetics, correlation of efficacy and safety with biomarkers of NECTIN4 amp, and measurement of antidrug antibody are additional exploratory endpoints. This study is actively recruiting."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • NECTIN4

Zelenectide pevedotin (BT8009) plus pembrolizumab in 1L cisplatin-ineligible locally advanced/metastatic urothelial carcinoma: Update on Duravelo-1 B7. (ASCO 2026) - P1/2, P2 | "Treatment with zele + pembro has promising clinical benefits in pts with la/mUC and a historically poor prognosis with first-line therapies (~50% ECOG PS of 2), including: mPFS of 13.0 months, 50% cORR, and mDOR not reached. Additionally, zele + pembro demonstrates a safety profile with the potential to differentiate from ADC combinations, including no skin-related serious AEs. These data support the Phase 2/3 study of zele as monotherapy and in combination with pembro versus chemotherapy in pts with la/mUC (NCT06225596; Duravelo-2)."

Metastases • Neutropenia • Oncology • Solid Tumor • Urothelial Cancer

Study BT8009-230 in Participants With Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2) (clinicaltrials.gov) - P2 | N=375 | Active, not recruiting | Sponsor: BicycleTx Limited | Phase classification: P2/3 ➔ P2 | N=956 ➔ 375 | Trial completion date: Dec 2030 ➔ Mar 2028 | Trial primary completion date: Dec 2030 ➔ Mar 2028

Enrollment change • Monotherapy • Phase classification • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

…Updated data from the Phase 1 trial (Duravelo-1) in previously untreated, cisplatin-ineligible mUC patients demonstrated encouraging median progression-free survival (PFS) comparable to published data for standard of care (SOC) (Businesswire) - "Updated results as of the August 1, 2025 data cutoff evaluating zelenectide in combination with pembrolizumab in previously untreated cisplatin-ineligible patients...showed: (i) 59% (13/22) ORR regardless of confirmation, 50% confirmed ORR (11/22), and a disease control rate (DCR) of 82%. Of the confirmed responses, 5 (23%) were CRs and 6 (27%) were PRs; (ii) Median PFS was 13.0 months and median duration of response (mDOR) was not mature at the time of the data cutoff. Updated results as of the August 1, 2025 data cutoff evaluating zelenectide as a monotherapy in EV-naïve recurrent, unresectable mUC patients...showed: (i) 38% (20/53) ORR regardless of confirmation, 32% confirmed ORR (17/53) and a DCR of 66%. Of the confirmed responses, 2 (4%) were CRs and 15 (28%) were PRs; (ii) Median PFS was 5.4 months and mDOR was 10.0 months (5.3-16.6) among patients with confirmed responses."

P1 data • Urothelial Cancer

Bicycle Therapeutics to Present Initial Duravelo-2 Data at 2026 ASCO Annual Meeting (Businesswire) - "Cohort 1 data were extracted for the interim analysis at Week 27, on July 23, 2025....At the time of the data cut, the median PFS was not mature, and the results at the optimal dose showed: (i) 65% (17/26) overall response rate (ORR) regardless of confirmation and blinded independent central review (BICR) confirmed ORR of 58% (15/26) at the 27-week cutoff....Cohort 2 data were extracted for the interim analysis at Week 27, on June 14, 2025....(i) 37% (10/27) ORR regardless of confirmation and 30% confirmed ORR (8/27) was achieved among efficacy-evaluable patients. Of the confirmed responses, 3 (11%) were complete responses (CRs) and 5 (19%) were partial responses (PRs); (ii) mDOT was 4.8 months (1.3-10.1)....Further data from the randomized Phase 2 trial are expected in 2H 2026."

P2 data • Urothelial Cancer

Study BT8009-230 in Participants With Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2) (clinicaltrials.gov) - P2/3 | N=956 | Active, not recruiting | Sponsor: BicycleTx Limited | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

As part of the reprioritization, Bicycle Therapeutics seeks to discontinue the Phase 1/2 Duravelo-3 trial for zelenectide in NECTIN4-amplified breast cancer and the Phase 1/2 Duravelo-4 trial for zelenectide in NECTIN4-amplified non-small cell lung cancer. (Bicycle Therapeutics Press Release) - "Enrollment for these trials is closed, and patients currently enrolled will complete their course of treatment."

Trial termination • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer • Triple Negative Breast Cancer

Promising Duravelo-2 data...provide a range of options for a Phase 3 trial and potential commercialization of zelenectide pevedotin (zelenectide) in mUC. (Bicycle Therapeutics Press Release) - "Initial dose selection data from the Duravelo-2 trial demonstrate response rates comparable to those published for existing standards of care, with physician assessed ORR of 65%, blinded independent central review (BICR) confirmed ORR of 58% at the 27-week cutoff and a differentiated safety profile. Subsequent to the 27-week cutoff, an additional confirmed BICR response was observed, which would result in an ORR of 62%. Zelenectide at 6mg/m2 two weeks on, one week off demonstrated a differentiated safety profile with only one patient discontinuing therapy due to a TRAE at the 27-week cutoff....Bicycle Therapeutics will present initial Duravelo-2 dose selection data at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 29-June 2 in Chicago. "

P3 data • Urothelial Cancer

While Bicycle Therapeutics evaluates preliminary regulatory feedback from the European Medicines Agency, U.S. Food and Drug Administration (FDA), and Medicines and Healthcare products Regulatory Agency, and the potential paths for this program, the company is converting the ongoing Duravelo-2 trial to a randomized Phase 2 trial and deprioritized the program for internal development. (Bicycle Therapeutics Press Release)

Pipeline update • Trial status • Urothelial Cancer

The future of urothelial carcinoma: a 2024-2025 update of early-phase trials of novel therapeutic agents. (PubMed, Curr Opin Urol) - "The findings indicate a shift towards more effective and tailored treatments. Future efforts must focus on biomarker validation, strategic sequencing, and managing combination toxicities to integrate these advances into practice and improve patient outcomes."

IO biomarker • Journal • Review • Oncology • Solid Tumor • Urothelial Cancer

Bicycle Therapeutics…announced an oral presentation and multiple poster presentations across five abstracts at the American Society of Clinical Oncology (ASCO) 2026 Annual Meeting (Businesswire)

Clinical data • Urothelial Cancer

Zelenectide Pevedotin in NECTIN4 Amplified Advanced or Metastatic Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=73 | Active, not recruiting | Sponsor: BicycleTx Limited | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • NECTIN4 • NTRK1 • NTRK2 • NTRK3 • ROS1