zelenectide pevedotin (BT8009) / Bicycle Therap - LARVOL DELTA

Phase I/II study (Duravelo-1) of zelenectide pevedotin, a Bicycle Toxin Conjugate: Additional cohort (B-8) in patients with advanced breast cancer (ESMO-BC 2025) - P1/2 | "Preliminary antitumor activity and a tolerable safety profile have been shown with zele in patients (pts) with solid tumors, including breast cancer (BC).Trial design: Duravelo-1 (NCT04561362; BT8009-100) is an ongoing, Phase I/II, open label, dose escalation and dose expansion study of zele monotherapy, and in combination with pembrolizumab, in adults with solid tumors associated with Nectin-4 expression. Exploratory endpoints include baseline tumor and peripheral biomarker analyses and ORR by biomarker status. Cohort B-8 opened to enrollment in November 2024 and is actively recruiting."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

A phase 2/3 study of bicycle toxin conjugate zelenectide pevedotin (BT8009) targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC; Duravelo-2). (ASCO 2025) - P2/3 | "Clinical Trial Registration Number: NCT06225596 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • P2/3 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

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 | "Clinical Trial Registration Number: NCT04561362 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • P1/2 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • NECTIN4

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

New P2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Evaluation of an additional cohort of patients with non-small cell lung cancer (NSCLC) in the phase I/II duravelo-1 study of zelenectide pevedotin (BT8009), a bicycle toxin conjugate (ELCC 2025) - P1/2, P2/3 | "Zele has shown promising antitumor activity and a generallywell tolerated safety profile in previously treated, enfortumab vedotin naïve patients with metastatic urothelial carcinoma (mUC) (Reig, 2024), and is currently being investigated as monotherapy and in combination with pembrolizumab in patients with mUC (Duravelo-2 [BT8009–230; NCT06225596]). Secondary endpoints are antitumor activity including ORR, DOR, CBR, PFS and OS by Investigator assessed response, (RECIST v1.1), PK, and incidence of anti-drug antibody development. Cohort B9 opened to enrollment November 2024, and is currently recruiting patients."

Clinical • P1/2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KRAS

Enhanced anti-tumor activity of zelenectide pevedotin in patients (pts) with non-small cell lung cancer (NSCLC) with NECTIN4 gene amplification (amp) (ELCC 2025) - P1/2 | "NECTIN4 amp has been shown to be a predictive biomarker for response to enfortumab vedotin in metastatic urothelial cancer (Klümper et al., 2024), and this post-hoc analysis assesses the utility of NECTIN4 amp as a predictor of zele response in NSCLC pts. Zele is being evaluated in the ongoing Ph 1/2 study BT8009-100/Duravelo-1 (NCT04561362) for safety and efficacy in pts with advanced solid tumors associated with Nectin-4 expression. NECTIN4 amplification appears to showpredictive clinical utility in identifying NSCLC pts with enhanced response to zelenectide pevedotin, with an ORR of 40.0% in NECTIN4 amp NSCLC pts. Further exploration of zele and NECTIN4 amp stratification strategies in NSCLC pts is warranted."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NECTIN4

Study to Assess Clinical Activity of Zelenectide Pevedotin in Participants With Advanced Breast Cancer (clinicaltrials.gov) - P2 | N=66 | Recruiting | Sponsor: BicycleTx Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Bicycle Therapeutics Announces Updated Topline Zelenectide Pevedotin Data… (Businesswire) - P1/2 | N=329 | Duravelo-1 (NCT04561362) | Sponsor: BicycleTx Limited | "As of Jan. 3, 2025, updated topline results from the ongoing Phase 1 Duravelo-1 trial evaluating zelenectide pevedotin 5 mg/m2 weekly plus pembrolizumab 200 mg once every three weeks in 22 first-line cisplatin-ineligible patients with mUC showed: 65% overall response rate (ORR) (13/20) among all efficacy-evaluable patients, and a 50% ORR (10/20) among patients with confirmed responses. Of the 3 unconfirmed responses, 1 patient remained on treatment at the time of the data cut. Median duration of response (mDOR) is not yet mature, with 12 patients still on treatment at the time of the data cut."

P1 data • Urothelial Cancer

Bicycle Therapeutics Reports Recent Business Progress and Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Updated topline Phase 1 combination data for zelenectide pevedotin plus pembrolizumab continue to show promising anti-tumor activity and a differentiated safety profile in first-line metastatic urothelial cancer; Duravelo-2 dose selection data expected in 2H 2025...The company plans to initiate several additional Phase 1/2 trials evaluating zelenectide pevedotin in NECTIN4 gene-amplified cancer, including breast cancer (Duravelo-3) in 1H 2025 and lung cancer (Duravelo-4) and multi-tumor (Duravelo-5) in 2H 2025....Bicycle Therapeutics continues to advance its emerging BRC pipeline, with additional MT1-MMP human imaging data anticipated in mid-2025 and initial EphA2 human imaging data expected in 2H 2025. The company is targeting clinical trials for its first radiotherapeutic program to begin in 2026."

Clinical data • New P1/2 trial • New trial • P2/3 data • Breast Cancer • Lung Cancer • Urothelial Cancer

Study to Assess Clinical Activity of Zelenectide Pevedotin in Participants With Advanced Breast Cancer (clinicaltrials.gov) - P2 | N=66 | Not yet recruiting | Sponsor: BicycleTx Limited

New P2 trial • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

A phase 2/3 study of bicycle toxin conjugate zelenectide pevedotin (BT8009) targeting Nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC) (Duravelo-2). (ASCO-GU 2025) - P1/2, P2/3 | "Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy...Cohort 1 will be randomized 1:1:1 to receive: 1) zele 5 mg/m2 on days [D]1, 8, and 15 + pembro 200 mg on D1; 2) zele 6 mg/m2 on D1 and 8 + pembro 200 mg on D1; or 3) chemotherapy (gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance in appropriate patients)...Efficacy endpoints will be assessed per RECIST v1.1. This study is actively recruiting."

Clinical • Metastases • P2/3 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

The validation and clinical bioanalysis of the Bicycle® Toxin Conjugate zelenectide pevedotin in human plasma. (PubMed, Bioanalysis) - P1/2 | "The Bicycle® toxin conjugate (BTC) zelenectide pevedotin, formerly known as BT8009, is a novel bicyclic peptide targeting the Nectin-4 tumor antigen conjugated to the cytotoxin monomethyl auristatin E (MMAE) via a valine-citrulline cleavable linker...The method was validated according to local standard operating procedures and has met all US Food and Drug Administration and European Medicines Agency regulatory guidance criteria. A bioanalytical method for measuring zelenectide pevedotin in plasma samples was developed and successfully applied in evaluating over 3000 samples from patients in a Phase 1/2 clinical study of zelenectide pevedotin in patients with advanced solid tumors."

Journal • Oncology • Solid Tumor • NECTIN4

Bicycle Therapeutics…Highlights 2025 Strategic Priorities and Milestones (Businesswire) - "Seek to transform treatment across multiple Nectin-4 associated cancers with zelenectide pevedotin: Report additional Phase 1 Duravelo-1 combination data with pembrolizumab in first-line cisplatin-ineligible mUC in 2H 2025. Report longer-term follow-up Phase 1 Duravelo-1 monotherapy data in late-line mUC in 2H 2025. Report Phase 2/3 Duravelo-2 Cohort 1 and Cohort 2 dose selection data in 2H 2025. Initiate Phase 1 trials in NECTIN4 gene-amplified breast cancer (Duravelo-3) in 1H 2025 and NECTIN4 gene-amplified lung cancer (Duravelo-4) and multi-tumor (Duravelo-5) in 2H 2025."

New P1 trial • P1 data • P2/3 data • Breast Cancer • Lung Cancer • Urothelial Cancer

@BGarmezy, of @SarahCannonDocs, discusses the phase 1/2 Duravelo-1 trial investigating zelenectide pevedotin in patients with metastatic urothelial #carcinoma. Watch more here: https://onclive.com/view/dr-garmezy-on-findings-from-the-duravelo-1-trial-in-metastatic-urothelial-carcinoma

Dr Garmezy on the Rationale for Developing Zelenectide Pevedotin in Urothelial Cancer (OncLive) - "Benjamin Garmezy, MD, discusses the rationale for developing zelenectide pevedotin in metastatic urothelial carcinoma."

Video

Topline Zelenectide Pevedotin Plus Pembrolizumab Combination Data in First-line mUC Highlights (Businesswire) - P1/2 | N=329 | Duravelo-1 (NCT04561362) | Sponsor: BicycleTx Limited | "Topline results from the ongoing Phase 1/2 Duravelo-1 trial evaluating zelenectide pevedotin 5 mg/m2 weekly plus pembrolizumab 200 mg once every three weeks in 22 first-line cisplatin-ineligible patients with mUC showed: 60% overall response rate (ORR) (12/20) among efficacy-evaluable patients. Of the responses, 5 were confirmed and 7 were unconfirmed at the time of the data cut. Fifteen patients remained on treatment at the time of the data cut. Safety and tolerability profile was broadly consistent with late-line Duravelo-1 monotherapy and combination cohorts....More detailed data from this study will be presented at a future medical meeting; Bicycle Therapeutics is currently conducting the Phase 2/3 Duravelo-2 trial...The company plans to report dose selection and topline data for both cohorts in the second half of 2025."

P1/2 data • P2/3 data • Urothelial Cancer

Topline Zelenectide Pevedotin Monotherapy Data in NSCLC Patients with NECTIN4 Gene Amplification Highlights (Businesswire) - P1/2 | N=329 | Duravelo-1 (NCT04561362) | Sponsor: BicycleTx Limited | "The company conducted a post-hoc analysis of 40 pretreated patients with NSCLC enrolled in Duravelo-1. The majority of patients received zelenectide pevedotin 5 mg/m2 weekly. Of the 40 patients enrolled, 34 patients were efficacy evaluable. Additionally, 19 patient samples were available for NECTIN4 testing, of which 6 demonstrated NECTIN4 gene amplification. Five out of 6 patients with NECTIN4 gene amplification were efficacy evaluable. Results showed: 40.0% ORR (2/5) among patients with NECTIN4 gene amplification, compared to 8.8% ORR (3/34) among all efficacy-evaluable patients. Of the 3 partial responses, 2 were confirmed and 1 was unconfirmed. Out of 19 patients tested for NECTIN4 gene amplification, none of the non-amplified patients responded....More detailed data from this study will be presented at a future medical meeting."

P1/2 data • Non Small Cell Lung Cancer

Overview of Development Strategy Leveraging NECTIN4 Gene Amplification (Businesswire) - "Bicycle Therapeutics plans to advance development of zelenectide pevedotin in broader indications outside of mUC utilizing a NECTIN4 gene amplification strategy to target patients who have the potential for significantly deeper responses. Over the course of 2025, Bicycle Therapeutics plans to initiate several additional Phase 1/2 trials to assess zelenectide pevedotin in NECTIN4 gene-amplified breast cancer, lung cancer and multiple other cancers."

New P1/2 trial • Breast Cancer • Non Small Cell Lung Cancer

Zelenectide Pevedotin Monotherapy Data in Breast Cancer Patients with NECTIN4 Gene Amplification Highlights (Presented at 2024 SABCS) (Businesswire) - P1/2 | N=329 | Duravelo-1 (NCT04561362) | Sponsor: BicycleTx Limited | "The company conducted a post-hoc analysis of 38 heavily pretreated breast cancer patients enrolled in Duravelo-1....Of the 38 breast cancer patients enrolled, 35 patients were efficacy evaluable.....62.5% ORR (5/8) among breast cancer patients with NECTIN4 gene amplification or polysomy, compared to 14.3% ORR (5/35) among all efficacy-evaluable breast cancer patients. Of the 5 partial responses, 4 were confirmed and 1 was unconfirmed....Of the 32 TNBC patients enrolled, 30 patients were efficacy evaluable. Additionally, 19 TNBC patient samples were available for NECTIN4 testing, of which 7 demonstrated NECTIN4 gene amplification or harbored a NECTIN4 polysomy. Results showed: 57.1% ORR (4/7) among TNBC patients with NECTIN4 gene amplification or polysomy, compared to 13.3% ORR (4/30) among all efficacy-evaluable TNBC patients. Of the 4 partial responses, 3 were confirmed and 1 was unconfirmed."

P1/2 data • Triple Negative Breast Cancer

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

Bicycle Therapeutics to Present Data for Zelenectide Pevedotin at 2024 San Antonio Breast Cancer Symposium and Provide Program Update (Businesswire) - "Bicycle Therapeutics...announced that the company will present data showing the enhanced anti-tumor activity of zelenectide pevedotin monotherapy in triple-negative breast cancer (TNBC) patients with NECTIN4 gene amplification at the 2024 San Antonio Breast Cancer Symposium (SABCS)....Bicycle Therapeutics will also announce topline combination data for zelenectide pevedotin plus pembrolizumab in previously untreated (first-line) cisplatin-ineligible patients with metastatic urothelial cancer, and topline monotherapy data for zelenectide pevedotin in non-small cell lung cancer patients with NECTIN4 gene amplification. The company will host a conference call and webcast for analysts and investors to review the updated data for zelenectide pevedotin."

P1/2 data • Non Small Cell Lung Cancer • Triple Negative Breast Cancer • Urothelial Cancer

Dr Garmezy on Findings From the Duravelo-1 Trial in Metastatic Urothelial Carcinoma (OncLive) - "Benjamin Garmezy, MD, discusses the phase 1/2 Duravelo-1 trial investigating zelenectide pevedotin in patients with metastatic urothelial carcinoma....These findings beg the question of how to further advance the development of zelenectidepevedotin, particularly given the availability of enfortumabvedotin in bladder cancer, Garmezy emphasizes. Both agents target Nectin-4 and have an MMAE payload. One key factor in this research will be to evaluate the adverse effect profiles of both agents, he notes. Not all patients are optimal candidates for enfortumabvedotin, especially those who experience neuropathy, he explains. Therefore, zelenectidepevedotin may be an alternative therapy for these patients, he states."

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Effects of Nectin-4 targeted Bicycle Toxin Conjugate, zelenectide pevedotin (BT8009), and enfortumab vedotin on a human corneal tissue model (EORTC-NCI-AACR 2024) - P1/2, P2/3 | "Notably, in the ongoing Phase I/II Duravelo-1 clinical study, we have observed ocular disorders in 7% of patients treated with zele at 5 mg/m2 QW (n=149). The low incidence of ocular disorders in zele-treated patients is recapitulated in the EpiCorneal model data, which could be explained by rapid BTC molecule clearance limiting Nectin-4 on-target toxicity in the cornea."

Oncology • NECTIN4

BT8009 monotherapy in enfortumab vedotin (EV)-naïve patients (pts) with metastatic urothelial carcinoma (mUC): Updated results of Duravelo-1 (ESMO 2024) - P1/2, P2/3 | "The ongoing phase 1/2 study (NCT04561362) is evaluating BT8009 ± pembrolizumab in pts with advanced solid tumors associated with Nectin-4 expression. This ongoing study of BT8009 monotherapy at 5 mg/m2 QW shows a promising response profile and a generally well-tolerated safety profile in pts with mUC. A phase 2/3 study (NCT06225596; Duravelo-2) is currently enrolling. Table: 652P *Contains data from dose escalation and dose expansion phases."

Clinical • IO biomarker • Metastases • Monotherapy • Oncology • Solid Tumor • Urothelial Cancer

Duravelo-1: Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=329 | Recruiting | Sponsor: BicycleTx Limited | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Metastases • Trial completion date • Trial primary completion date • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • ALK • ER • HER-2 • NECTIN4 • PGR • ROS1