Bicycle Therapeutics (BCYC) has announced encouraging data updates for its investigational Bicycle Toxin Conjugate (BTC) zelenectide pevedotin, targeting Nectin-4. The data highlight the drug's potential in treating various cancers, particularly those with NECTIN4 gene amplification.
Combination Therapy in Metastatic Urothelial Cancer
In a Phase 1/2 Duravelo-1 trial, the combination of zelenectide pevedotin (5 mg/m2 weekly) and pembrolizumab (200 mg every three weeks) showed a 60% overall response rate (ORR) in first-line cisplatin-ineligible patients with metastatic urothelial cancer (mUC). Out of 20 efficacy-evaluable patients, 12 responded, with 5 confirmed and 7 unconfirmed responses at the data cutoff. The safety profile was consistent with previous data, with primarily low-grade adverse events.
Monotherapy in Breast Cancer with NECTIN4 Amplification
A post-hoc analysis of 38 heavily pretreated breast cancer patients from the Duravelo-1 trial revealed that those with NECTIN4 gene amplification or polysomy had a significantly higher response rate to zelenectide pevedotin monotherapy. Specifically, 62.5% (5/8) of patients with NECTIN4 gene amplification or polysomy achieved an ORR, compared to only 14.3% (5/35) in the overall breast cancer cohort. Notably, all three triple-negative breast cancer (TNBC) patients with NECTIN4 gene amplification who responded had prior treatment with sacituzumab govitecan.
Professor Sherene Loi, M.D., Ph.D., from the Peter MacCallum Cancer Centre, commented, "Although the sample size was limited, this post-hoc analysis highlights the encouraging anti-tumor activity of zelenectide pevedotin in breast cancer patients with NECTIN4 gene amplification, particularly among those with TNBC who urgently need new treatment options."
Monotherapy in NSCLC with NECTIN4 Amplification
In a similar post-hoc analysis of 40 pretreated non-small cell lung cancer (NSCLC) patients, 40.0% (2/5) with NECTIN4 gene amplification responded to zelenectide pevedotin monotherapy, compared to 8.8% (3/34) in the overall NSCLC cohort. None of the non-amplified patients responded, further suggesting NECTIN4 gene amplification as a predictive biomarker.
Future Development Strategy
Bicycle Therapeutics plans to leverage NECTIN4 gene amplification as a key strategy for further development of zelenectide pevedotin. The company intends to initiate Phase 1/2 trials in 2025, evaluating the drug in NECTIN4 gene-amplified breast cancer, lung cancer, and other solid tumors. This approach aims to target patients most likely to benefit from the therapy and potentially expand its use beyond bladder cancer.
Kevin Lee, Ph.D., CEO of Bicycle Therapeutics, stated, "By leveraging NECTIN4 gene amplification, we expect to be able to identify the patients who may most benefit from zelenectide pevedotin and accelerate development for solid tumor indications beyond bladder cancer."
