(UroToday.com) The 2023 GU ASCO annual meeting included a trials in progress session for bladder cancer, featuring a presentation by Dr. Evan Yu discussing the trial design of the urothelial cancer cohort of SGNTUC-019, a phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations. Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor approved in multiple regions for HER2-positive metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other solid tumors:
In xenograft models of HER2-positive and HER2-mutated tumors, dual targeting of HER2 with tucatinib plus trastuzumab showed superior activity to either alone.1 Despite development of several new therapies for metastatic urothelial cancer, most patients are refractory to subsequent therapies and die from the disease, highlighting the need for additional therapeutic approaches. Given that 20%–30% of metastatic urothelial cancers have molecular alterations of the ErbB family, tucatinib plus trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, phase 2 study evaluating tucatinib plus trastuzumab in patients with previously treated solid tumors displaying HER2-positive or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic urothelial cancer.
Eligible patients in the urothelial cancer cohort must have HER2-positive locally advanced or metastatic disease, with progression during or after, or intolerance of, the most recent line of systemic therapy. Patients must have:
- An ECOG PS ≤1
- Adequate hepatic, hematologic, renal, and cardiac function
- No prior exposure to HER2-directed therapy
HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH or by HER2 amplification in prior or prescreening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification urothelial cancer cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. The trial design is as follows:
The primary objective is antitumor activity, with confirmed objective response rate as the primary endpoint and disease control rate, duration of response, PFS, and OS as secondary efficacy endpoints. Confidence intervals (CIs) will be calculated for confirmed objective response rate and disease control rate. For time-to-event endpoints, median survival time will be estimated by the Kaplan-Meier method, and the associated 95% CI will be calculated using complementary log-log transformation. Safety endpoints will be assessed using descriptive statistics. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1:
Disease assessments per RECIST 1.1 will occur every 6 weeks for 24 weeks, then every 12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2–6, with peak concentration sampled in Cycle 3. Quality of life will be evaluated every second cycle using the EQ-5D-5L. Dr. Yu concluded his presentation by highlighting that 75 sites are currently enrolling within the US, European Union, and Asia Pacific.
Presented by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA
Co-Authors: Fan Jin, Jorge Ramos, Qianwen Tan, Matt D. Galsky
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.
References:
- Kulukian A, Lee P, Taylor J, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020 Apr;19(4):976-987.