K Kalinsky1, J R Diamond2, L T Vahdat3, S M Tolaney4, D Juric5, J O'Shaughnessy6, R L Moroose7, I A Mayer8, V G Abramson8, D M Goldenberg9, R M Sharkey9, P Maliakal9, Q Hong9, T Goswami9, W A Wegener9, A Bardia5. 1. Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center-Herbert Irving Comprehensive Cancer Center, New York, USA. Electronic address: kk2693@cumc.columbia.edu. 2. Department of Medicine, Medical Oncology, University of Colorado Cancer Center, Aurora, USA. 3. Department of Medicine, Weill Cornell Medical College, New York, USA. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. 5. Department of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA. 6. Department of Medical Oncology, Texas Oncology, Baylor University Medical Center, US Oncology, Dallas, USA. 7. Department of Hematology/Oncology, Orlando Health UF Health Cancer Center, Orlando, USA. 8. Department of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, USA. 9. Clinical Development, Immunomedics, Inc., Morris Plains, USA.
Abstract
BACKGROUND: Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody-drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. PATIENTS AND METHODS: We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2-) HR+/HER2- mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%-45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7-12.7), median PFS was 5.5 months (95% CI 3.6-7.6), and median OS was 12 months (95% CI 9.0-18.2). CONCLUSIONS: SG shows encouraging activity in patients with pretreated HR+/HER2- mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). TRIAL REGISTRATION: ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552.
BACKGROUND: Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody-drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. PATIENTS AND METHODS: We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2-) HR+/HER2- mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%-45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7-12.7), median PFS was 5.5 months (95% CI 3.6-7.6), and median OS was 12 months (95% CI 9.0-18.2). CONCLUSIONS: SG shows encouraging activity in patients with pretreated HR+/HER2- mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). TRIAL REGISTRATION: ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552.
Authors: James T Coates; Sheng Sun; Ignaty Leshchiner; Nayana Thimmiah; Elizabeth E Martin; Daniel McLoughlin; Brian P Danysh; Kara Slowik; Raquel A Jacobs; Kahn Rhrissorrakrai; Filippo Utro; Chaya Levovitz; Elyssa Denault; Charlotte S Walmsley; Avinash Kambadakone; James R Stone; Steven J Isakoff; Laxmi Parida; Dejan Juric; Gad Getz; Aditya Bardia; Leif W Ellisen Journal: Cancer Discov Date: 2021-08-17 Impact factor: 39.397
Authors: Milan Radovich; Jeffrey P Solzak; Chao J Wang; Bradley A Hancock; Sunil Badve; Sandra K Althouse; Steven M Bray; Anna Maria V Storniolo; Tarah J Ballinger; Bryan P Schneider; Kathy D Miller Journal: Clin Cancer Res Date: 2022-08-02 Impact factor: 13.801