O Metzger Filho1, J P Leone1, T Li2, Z Tan-Wasielewski2, L Trippa2, W T Barry2, J Younger3, E Lawler1, L Walker4, R A Freedman1, S M Tolaney1, I Krop1, E P Winer1, N U Lin5. 1. Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA. 2. Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, USA. 3. Medical Oncology, Massachusetts General Hospital, Boston, USA. 4. Seattle Genetics, Seattle, USA. 5. Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA. Electronic address: nancy_lin@dfci.harvard.edu.
Abstract
BACKGROUND: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. PATIENTS AND METHODS: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). RESULTS: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.
BACKGROUND: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. PATIENTS AND METHODS: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). RESULTS: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.
Authors: Ariel Topletz-Erickson; Anthony Lee; Evelyn L Rustia; Hao Sun; JoAl G Mayor; Layth I Abdulrasool; Luke Walker; Christopher J Endres Journal: Clin Pharmacokinet Date: 2022-08-06 Impact factor: 5.577
Authors: Nancy U Lin; Virginia Borges; Carey Anders; Rashmi K Murthy; Elisavet Paplomata; Erika Hamilton; Sara Hurvitz; Sherene Loi; Alicia Okines; Vandana Abramson; Philippe L Bedard; Mafalda Oliveira; Volkmar Mueller; Amelia Zelnak; Michael P DiGiovanna; Thomas Bachelot; A Jo Chien; Ruth O'Regan; Andrew Wardley; Alison Conlin; David Cameron; Lisa Carey; Giuseppe Curigliano; Karen Gelmon; Sibylle Loibl; JoAl Mayor; Suzanne McGoldrick; Xuebei An; Eric P Winer Journal: J Clin Oncol Date: 2020-05-29 Impact factor: 44.544
Authors: Ali Alsalme; T Pooventhiran; Nabil Al-Zaqri; D Jagadeeswara Rao; Siriki Srinivasa Rao; Renjith Thomas Journal: J Mol Model Date: 2020-11-16 Impact factor: 1.810