C H Barcenas1, S A Hurvitz2, J A Di Palma3, R Bose4, A J Chien5, N Iannotti6, G Marx7, A Brufsky8, A Litvak9, E Ibrahim10, R H Alvarez11, M Ruiz-Borrego12, N Chan13, Y Manalo14, A Kellum15, M Trudeau16, M Thirlwell17, J Garcia Saenz18, D Hunt19, R Bryce19, L McCulloch19, H S Rugo5, D Tripathy20, A Chan21. 1. The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: chbarcenas@mdanderson.org. 2. University of California Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, USA. 3. University of South Alabama College of Medicine, Mobile, USA. 4. Washington University School of Medicine, St Louis, USA. 5. University of California San Francisco Comprehensive Cancer Center, San Francisco, USA. 6. Hematology Oncology Associates of the Treasure Coast, Port St. Lucie, USA. 7. Adventist Health Care, Wahroonga, Australia. 8. Magee-Womens Hospital of UPMC, Pittsburgh, USA. 9. Saint Barnabas Medical Center, Livingston, USA. 10. Redlands Community Hospital, Redlands, USA. 11. Southeastern Regional Medical Center, Inc., Newnan, USA. 12. Hospital Universitario Virgen del Rocio, Sevilla, Spain. 13. Rutger Cancer Institute of New Jersey, New Brunswick, USA. 14. Coastal Bend Cancer Center, Corpus Christi, USA. 15. North Mississippi Medical Center Hematology and Oncology Clinic, Tupelo, USA. 16. Sunnybrook Research Institute, Toronto, Canada. 17. McGill University Health Centre, Montreal, Canada. 18. Hospital Clínico San Carlos, Madrid, Spain. 19. Puma Biotechnology Inc., Los Angeles, USA. 20. The University of Texas MD Anderson Cancer Center, Houston, USA. 21. Breast Cancer Research Centre-WA & Curtin University, Perth, WA, Australia.
Abstract
BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.
BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.
Authors: Ilana Schlam; Paolo Tarantino; Stefania Morganti; Filipa Lynce; Dario Trapani; Erica L Mayer; Ana C Garrido-Castro; Ada Waks; Sara M Tolaney Journal: Drugs Date: 2022-10-07 Impact factor: 11.431
Authors: Anne L Loeser; Lucy Gao; Aditya Bardia; Mark E Burkard; Kevin M Kalinsky; Jeffrey Peppercorn; Hope S Rugo; Martha Carlson; Janice Cowden; Lesley Glenn; Julia Maues; Sheila McGlown; Andy Ni; Natalia Padron; Maryam Lustberg Journal: Breast Cancer Res Treat Date: 2022-10-06 Impact factor: 4.624