Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial

Autor: Manuel Ruiz-Borrego, W. Lawler, A. Kellum, L. Carcas, K.D. Nahum, M. Wilkinson, K. Tkaczuk, Ron Bose, E. Ibrahim, D. Hunt, Sara A. Hurvitz, N. Erickson, M. Kozloff, R.H. Alvarez, M. Trudeau, I. Gore, D. Chan, K. Cheong, M. Coleman, F. Kass, A. Conlin, B. Choi, J. A. Di Palma, N. Iannotti, Adam Brufsky, Aurelio Castrellon, G. Marx, Debu Tripathy, M. Thirlwell, I. Vaziri, A.J. Chien, L. McCulloch, Gary Thomas, Vincent Hansen, A. Chan, Carlos H. Barcenas, D. Ellison, R. Dichmann, E. Reyes, J. A. Garcia Saenz, J. Seeger, N. Chan, S.D. Kendall, Barbara Pistilli, A. Litvak, R. Somer, D. Huang, D. Hufnagel, James L. Wade, Hope S. Rugo, Richard A. Bryce, E. Tan Chiu, Y. Manalo
Přispěvatelé: Puma Biotechnology, Miller Institute for Basic Research in Science, National Institutes of Health (US), National Cancer Institute (US)
Rok vydání: 2020
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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Popis: [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.
CONTROL was sponsored by Puma Biotechnology Inc. Puma Biotechnology Inc. also funded the provision of writing/editorial support provided by Miller Medical Communications Ltd. CHB was supported in part by the National Institutes of Health [K12 grant Paul Calabresi Clinical Oncology Award grant number: 5K12CA088084-17] and the National Cancer Institute at the National Institutes of Health MD Anderson Cancer Support Grant [grant number P30CA016672].
Databáze: OpenAIRE
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