Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial
CH Barcenas, Sara A. Hurvitz, Jack A. Di Palma, Ron Bose, A. Jo Chien, Nicholas Iannotti, Gavin Marx, Adam Brufsky, Anya M. Litvak, Elsayed Ibrahim, Ricardo H. Álvarez, Manuel Ruíz‐Borrego, Nancy Chan, Yvonne Manalo, A. Kellum, Maureen Trudeau, Michael P. Thirlwell, J. García Saenz, Daniel Hunt, Richard Bryce, Leanne McCulloch, Hope S. Rugo, Debu Tripathy, Arlene Chan, Lauren Carcas, Aurelio Castrellon, Derwin King Chung Chan, K. Cheong, Byung Ock Choi, Michel P. Coleman, Alison Conlin, Robert Dichmann, David H. Ellison, Nicholette Erickson, Ira Gore, Vincent Hansen, D B Huang, David Hufnagel, Frederic Kass, Stephan D. Kendall, Mark Kozloff, W Lawler, Kelly Nahum, Barbara Pistilli, Eduardo Reyes, Janell Seeger, Robert A. Somer, Elizabeth Chiu, Gary W. Thomas, Katherine H. R. Tkaczuk, Irfan Vaziri, James L. Wade, M. Wilkinson
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.