Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial
Authors: C.H. Barcenas, S.A. Hurvitz, J.A. Di Palma, R. Bose, A.J. Chien, N. Iannotti, G. Marx, A. Brufsky, A. Litvak, E. Ibrahim, R.H. Alvarez, M. Ruiz-Borrego, N. Chan, Y. Manalo, A. Kellum, M. Trudeau, M. Thirlwell, J. Garcia Saenz, D. Hunt, R. Bryce, L. McCulloch, H.S. Rugo, D. Tripathy, A. Chan, L. Carcas, A. Castrellon, D. Chan, K. Cheong, B. Choi, M. Coleman, A. Conlin, R. Dichmann, D. Ellison, N. Erickson, I. Gore, V. Hansen, D. Huang, D. Hufnagel, F. Kass, S.D. Kendall, M. Kozloff, W. Lawler, K.D. Nahum, B. Pistilli, E. Reyes, J. Seeger, R. Somer, E. Tan Chiu, G. Thomas, K. Tkaczuk, I. Vaziri, J. Wade, M. Wilkinson
Journal: Annals of Oncology (2020)

•CONTROL trial investigated antidiarrheal strategies including dose escalation in neratinib-treated patients with early HER2+ breast cancer.•Preemptive prophylaxis and dose escalation reduced the rate, severity, and duration of grade 3 diarrhea compared with ExteNET.•Lower diarrhea-related discontinuations and dose reductions in multiple cohorts compared with ExteNET suggested improved tolerability.•Neratinib dose escalation is a particularly promising strategy as it eliminates mandatory prophylaxis and related side-effects. BackgroundNeratinib 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 methodsPatients 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.ResultsFinal 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.ConclusionsNeratinib 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.govNCT02400476. 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 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. 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. 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.