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

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.

• 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, CONTROL Study Investigators
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 31 Issue 9 Pg. 1223-1230 (09 2020) ISSN: 1569-8041 [Electronic] England
• PMID: 32464281 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Quinolines
• Receptor, ErbB-2
• neratinib
• Trastuzumab

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Breast Neoplasms (drug therapy)
• Humans
• Quality of Life
• Quinolines (therapeutic use)
• Receptor, ErbB-2 (genetics)
• Trastuzumab (therapeutic use)