Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer. (February 2023)

• Record Type: Journal Article
• Authors: Chan, Arlene; Ruiz-Borrego, Manuel; Marx, Gavin; Chien, A. Jo; Rugo, Hope S.; Brufsky, Adam; Thirlwell, Michael; Trudeau, Maureen; Bose, Ron; García-Sáenz, José A.; Egle, Daniel; Pistilli, Barbara; Wassermann, Johanna; Cheong, Kerry A.; Schnappauf, Benjamin; Semsek, Dieter; Singer, Christian F.; Foruzan, Navid; DiPrimeo, Daniel; McCulloch, Leanne; Hurvitz, Sara A.; Barcenas, Carlos H.
• Is Part Of: Breast. Volume 67(2023)
• Page Start: 94
• Page End: 101
• Publication Date: 2023-02
• Subjects: Neratinib -- Tyrosine kinase inhibitor -- HER2-positive -- Breast cancer -- Early stage -- Diarrhea prophylaxis -- Dose escalation -- Health-related quality of life; Breast -- Diseases -- Periodicals; Breast -- Tumors -- Periodicals; Breast -- Periodicals; Electronic journals; Periodicals; 616
• DOI: 10.1016/j.breast.2022.12.003
• Languages: English
• ISSNs: 0960-9776

Abstract

Abstract: Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. Methods: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. Results: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. Conclusions: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. ClinicalTrials.gov registration number: NCT02400476. Graphical abstract: Image 1 Highlights: All antidiarrheal strategies reduced rates of grade ≥3 diarrhea vs ExteNET trial. Two-week neratinib dose escalation had the lowest rate of grade ≥3 diarrhea. Pre-emptive management of diarrhea allowed patients to stay on treatment longer. Prior pertuzumab use did not appear to impact diarrhea rates or discontinuations. All antidiarrheal strategies were associated with stable on-study HRQoL.