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
Arlene Chan,
Manuel Ruiz-Borrego,
Gavin Marx,
A. Jo Chien,
Hope S. Rugo,
Adam Brufsky,
Michael Thirlwell,
Maureen Trudeau,
Ron Bose,
José A. García-Sáenz,
Daniel Egle,
Barbara Pistilli,
Johanna Wassermann,
Kerry A. Cheong,
Benjamin Schnappauf,
Dieter Semsek,
Christian F. Singer,
Navid Foruzan,
Daniel DiPrimeo,
Leanne McCulloch,
Sara A. Hurvitz,
Carlos H. Barcenas
Affiliations
Arlene Chan
Breast Cancer Research Centre-WA, Perth & Curtin University, Nedlands, Australia; Corresponding author. Breast Cancer Research Centre-WA, Perth & Curtin University, Nedlands, WA 6909, Australia.
Manuel Ruiz-Borrego
Hospital Universitario Virgen del Rocío, Seville, Spain
Gavin Marx
Sydney Adventist Hospital and Australian National University, Sydney, Australia
A. Jo Chien
University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
Hope S. Rugo
University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
Adam Brufsky
Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA
Michael Thirlwell
McGill University Health Centre, Montreal, QC, Canada
Maureen Trudeau
Sunnybrook Health Sciences Centre, Toronto, ON, Canada
Ron Bose
Washington University School of Medicine, St. Louis, MO, USA
José A. García-Sáenz
Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), CIBERONC, Madrid, Spain
Daniel Egle
Medical University Innsbruck, Innsbruck, Austria
Barbara Pistilli
Gustave Roussy Cancer Center, Villejuif, France
Johanna Wassermann
APHP Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
Kerry A. Cheong
Adelaide Cancer Centre, Adelaide, Australia
Benjamin Schnappauf
Sana Klinikum Offenbach GmbH, Offenbach, Germany
Dieter Semsek
Praxis am Diakonie Krankenhaus Onkologische Schwerpunktpraxis, Freiberg, Germany
Christian F. Singer
Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
Navid Foruzan
Puma Biotechnology Inc., Los Angeles, CA, USA
Daniel DiPrimeo
Puma Biotechnology Inc., Los Angeles, CA, USA
Leanne McCulloch
Puma Biotechnology Inc., Los Angeles, CA, USA
Sara A. Hurvitz
University of California Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
Carlos H. Barcenas
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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.
