by 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
The Breast: Published: December 13, 2022
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.
