Background

Tucatinib (TUC), approved in multiple regions for HER2+ metastatic breast cancer (MBC), is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition. HER2CLIMB is a randomized trial of TUC vs placebo (Pbo) in combination with trastuzumab and capecitabine in patients (pts) with HER2+ MBC. The most common G ≥3 adverse events (AEs) with higher incidence on TUC (diarrhea, palmar-plantar erythrodysesthesia syndrome [PPE], and elevated liver enzymes) are described herein.

Method

AEs were classified by MedDRA Version 22.0 or higher and severities were classified using Version 4.03 of the CTCAE criteria. Safety data were reviewed annually by an Independent Data Monitoring Committee. AEs were treatment-emergent, and recorded after the first dose through 30 days after the last dose. Time-to-event analyses were conducted for AST/ALT/bilirubin (in aggregate), diarrhea, and PPE.

Results

Diarrhea and elevated AST/ALT/bilirubin on both TUC and Pbo were primarily G1/2 and manageable with dose modifications, and in some cases of diarrhea, with antidiarrheal treatment. Median time to diarrhea onset was shorter on TUC than control. For AST/ALT/bilirubin and PPE, median time to first onset was Cycles 1 and 2.

On TUC, antidiarrheals were used in 49.7% of cycles in which diarrhea was reported (39.8% on Pbo); when used, the median duration of use on each arm was 3 days/cycle. Prophylactic antidiarrheals were not required per protocol.

Conclusion

TUC with trastuzumab and capecitabine was well-tolerated. Rates of G ≥3 diarrhea and PPE were similar between treatments. Elevated liver enzymes were higher on TUC, but were transient and reversible. Discontinuation of TUC due to AEs was rare.

Impact statement