The addition of the tyrosine kinase inhibitor tucatinib (Tukysa) to trastuzumab (Herceptin) and capecitabine continued to improve overall survival (OS) and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer, according to updated results from the pivotal HER2CLIMB trial. The findings were presented at the American Society of Clinical Oncology 2021 virtual annual meeting by lead investigator Giuseppe Curigliano, MD, PhD, Associate Professor, Medical Oncology, University of Milano, Italy, and Director, New Drugs and Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.
“Late-stage, HER2-positive metastatic cancer has proven difficult to treat. These data further support that treatment with the tucatinib regimen helps patients live longer compared to trastuzumab and capecitabine alone,” Dr Curigliano said.
The HER2CLIMB Study
Patients with HER2-positive locally advanced or metastatic breast cancer who had received prior treatment with trastuzumab, pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla) were randomized in a 2:1 ratio to 300 mg tucatinib twice daily plus trastuzumab and capecitabine (N = 410) or placebo plus trastuzumab and capecitabine (N = 202). Trastuzumab was given at a loading dose of 8 mg/kg on day 1 of cycle 1 if needed and then at a maintenance dose of 6 mg/kg on day 1 of 21-day cycles thereafter. Capecitabine was given at 1000 mg/m2 twice daily on days 1 through 14 of every 21-day cycle. The trial enrolled patients with and without brain metastases at baseline, including those with active brain metastases.
The trial met all primary and secondary end points at the time of the primary analysis, with clinically meaningful prolongation of PFS and OS. Since the primary analysis, the protocol was amended for unblinding of sites to treatment assignment, to allow for crossover from the placebo arm to tucatinib. At the time of data cutoff in February 2021, 35 patients in the tucatinib arm and 1 patient in the placebo arm were still on their respective treatments, whereas the other patients had completed treatment. In total, 26 patients crossed over from the placebo arm to receive tucatinib, and 9 of these patients remain on treatment.
Results from Updated Analysis
For the updated analysis, the median duration of follow-up was 29.6 months, including 15.6 months since the primary analysis. A 27% reduction in the risk for death was observed in the tucatinib arm, with a median OS of 24.7 months, compared with 19.2 months in the placebo arm. More importantly, the OS benefit seen with tucatinib was consistent across all prespecified patient subgroups, including those with or without brain metastases.
“These data demonstrated that the OS benefit with tucatinib was maintained with an additional 15.6 months of follow-up,” said Dr Curigliano.
The PFS benefit with tucatinib was also maintained with longer follow-up, with a 43% reduction in the risk for progression in the tucatinib arm and a median PFS of 7.6 months with tucatinib compared with 4.9 months with placebo.
Safety Profile
Tucatinib was well-tolerated, and its safety profile was consistent with previous reports. Grade ≥3 adverse events (AEs) were observed in 60.6% of patients in the tucatinib arm and 51.3% of patients in the placebo arm. The most common AEs with tucatinib included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting.
Treatment-emergent AEs of any grade occurred in 99.3% of patients in the tucatinib arm and 97% of those in the placebo arm. Study treatment discontinuation due to treatment-emergent AEs remained low, similar to the primary analysis, at 12.9% and 11.7%, respectively.
“In the 15.6 months since the primary analysis, only 1 additional patient discontinued tucatinib due to an adverse event,” Dr Curigliano said.
