medwireNews: The addition of tucatinib to trastuzumab plus capecitabine continues to confer an overall survival (OS) benefit in advanced HER2-positive breast cancer over longer follow-up, show phase 2 data.
The researchers explain that the primary analysis of the pivotal HER2CLIMB study showed significantly improved OS and progression-free survival (PFS) with the use of tucatinib rather than placebo alongside trastuzumab and capecitabine in patients with locally advanced or metastatic disease who had previously received trastuzumab, pertuzumab, and trastuzumab emtansine in any setting.
The current report presents the final efficacy and safety analysis of the study, conducted at a median of 29.6 months, which was an additional 15.6 months from the primary analysis.
OS was a median of 24.7 months for the 410 patients who were randomly assigned to receive oral tucatinib 300 mg twice daily together with trastuzumab 6 mg/kg (initial loading dose of 8 mg/kg) on day 1 of each 21-day cycle and capecitabine 1000 mg/m2 twice daily on days 1–14.
This was significantly longer than the median of 19.2 months for the 202 participants who instead received placebo plus trastuzumab and capecitabine on the same schedule, and equated to a hazard ratio (HR) for death of 0.73 in favor of the highly selective HER2-directed tyrosine kinase inhibitor.
The estimated 2-year OS rates were 51% and 40% in the tucatinib and placebo arms, respectively, report Giuseppe Curigliano (University of Milan, Italy) and co-researchers in the Annals of Oncology.
They add: “The results of sensitivity analyses accounting for cross-over were similar to the [intention-to-treat] analysis, with estimated HRs ranging from 0.71 to 0.72.”
PFS was similarly significantly improved among tucatinib- compared with placebo-treated patients, at median durations of 7.6 versus 4.9 months, and an HR for progression or death of 0.57. The corresponding estimated PFS rates at 1 year were 29% and 14%.
The investigators caution, however, that “the primary and key secondary endpoints of the study met statistical significance at primary analysis, therefore, the analyses reported here [are] descriptive with no formal statistical comparisons.”
Tucatinib continued to be well tolerated, they say, with similar rates, compared with placebo, of grade 3 or higher treatment-emergent adverse events (TEAEs; 60.6 vs 51.3%), serious TEAEs (30.4 vs 29.4%), and treatment discontinuation due to TEAEs (12.9 vs 11.7%).
“Beyond the primary analysis, only 1 additional patient discontinued tucatinib due to an adverse event,” highlight Curigliano and colleagues. They add that “[r]ates of the most common grade 3 or higher adverse events in patients on the tucatinib combination ([palmar–plantar erythrodysesthesia] syndrome, diarrhea, elevations in alanine aminotransferase and aspartate aminotransferase levels, and fatigue) […] remained stable with additional follow-up.”
The team concludes: “The continued OS benefit and tolerability of tucatinib in combination with trastuzumab and capecitabine augments data from the primary analysis and further supports the use of this combination in patients with previously treated HER2+ metastatic breast cancer after progression on 2 HER2-targeted therapies.
“Tucatinib in combination with trastuzumab and capecitabine is an important treatment option in the rapidly evolving HER2+ metastatic treatment landscape.”
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