HER2+ Breast Cancer: Key Takeaways From HER2CLIMB

Giuseppe Curigliano, MD, PhD: Tucatinib is a highly selective HER2 [human epidermal growth factor receptor 2]–directed tyrosine kinase inhibitor. The specificity of this type of tyrosine kinase is that it can directly target HER2 and also be active in patients with brain metastases.

HER2CLIMB was a prospective randomized trial comparing tucatinib with trastuzumab and capecitabine vs placebo, trastuzumab, and capecitabine in patients with HER2-positive metastatic breast cancer who received a previous treatment with pertuzumab, trastuzumab, and T-DM1 [trastuzumab emtansine]. The unique characteristic of HER2CLIMB is that patients with brain metastases were eligible, specifically patients with previously treated stable brain metastases, patients with untreated brain metastases not needing immediate local therapy, and patients with previously treated progressing brain metastases not needing immediate local therapy.

The final data of HER2CLIMB demonstrated a statistically significant improvement in terms of overall survival, with an increase in overall survival from 19.2 months in the placebo arm to 24.7 months in the tucatinib arm. The overall survival benefit was maintained in longer follow-up with a 5.5-month improvement in median overall survival. Sensitivity analysis was also performed for crossover and showed consistent results with intent-to-treat analysis.

If we analyze the data of overall survival in prespecified subgroup analysis, we confirm the benefit of tucatinib in terms of overall survival independent of age higher than 65 vs lower than 65; race, white vs nonwhite; hormone receptor status, positive vs negative; baseline brain metastases, yes vs no; and ECOG performance status, 0 vs 1. Another important end point that was met in the longer follow-up of HER2CLIMB was progression-free survival [PFS]. The PFS benefit with tucatinib was maintained with longer follow-up, with a median PFS of 4.9 months in the placebo arm vs 7.6 months in the tucatinib arm.

The most common adverse event remained stable with longer follow-up. We had any grade of diarrhea observed in 81% of patients in the tucatinib arm vs 53% in the placebo arm. Nausea and palmar-plantar erythrodysesthesia were also very similar to the shorter follow-up. Any grade palmar-plantar erythrodysesthesia was observed in 65% of patients in the tucatinib arm vs 53% in the placebo arm. Nausea was seen in 60% of patients in the tucatinib arm vs 44% in the placebo arm. Importantly, liver toxicity was 22% in the tucatinib arm vs 11% in the placebo arm. The most important comment I can make on toxicity was that capecitabine was the most commonly reduced drug in both arms, the tucatinib and placebo arms. And the majority of discontinuations were related to capecitabine.

Transcript edited for clarity.