Dr McAndrew on the HER2CLIMB-02 Trial in HER2+ Breast Cancer

Nicholas P. McAndrew, MD, MSCE, health sciences clinical assistant professor, Hematology/Oncology, University of California, Los Angeles (UCLA), UCLA Health, discusses the phase 3 HER2CLIMB-02 trial (NCT03975647) of tucatinib (Tukysa) plus ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive early breast cancer.

The HER2CLIMB-02 study aims to further investigate potential roles for existing drugs. Tucatinib gained FDA approval for patients with HER2-positive breast cancer based on findings from the phase 2 HER2CLIMB study (NCT02614794), which demonstrated superior progression-free survival (PFS) when the agent was added to capecitabine plus trastuzumab and compared with capecitabine plus trastuzumab alone. Tucatinib particularly benefited patients with brain metastases, McAndrew begins. Subsequently, various studies explored tucatinib in different combinations. HER2CLIMB-02 examined its use beyond the first line in combination with T-DM1, he says. Patients were randomly assigned to receive T-DM1 plus either placebo or tucatinib, with PFS as the primary end point and secondary end points including overall survival (OS) and PFS in patients with brain metastases, McAndrew elucidates.

A considerable proportion of patients in the tucatinib arm had brain metastases (43.4%) or de novo metastatic disease (45.2%), and patients had received a median of 1 prior line of therapy (range, 0-8), indicating a relatively less heavily treated population, primarily in the second-line metastatic setting, he expands. In the overall population, a modest improvement in PFS was observed with tucatinib compared with placebo, at 9.5 months (95% CI, 7.4-10.9) vs 7.4 months (95% CI, 5.6-8.1), respectively, although this PFS improvement was statistically significant with an HR of 0.76 (95% CI, 0.61-0.95; P = .0163), he explains. Similar PFS trends were noted in patients with brain metastases, suggesting a potential benefit with the combination in this subgroup. Although OS data are still immature, initial OS indications favor the tucatinib arm, with a median OS not reached (NR) compared with 38.0 months (95% CI, 31.5-NR) in the placebo arm (HR, 1.23; 95% CI, 0.87-1.74), McAndrew reports.

However, the rapidly evolving treatment paradigm for HER2-positive breast cancer necessitates consideration, he continues. By the completion of HER2CLIMB-02, the preferred antibody-drug conjugate (ADC) in the second-line metastatic breast cancer setting had shifted. Although the findings from HER2CLIMB-02 are clinically relevant, their immediate applicability to clinical practice may vary, according to McAndrew. The phase 3 DESTINY-Breast03 trial (NCT03529110) established fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as a significantly more efficacious ADC than T-DM1; thus, T-DXd has emerged as the preferred second-line ADC in metastatic HER2-positive breast cancer, McAndrew concludes.