Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer

For breast cancers in which HER2 is not overexpressed, activating mutations in the ERBB3 gene, coding for the HER3 tyrosine kinase receptor, have an oncogenic role, and targeting them may offer new perspectives of treatment. Pre-clinical data suggest that HER2 is essential for the pro-tumoral effect of HER3, which does not have a functional tyrosine kinase domain and requires heterodimerization with other members of the HER family of tyrosine kinase receptors for signaling. There is limited clinical evidence of the activity of drugs targeting HER2 in cancers harboring ERBB3 mutations, but few patients with breast cancer have been evaluated. Furthermore, the distribution of ERBB3 mutations seems to differ in breast carcinoma when compared to other cancer types. A few patients with a HER2 non-amplified metastatic breast cancer were treated at Institut Curie with the combination of a HER2-directed antibody and of a HER2 tyrosine kinase inhibitor (TKI) and all responded, warranting further explorations in this setting. The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody, with a Bayesian design in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation. To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles, until cancer progression, inacceptable toxicity or patient's withdrawal from the trial. Tumor radiological assessments will be performed every 6 weeks during the 6 first months (first 8 cycles), then every 9 weeks until disease progression. In addition, Quality of Life will be evaluated throughout the treatment. Blood samples (at baseline, cycles 1, 2 and 3, and at end of treatment) and tissue samples (at baseline and optionally at progression) will be collected as part as exploratory objective analyses on biomarkers (ctDNA monitoring and next-generation sequencing (NGS)).