GIM27-THERapy: a Study to Describe the Effectiveness of Tucatinib in Combination With Capecitabine and Trastuzumab in the Treatment of Metastatic HER-2 Positive Breast Cancer Patients in Real World Setting

Non-interventional, multicenter, prospective observational study of tucatinib-trastuzumab capecitabine administered according to the standard local clinical practice following approved SmPC indication and dose.

About 300 Her2 positive metastatic breast cancer patients who are candidate to tucatinib treatment in real world setting including patients previously treated with trastuzumab, pertuzumab, T-DM1, T-DXd as per authorized therapy setting and NPP/EAP ongoing program.

Primary Objective:

To assess the treatment safety and effectiveness as measured by investigator criteria in metastatic breast cancer patients within the real-world setting treated with tucatinib in combination with trastuzumab and capecitabine according to standard local clinical practice following approved Summary of Product Characteristics (SmPC) indication and dose.

The primary purpose of this study is to evaluate the real word effectiveness of the combination therapy "tucatinib/trastuzumab/capecitabine" in mBC patients according to the approved SmPC indication and dose in the real-world setting. Patients with human epidermal growth factor receptor 2 (HER2)- positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity has been demonstrated to be effective in treating HER2-driven cancers. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. On April 17, 2020, the Food and Drug Administration approved tucatinib in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2- positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. On 10 December 2020, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for Tukysa (tucatinib) in combination with trastuzumab and capecitabine for the treatment of adult patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC) who have received at least two prior anti-HER2 treatment regimens. Tucatinib received a marketing authorization valid throughout the EU on February 2021. The approvals were based on the results of the phase II HER2CLIMB trial in which HER2-positive breast cancer patients, previously treated with trastuzumab, pertuzumab (Perjeta) and trastuzumab emtansine (T-DM1; Kadcyla), have been randomized to receive trastuzumab and capecitabine with either tucatinib or placebo (randomization 2:1).Among the 511 patients with measurable disease at baseline, an objective response was confirmed in 40.6% of patients in the tucatinib-combination group and 22.8% of patients in the placebo-combination group. The primary endpoint of the trial was PFS and the secondary end points comprised overall survival (OS), as well as confirmed objective response rate (ORR). Tucatinib demonstrated efficacy compared with placebo in PFS (7.8 months versus 5.6months) and OS (21.9 months versus 17.4 months). The most common adverse events in the tucatinib arm were diarrhea, palmar-plantar erythrodysesthesia syndrome, fatigue, nausea, and vomiting and transaminitis, even though typically low-grade, transient, and reversible. In addition, out of the ∼600 patients enrolled, 291 patients had brain metastases at baseline. Brain mets including those with active brain mets. Among patients with brain mets PFS at 1 y was 24,9% in the tucatinib combination group vs 0% in the placebo combination group, HR: 0.48;95% CI to 69%;p<0.0001 and median PFS was 7.6 and 5.4 respectively. This represents for many patients the availability of a new valuable therapeutic option especially where the occurrence of brain metastases is frequent. Based on the reported data and considering the clinical benefit of the therapy such as prolongation of PFS/OS, a prospective study on the efficacy and safety profile of the tucatinib in the real-world population can be very useful to follow the evolution of HER2- positive metastatic breast cancer with this promising treatment.