FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer

Abstract

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of 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. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progres-sion-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P ¼ 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens

“…As there are other treatment options beyond the second line for patients with HER2-positive MBC, it is important to have comprehensive QoL data to help inform patient treatment decisions. In addition to approving neratinib in third-line MBC, the FDA recently approved trastuzumab deruxtecan (DS-8201; Daiichi Sankyo and AstraZeneca) and tucatinib (Seattle Genetics) [21,22]. Although HRQoL was not measured in the pivotal trastuzumab deruxtecan trial, DESTINY-Breast01, other trials in the program have included the QLQ-C30 and QLQ-BR45 (the updated version of QLQ-BR23) [23].…”

Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

“…As there are now at least seven FDA-approved HER2 inhibitors 26 , we wanted to corroborate our findings with some of the newer HER2 inhibitors. Tucatinib is a novel, FDA-approved agent that has demonstrated more than 1000-fold selectivity for HER2 over EGFR in in vitro assays 27 and significant efficacy in clinical trials for the treatment of metastatic HER2-positive breast cancer (NCT02614794) [28][29][30][31][32] . As expected from a HER2 inhibitor, tucatinib inhibited p-HER2, p-AKT and p-ERK in the HER2-amplified breast cancer cells BT-474 and MDA-MB-453 17 (Fig.…”

US Food and Drug Administration regulatory updates in neuro-oncology

“…Approval of tucatinib was based on results of a randomized (2:1), double-blind, placebo-controlled trial (HER2CLIMB, NCT02614794), which included 612 patients with HER2-positive metastatic breast cancer who had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) [ 13 , 14 ]. Patients were randomized to receive either tucatinib (300 mg twice daily) plus trastuzumab and capecitabine (n = 410) or placebo plus trastuzumab and capecitabine (n = 202).…”

“…Median PFS brainmets was 7.6 months in the tucatinib arm (n = 198; 95% CI 6.2–9.5 months) and 5.4 months in the placebo arm (n = 93; 95% CI 4.1–5.7 months), which represented a significant difference (Hazard Radio [HR] 0.48; 95% CI 0.34–0.69; P < 0.00001). [ 14 , 16 , 17 ]. Although exploratory, in the subset of patients with active brain metastases, median PFS was also greater in the tucatinib arm compared to the control arm (9.5 vs. 4.1 months; HR, 0.36; 95% CI 0.22–0.57; P < 0.00010).…”