Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib

Abstract

The management of HER2 positive breast cancer has been transformed by the development of targeted therapies. Dual blockade with the monoclonal antibodies, trastuzumab and pertuzumab, added to first-line taxane chemotherapy and second-line therapy with the antibody-drug conjugate, T-DM1, are internationally agreed standards of care for advanced HER2 positive breast cancer, where available. However, until recently, options for patients for third-line therapy and beyond were of modest efficacy or limited by toxicity. In 2019, the results of trials of two exciting new agents for this space were presented. A third-generation HER2 tyrosine kinase inhibitor, tucatinib, combines the efficacy of the second-generation drug, neratinib, with a more manageable toxicity profile and has become a new standard of care after T-DM1, in combination with capecitabine and trastuzumab. The antibody-drug conjugate, trastuzumab deruxtecan, demonstrated remarkable efficacy in heavily pre-treated patients and received accelerated approval in the United States, whilst confirmatory Phase 3 trials are completed. This review will discuss the available data for the post-T-DM1 setting, focusing on tyrosine kinase inhibitors including tucatinib.

New and Emerging Targeted Therapies for Advanced Breast Cancer

“…Most recently, tucatinib received approval by the FDA in 2020 to treat HER2-positive metastatic breast cancer. Compared to the other TKIs, tucatinib is highly selective, proven to be 1000-fold more specific to HER2 than EGFR [38,49]. Tucatinib is also found to have higher central nervous system (CNS) penetration than either lapatinib or neratinib, putting it at the forefront of possible HER2-positive metastatic breast cancer with CNS metastasis treatment [49].…”

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

“…In this setting, neratinib as monotherapy could also provide some therapeutic benefit [ 66 ]. However, it shows more efficacy in combination with capecitabine [ 65 ], and indeed, current clinical trials are also evaluating its utility in combination with other therapies: fulvestrant (NCT03289039 and NCT01670877, only in HER2-mutant patients) or T-DM1 (NCT02236000 or NCT01494662 in patients with brain metastasis) [ 7 , 67 ].…”

“…In April 2020, the FDA approved the triple combination of tucatinib + trastuzumab + capecitabine for patients with advanced disease (including CNS metastasis) that had progressed from previous anti-HER2 treatments [ 74 ]. Ongoing clinical trials in different phases are investigating the utility of tucatinib in various drug combinations, such as chemotherapy, T-DM1, T-DXd, the aromatase inhibitor (letrozole), CDK4/6 inhibitors (palbociclib), or immunotherapy (Pembrolizumab) (revised in [ 67 ]).…”

“…Multiple clinical trials are ongoing in China in metastatic patients with diverse drug combinations, including chemotherapies and other anti-HER2 agents. Some of the studies are designed to assess pyrotinib utility in patients who have progressed from previous HER2 therapy, where its efficacy in overcoming resistance to standard HER2 treatments is being evaluated [ 67 ].…”

“…As commented above, one effective way to overcome resistance to anti-HER2 single agents is the combination of diverse anti-HER2 drugs (antibodies, ADCs, and TKIs) with/without chemotherapy. This is a possibility in current practice (for example, combining tucatinib plus trastuzumab + capecitabine is approved for metastatic disease), and numerous clinical trials are evaluating the safety and effectiveness of diverse combinatorial strategies: for instance, tucatinib + TDM1 or tucatinib + T-DXd (HERCLIMB02-04 trials) (revised in [ 67 ]).…”