Tucatinib Together With Pembrolizumab and Trastuzumab

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Despite significant advances in systemic treatment options, advanced HER2-positive breast cancer post treatment with trastuzumab, pertuzumab and T-DM1 still remains incurable, with brain metastases remaining a major cause of patient morbidity and mortality. HER2-positive breast cancers have relative...

Despite significant advances in systemic treatment options, advanced HER2-positive breast cancer post treatment with trastuzumab, pertuzumab and T-DM1 still remains incurable, with brain metastases remaining a major cause of patient morbidity and mortality. HER2-positive breast cancers have relatively high tumour infiltrating lymphocytes (TILs) that may be targeted with immune checkpoint blockade. Studies in metastatic breast cancer with PD1 or PD-L1 inhibition have shown an overall survival (OS) benefit for those that are enriched for pre-existing immunity, such as positive expression of PD-L1 protein or TILs present. One of the main areas of disease progression in HER2 positive disease is in the central nervous system (CNS), supporting the need to find an effective combination for patients with brain metastases. Tucatinib (ONT-380) is a potent, highly selective, oral HER2 small molecule tyrosine kinase inhibitor (TKI) with demonstrated clinical benefit notable for its minimal inducement of EGFR-type toxicities when administered in combination-type studies including proven intra-cranial efficacy in studies of patients with brain metastases. The investigators hypothesise that the combination of tucatinib with trastuzumab and PD-1 inhibition will result in a similar ORR as that seen in HER2CLIMB, along with comparable PFS and duration of response, particularly through prevention and treatment of CNS metastases. The advantage of adding PD-1 inhibition and omitting capecitabine in the PD-L1 positive group is to increase the durability of the response, with hopefully less added toxicity for patients. The investigators believe this regimen will result in comparable outcomes as those seen in HER2CLIMB, with fewer adverse events. In the PD-L1 negative cohort, the HER2CLIMB regimen (tucatinib + capecitabine) will be used with the addition of pembrolizumab with the hypothesis that its anti-tumour activity may overcome the lower immunogenicity of this subgroup. Importantly, the side effect profiles of all agents in the proposed combination are non-overlapping and this combination provides a unique opportunity for excellent tolerability and durable disease control in this patient group.

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