A Phase II, Two-arm, Non-comparative, Multicentre Study of Tucatinib (ONT-380), Pembrolizumab and Trastuzumab in Patients With Pre-treated Advanced HER2-positive Breast Cancer

Brief Summary

Detailed Description

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 potential 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. Importantly, the side effect profiles of all agents in our proposed combination are non-overlapping and this combination provides a unique opportunity for excellent tolerability and durable disease control in this patient group. The study design initially included two treatment cohorts, with the PD-L1 negative/unknown cohort being treated with the HER2CLIMB regimen with the addition of pembrolizumab (MK-3475), under the hypothesis that the anti-tumour activity of this regimen will overcome the lower immunogenicity of this subgroup. However, Protocol Amendment 2 will omit capecitabine in the PD-L1 negative/unknown cohort due to a high frequency of liver test abnormalities within the first seven participants in this cohort.

Primary Outcomes

Secondary Outcomes

• Progression free survival (PFS) in each PD-L1 cohort(From the time of registration until documented disease progression by RECIST 1.1 or death due to any cause (whichever occurs first), assessed up to 24 months)
• Clinical benefit rate (CBR) in each PD-L1 cohort(From time of registration to CR or PR, assessed up to 24 months)
• Overall survival (OS) in each PD-L1 cohort(From time of registration until death from any cause, assessed at 24 months)
• Incidence of treatment-emergent adverse events [Safety](From registration until 30 days after end of study treatment)
• Objective response rate (ORR) in the PD-L1 negative/unknown cohort(Through to study completion, an average of 24 months)
• Duration of response (DoR) in each PD-L1 cohort(From the time of registration to first documentation of progressive disease or death, assessed up to 24 months)
• Incidence of treatment-emergent adverse events [Tolerability of pembrolizumab](From start of study treatment to end of study treatment, assessed at 24 months)
• Incidence of treatment-emergent adverse events [Tolerability of tucatinib](From start of study treatment to the end of study treatment, assessed at 24 months)