A pilot study of palbociclib in patients with HER2-positive breast cancer with brain metastasis.

Abstract

TPS1110 Background: HER2+ breast cancers have the propensity to metastasize to the CNS. Most systemic therapy does not cross the blood-brain barrier (BBB) effectively, limiting treatment options. Palbociclib is a small molecule inhibitor of cyclin dependent kinases (CDK) 4 and 6, which has been studied in hormone positive breast cancers and found to have significant anti-tumor activity. Preclinical models demonstrate HER2+ tumors require cyclin D1 and CDK4 for progression and maintenance, and palbociclib has been found to have single agent activity in transgenic HER2+ models. Preclinical studies have also found that palbociclib crosses the BBB and exerts anti-cancer effects; indeed, clinical trials investigating its activity in primary brain tumors are ongoing. The summary of these data provide rationale for investigation of palbociclib in patients with HER2+ breast cancer and brain metastasis. Methods: A single arm study of palbociclib in patients with metastatic HER2+ breast cancer with brain metastasis was designed. The primary objective is to determine overall radiographic response rate in the CNS using modified RANO-BM criteria. Secondary objectives include PFS, OS, systemic response rates, safety, and tolerability. Exploratory objectives include assessment of mutational profiles in tissue and ctDNA, and quality of life endpoints using FACT-Cog and FACT-Br. Eligible patients must have metastatic HER2+ breast cancer with measurable brain metastasis (at least 1 lesion > = 5mm). Patients with rapidly progressive symptoms or with leptomeningeal disease are excluded. Concurrent therapy with trastuzumab is allowed. Eligible patients are treated with palbociclib 125mg PO (21 days on, 7 days off) until progressive disease or unacceptable toxicity. Available archival tissue will be obtained, ctDNA/FACT-Cog/Br will be assessed at baseline, 2, and 4 months. A total of 20 patients will be enrolled. To detect a radiographic response rates increase from 23% to 40%, a Bayesian posterior probability will be calculated after the response status in 20 patients has been assessed. The goal is that there is at least an 80% probability that the response rate exceeds 40%. Clinical trial information: NCT02774681.