Palbociclib in combination with TDM1 for metastatic HER2+ breast cancer

Abstract

Purpose: HER2+ breast cancer is treated using agents that target the amplified receptor. Such drugs are effective; however, recurrence and progression can occur in spite of multiple HER2-targeted therapies. This study evaluated the safety and potential efficacy of the combination of TDM-1 and palbociclib in previously treated metastatic HER2+ breast cancer. Background: Preclinical data indicate that the CDK4/6 inhibition suppresses proliferation of HER2+ tumor models, including those resistant to HER2-targeted therapies. The action of CDK4/6 inhibitors is distinct from HER2-targeted agents. In particuar TDM1 elicits a cytotoxic response; while CDK4/6 inhibition prevents outgrowth of tumors that survive T-DM1. These data were used to develop scheduling for a study to evaluate the safety and preliminary efficacy of palbociclib combined with TDM-1 in advanced HER2+ breast cancer. Experimental design: A standard 3X3 design Phase I trial design was applied. Centrally confirmed HER2+ and RB-intact advanced breast cancer patients, including those previously exposed to TDM-1, were enrolled. Patients received TDM-1 (3.6 mg/kg) IV every 21 days and palbociclib orally on days 5-18 of each cycle. Dose escalation occurred in 100, 150 and 200 mg cohorts. Of 18 patients screened, two were excluded due to lack of HER2-positivity or observed RB-deficiency. Nine patients were in the dose escalation and 44% (4/9) had received prior TDM-1 therapy. Results: Predominant study drug related toxicities were hematologic, with 33% of patients experiencing grade 3 thrombocytopenia. Grade 3 neutropenia related to palbociclib was seen in 33% of patients at 100 mg, 66% at 150 mg, and 100% at 200 mg dose level. Toxicity resolved with dose interruption. Best observed responses included 3 partial responses, 5 stable diseases, and 1 progressive disease. Median cycles was 8, with average time on study 193 days. Of four patients previously relapsing on TDM-1, two had stable disease and one partial response. Conclusions: The TDM-1 and palbocicilb combination was well tolerated with reversible hematologic toxicity and evidence of clinical efficacy. The recommended dose for further study is TDM-1 (3.6 mg/kg) day 1, with 150 mg of palbociclib on days 5-18 of a 21 day cycle.