Phase Ii Trial Of Lapatinib And Everolimus For Her2 Positive Metastatic Breast Cancer

Background: Although the treatment of HER2 positive metastatic breast cancer (MBC) has improved with anti-HER2 agents and chemotherapy, most patients will eventually develop resistance to these agents. Preclinical studies have shown that mTOR inhibition may reverse trastuzumab resistance. We hypothesize that combining mTOR inhibitor everolimus with lapatinib will be an effective strategy for patients who have progressed on prior anti-HER2 therapies. Trial Design: We are conducting an open-label phase II pilot study of the combination of everolimus and lapatinib for pts with HER-2 positive MBC. Eligible pts must have histologically documented locally advanced (inoperable) or metastatic HER-2 positive breast cancer that have progressed on at least one HER-2 based regimen in the metastatic or locally advanced setting. Pts with disease progression during or within 12 mos of the completion of adjuvant trastuzumab are eligible. Pts with untreated asymptomatic brain metastases are allowed. Pts with symptomatic brain metastases are allowed to enroll after they have completed radiation and are off steroids. Eligible pts are started on everolimus 5 mg PO daily and lapatinib 1250 mg PO daily without interruption. Among subjects progressing on lapatinib, lapatinib is continued and everolimus initiated. Pts will continue to receive treatment until there is evidence of progressive disease (PD), unacceptable toxicity, or withdrawal of consent. Pts will have radiological evaluation every 8 weeks with CT, bone scan, and MRI brain (for pts with known brain metastasis at baseline). Specific Aims: Primary objective is to assess the effectiveness of the combination of RAD-001 and lapatinib as measured by the six-month Overall Response Rate in women with MBC who have progressed on trastuzumab and/or lapatinib based therapies. Secondary objectives are six-month PFS, safety and tolerability of the combination, six-month objective CNS response rate, six-month clinical benefit rate of systemic disease, and six-month clinical benefit rate in CNS. Statistical methods: The response rate of lapatinib monotherapy in heavily pre-treated patients is estimated to be 7% (Blackwell 2009). For an expected ORR of 17%, a sample size of 45 subjects will provide 79% power to detect the difference at 0.10 Type I error rate according to 1-sided exact binomial test. Present accrual and target accrual: The trial has accrued 20 patients with a target accrual of 45 patients. Citation Format: Barr JA, Sharma P, Fabian CJ, Yeh H, Baccaray S, Springer M, Khan QJ. Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-12.