Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer

Twenty to twenty five percent of Human Breast Cancers are HER2 positive. HER2 positivity confers a poor prognosis in the absence of HER2 targeted therapies (trastuzumab and lapatinib). With these targeted agents often combined with chemotherapy, the treatment of HER2 positive breast cancer has improved greatly, both in metastatic and adjuvant settings. However most patients with metastatic HER2 positive breast cancer will eventually develop resistance to these agents and succumb to their disease. Therefore, there is a need to test new agents and new combinations that can increase the efficacy of HER2 targeted therapy and/or prevent resistance to HER2 targeted therapies. A unique feature of HER2 positive breast cancers is a rather high incidence of brain metastasis in this population. Brain metastases develop in one third to one half of patients with advanced HER2+ breast cancer and CNS is a frequent site of trastuzumab failure. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Compared to trastuzumab, which has no CNS activity, lapatinib, an epidermal growth factor receptor/HER2 inhibitor, has modest CNS activity. In a study of more than 200 patients by Lin et al, 21% of patients experienced a 20% volumetric reduction in their CNS lesions on lapatinib. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a 20% volumetric reduction in their CNS lesions. Mammalian target of Rapamycin (mTOR) is a serine/threonine kinase that regulates key functions associated with cell growth, survival and angiogenesis. mTOR is activated by HER signaling, PI3K oncogenic mutation and loss of PTEN function. In vitro data suggests that activation of mTOR by PTEN loss and PI3K mutation induces trastuzumab resistance. Preclinical studies have shown that mTOR inhibition enhances the efficacy of trastuzumab and reverses trastuzumab resistance caused by PTEN loss. This preclinical finding was confirmed in 2 recent Phase 1 studies where addition of mTOR inhibitor (RAD-001) to trastuzumab and chemotherapy reversed the resistance to Trastuzumab in patients with heavily pretreated metastatic HER2 positive breast cancer. Thus, mTOR inhibition would be an attractive modality to add to HER2 targeted therapy for improving outcomes in women with HER2 positive breast cancer. Everolimus (RAD001), a rapamycin analogue, is an orally administered inhibitor of mTOR. Everolimus has shown promising activity in solid tumors. PK data in mouse models indicated that penetration of rapamycin and Everolimus into the CNS is substantial. Everolimus brain levels are approximately one-third that of systemic levels at 48 hours after a dose. A small molecule inhibitor of HER2, lapatinib is clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, Eichhorn et al performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib. Tumor suppressor PTEN was identified as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, they show that two dominant activating mutations in PI3K pathway which are prevalent in breast cancer, also confer resistance to lapatinib. They also showed that PI3K-induced lapatinib resistance could be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. This suggests that deregulation of the PI3K pathway leads to lapatinib resistance, which can be effectively reversed by inhibition of PI3K/mTOR pathway. In summary, the combination of Everolimus and lapatinib needs to be studied in women with metastatic breast cancer who have progressed on at least one prior anti-HER2 therapy. If RAD-001 is able to overcome resistance to anti-HER2 therapies, a very desirable response rate and prolongation in TTP can be expected. Moreover, both lapatinib and Everolimus appear to be able to cross the blood brain barrier, and this combination may prove to be effective in controling CNS metastases in this population. The investigators hypothesize that combining mTOR inhibitor Everolimus with lapatinib will be an effective strategy for patients who have progressed on a prior anti-HER2 therapy, both systemically and within the CNS.