Inhibition of the mammalian target of rapamycin (mTOR) is important for overcoming endocrine resistance in ER-positive breast cancer, and positive results from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366:520) led to the approval of the mTOR inhibitor everolimus in combination with exemestane for patients who develop progressive disease after treatment with a nonsteroidal aromatase inhibitor. The importance of the mTOR signaling pathway is not restricted to endocrine-sensitive breast cancer. Preclinical data suggest that targeting human epidermal growth factor receptor-2 (HER2) and mTOR may overcome trastuzumab resistance.

Now, O’Regan and colleagues have conducted the multicenter, phase III, randomized, controlled, double-blind BOLERO-3 trial (Abstract 505) to evaluate the combination of the mTOR inhibitor everolimus, the chemotherapy agent vinorelbine, and the HER2 inhibitor trastuzumab versus vinorelbine and trastuzumab in 569 patients with HER2-positive advanced breast cancer; 84% of patients received trastuzumab in the metastatic disease setting and developed disease progression, whereas 16% developed disease progression while receiving adjuvant trastuzumab or within 12 months of receiving it. Patients could have received up to three treatment regimens for metastatic disease; 27% of patients received prior lapatinib.

The inclusion of everolimus conferred a significant improvement in progression-free survival (7.0 vs. 5.8 months; P=0.0067) but no improvement in rates of overall survival (at current follow-up), objective response, or clinical benefit. The addition of everolimus to chemotherapy (5 mg daily) was associated with toxicities similar to that seen when everolimus was combined with the AI exemestane: stomatitis, fatigue, rash, hyperglycemia, and rare pneumonitis.

The combination of everolimus, vinorelbine, and trastuzumab may provide yet another option for patients with HER2-positive metastatic breast cancer. But, if approved, it will likely be positioned after both first-line trastuzumab, pertuzumab, and a taxane and second-line trastuzumab emtansine (T-DM1; JW Oncol Hematol Feb 26 2013). Other treatment considerations in this space include lapatinib and capecitabine, alternative trastuzumab/chemotherapy combinations, and the combination of trastuzumab and lapatinib.

Source: Journal Watch Oncology and Hematology