Oral Ridaforolimus Plus Trastuzumab for Patients With HER2+ Trastuzumab-Refractory Metastatic Breast Cancer

Resistance to trastuzumab treatment is potentially mediated by aberrant phosphatidylinositide 3-kinase (PI3K)/ AKT signaling; ridaforolimus may overcome trastuzumab resistance by inhibiting PI3K signaling. A single-arm phase Ilb trial was conducted to evaluate the efficacy and safety of ridaforolimus-trastuzumab in such resistance in patients with human epidermal growth factor receptor 2 positive (HER2+) trastuzumabrefractory metastatic breast cancer (MBC). The combination showed antitumor activity and may allow for combination with cytotoxic agents that could increase efficacy. Background: Although trastuzumab-containing therapies prolong survival in patients with metastatic breast cancer (MBC), Most tumors develop trastuzumab resistance, potentially mediated by aberrant phosphatidylinositide 3-kinase (PI3K)/AKT signaling. Ridaforolirnus (a mammalian target of rapamycin [mTOR] inhibitor) may overcome trastuzumab resistance by inhibiting PI3K signaling. Methods: A single-arm, phase IIb trial was conducted to evaluate the efficacy and safety of ridaforolimus-trastuzumab in human epidermal growth factor receptor 2 positive (HER2(+)) trastuzumab-refractory MBC (NCT00736970). Ridaforolimus was administered orally (40 mg daily) for 5 d/wk plus weekly trastuzumab. The primary end point was objective response (OR). Results: Thirty-four patients were enrolled (91% had received 1 or 2 previous trastuzumab-based therapies, whereas 9% had received 3 previous therapies). The most common reasons for discontinuation were disease progression (62%) and adverse events (AEs; 24%). Three patients died; 1 because of bowel perforation, which was possibly ridaforolimus related. Partial response was observed in 5 patients (15%). Median duration of response was 19.1 weeks (range, 15.9-80.1 weeks). Fourteen patients (41%) achieved stable disease (SD); 7 patients (21%) maintained SD for >= 24 weeks. The clinical benefit response (CBR) rate was 34.3%. Median progression-free survival (PFS) and overall survival (OS) were 5.4 months (range, 0-20.3 months; 95% confidence interval [CI], 2.0-7.4) and 17.7 months (range, 0-25.9 months; 95% CI, 8.8-20.8), respectively. PFS rate at 6 months was 37%. The most common treatment-related AEs were stomatitis (59%), diarrhea (27%), and rash (27%). Conclusion: Ridaforolimus-trastuzumab was well tolerated and demonstrated antitumor activity in trastuzumab-resistant HER2(+) MBC.