Novel Agent Motesanib (AMG-706) Active in Recurrent or Metastatic Breast Cancer

Motesanib diphosphate (AMG-706) is a novel compound that has demonstrated activity in a number of solid tumors, including gastrointestinal stromal tumors, lung cancer, thyroid cancer, and breast cancer. In a poster presentation at the ECCO 15 - ESMO 34 Joint Congress today, Peter A. Kaufman, MD, Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, discussed the promising activity demonstrated by motesanib in a small phase Ib trial of women with locally recurrent, unresectable, or metastatic breast cancer.

Oral motesanib is a small molecule tyrosine kinase inhibitor that Dr Kaufman describes as a “very potent inhibitor of all the vascular endothelial growth factor receptors (VEGFRs).” He said it is particularly potent at inhibiting VEGFR 2, a receptor essential to angiogenesis. VEGF expression in breast cancer is associated with poor clinical outcomes, such as treatment resistance, recurrence, and poor survival rates. In addition to VEGFR, motesanib inhibits platelet-derived growth factor receptor and c-KIT.

The trial sought to determine the maximum tolerated dose of motesanib when administered with paclitaxel (Taxol) or docetaxel (Taxotere). Investigators also evaluated the pharmacokinetics of motesanib administered in conjunction with these chemotherapy agents and assessed tumor response.

The 45 women in the trial had been treated with no more than one prior chemotherapy regimen for metastatic disease. They all received 50 mg or 125 mg of daily oral motesanib combined with paclitaxel or docetaxel, and cycles were repeated until signs of disease progression. Dr Kaufman described the adverse effects profile as reasonable. He noted that a phase II study of motesanib presented yesterday associated motesanib with worse adverse effects than bevacizumab (Avastin), but he disagreed with this conclusion. “They each have side effects,” he told Oncology & Biotech News, “but they’re different.” He explained that, for reasons not yet determined, motesanib is uniquely associated with a 3% to 5% rate of cholecystitis; in this trial, cholecystitis was manageable. “Unlike some of the other antiangiogenesis inhibitors, particularly Avastin, we’re seeing really no significant increase of either hypertension or thrombosis,” he said. “So we definitely have side effects, as bevacizumab does, but it’s a different side effects profile.”

Although response was not the trial’s primary endpoint, Dr Kaufman described preliminary results as “impressive” and pointed to a figure showing that “all but one patient…had some evidence of response.” Although no patient had complete response, partial response was 57% for patients in the paclitaxel plus motesanib cohort and 56% for patients who received 75 mg/m² of docetaxel plus the higher dose of motesanib. Several patients also experienced stable disease. In both arms, the response rate was higher in patients taking the 125-mg dose of motesanib, which will likely be the maximum tolerated dose, Dr Kaufman said.

Although Dr Kaufman labeled the results “interesting,” he recommended caution because it was a phase Ib study with a small number of patients. In conclusion, he said “The data clearly demonstrate activity and suggest a very favorable side effects profile, so I think we should move ahead in further studies in breast cancer.”

ECCO/ESMO Abstract PF-5029; Poster 5029 (accessible at www.poster-submission.com/visitor/pstlist)