P3-16-15: Phase I Study with Biomarker Evaluation of Neoadjuvant Sunitinib in Combination with Exemestane in Post-Menopausal Women with Hormone-Sensitive, Her-2 Negative Primary Breast Cancer.
Authors: Morales S , Gil M , Llombart A , Garcia M , Urruticoechea A , Pernas S 
Published: June 2012

Abstract
Background
In preclinical models, oestrogen causes a rapid induction of VEGF in mammary tumours leading to tumour angiogenesis, tumor growth and cell migration whereas aromatase inhibitors (AI) have the opposite effect. Exemestane (E) is an AI, effective in metastatic hormone-dependent breast cancer, as well as in the adjuvant and neoadjuvant settings. Sunitinib (S) is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic activities via inhibition of VEGFR, PDGFR, KIT, RET, CSF-1R and FLT-3, and direct antitumor activity shown in heavily pretreated subjects with advanced breast cancer. The use of antiangiogenic agents at initial stages of the disease, when fewer proangiogenic factors are present, may result in significantly greater efficacy than using these agents at a later stage. Safety profiles of both agents indicate only modest toxicity and do not overlap. We hypothesize that since antiangiogenic and hormonal agents use different mechanisms of action, combination will have additive activity. Regarding (S), continuous dosing (CD) at low doses might result in improved efficacy while maintaining good tolerability.
Methods: This is a phase I study to evaluate the safety of (S) in combination with (E) administered for 24 weeks (1cycle=4weeks) as neoadjuvant therapy for post-menopausal women with newly diagnosed hormone-sensitive, Her-2 negative primary breast cancer. We report the results of the first dose escalation part of the study intended to determine a safe dose level of (S) that can be combined with (E) at conventional fixed dose of 25mg/d. Preliminary efficacy data in terms of objective clinical response by WHO criteria will also be reported.
Results: 18 postmenopausal women with ER-positive invasive breast cancer, adequate organ function and ECOG 0–1 were enrolled in the study (median age 74, range 57–84) to be treated at two dose levels: 25 mg of (E) with either 25mg or 37.5mg of (S) CD. Two DLTs were identified: grade 3 mucositis at level 25mg of (S) and grade 3 asthenia at level 37.5mg of (S). Main toxicities were asthenia, leucopenia, mucositis, diarrhea and HBP. 78% of patients had grade 2 toxicities; 22% had grade 3. There were no serious adverse events reported. Median time on treatment with the combination was 23 weeks (range 2–24). 16% of patients needed one dose reduction of (S), 16% needed two or more and 28% suspended (S) administration due to toxicity. 50% of patients completed 24 weeks of treatment. None of the patients at 37.5mg (S) level could tolerate full doses for the entire treatment period, therefore in our study the recommended dosage of (S) that can be safely combined with (E) is 25mg. Concerning efficacy, 11 out of 18 patients had partial response (61%), 6 out of 18 had SD (33%) and only one patient had PD (5%) as best response.
Conclusion: Safety profile of the combination seems to be manageable in most patients. Toxicities were observed mainly within the two first cycles. Response rates were similar than those previously observed with (E) as monotherapy in the neoadjuvant setting. Biomarkers information will be provided.
This study was supported by an Independent Investigator Research grant from Pfizer, Inc.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-15.