An Exploratory Study of Sunitinib (SU) Plus Docetaxel (D) and Trastuzumab (T) for First-Line Therapy of HER2+ Advanced Breast Cancer (ABC).
Authors: Dirix L. , Canon J. , Amadori D. , Villa E. , Aldrighetti D. , Machiels J. , Verkh L. , Bouko Y. , Kern K. , Giorgetti C. , Cardoso F. 
Published: December 2010

Abstract
Background: T + D is a standard 1st-line treatment (tx) for HER2+ ABC (locally recurrent or metastatic BC). SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3 with single-agent activity in previously treated ABC. In this study, a SU/D/T combination was investigated as 1st-line tx for pts with HER2+ ABC.Materials and methods: Female pts (≥18 yrs, ECOG PS ≤1) with HER2+ ABC were enrolled. Starting doses were D: 75 mg/m2, q3w, iv, day 1; T q1w: 4 mg/kg, day 1, followed by 2 mg/kg q1w, iv or q3w: 8 mg/kg, day 1, followed by 6 mg/kg q3w, iv; SU: 37.5 mg/d, Schedule 2/1, po, day 2. The primary objective was safety. Antitumor activity and pharmacokinetics were secondary endpoints. On discontinuation of D, responsive pts (PR or SD) could continue SU + T until disease progression.Results: As of Mar 2009, 25 pts were enrolled. 1 pt did not receive tx, 1 pt received a dose of D/T (pt died from multiorgan failure after T administration), and 23 pts received ≥1 dose of SU/D/T; data from the latter group are reported. 12 pts (52%) were chemo-naïve. 5 pts continue on study tx; 18 have discontinued (8 due to PD, 2 due to pt decision, 7 due to AEs, 1 due to global deterioration). Pts received 201/128/211 cycles of SU/D/T, respectively, with a median of 9/6/10 cycles/pt (range: 1–18/1–12/1–18). The 37.5 mg/d SU dose was reduced to 25 mg/d in 14/23 pts and interrupted in 17/23 pts. AEs led to SU dose reductions/interruptions in 17 pts, most frequently grade (G) 3/4 neutropenia (n=8) and G3 febrile neutropenia, G3 fatigue, and G3 diarrhea (each n=2). In 23 evaluable pts, the most frequent non-hematologic G3 AEs were fatigue/asthenia (26%), diarrhea (13%), and stomatitis, vomiting, and dyspnea (each 9%). G4 AEs were transaminase increase, accidental overdose of SU, and intestinal perforation (each n=1). 1 cardiac AE was reported (G3 supraventricular tachycardia) and transient G1/2 LVEF decline was seen in 2 pts (9%). G3/4 neutropenia was reported in 20 pts (91%); 5 pts (22%) had febrile neutropenia. 2 pts (9%) had G3 anemia and 1 pt (4%) had G3 thrombocytopenia. G-CSF was administered to 11 pts without complications. Preliminary median steady-state levels of SU and its metabolite: 40.6 and 15.6 ng/mL, respectively; end D infusion: 993 ng/mL; T levels: &lt;20 µg/mL. In 19 evaluable pts, ORR was 79% (1 CR [5%], 14 confirmed PRs [74%], 2 SD [11%]). Preliminary median PFS was 10.5 months (95% CI: 8.1–13.6) and median DR was 9.0 months (95% CI: 7.3–12.3).Conclusions: The combination of SU/D/T, given as 1st-line tx to HER2+ pts with ABC, is feasible. AEs were manageable through dose delay/reduction, and no new, unexpected AEs occurred. SU and D levels were consistent with known single-agent levels; evaluation of T levels is ongoing. Preliminary evidence of antitumor activity is encouraging and warrants further evaluation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6088.