A multicenter, open-label phase II trial of dovitinib, an FGFR1 inhibitor, in FGFR1 amplified and non-amplified metastatic breast cancer.

Abstract

508 Background: Amplification of the FGFR1 gene occurs in ≈ 10% of breast cancers (BC), correlates with FGFR1 overexpression, and is mainly observed in ER+/Her2− BCs. Preclinical (pc) studies suggest that FGFR1 is a candidate therapeutic target in BC. Dovitinib (TKI258) is a tyrosine kinase inhibitor that targets FGFR, VEGFR, and PDGFR. In pc models, dovitinib demonstrated potent antitumor activities in FGFR1−amplified tumor cell lines. Methods: A 2-stage, phase 2 study to determine the efficacy and safety of dovitinib in 4 groups (gps) of metastatic BC patients (pts): (gp 1: FGFR1+, HR+), (gp 2: FGFR1+, HR−) (gp 3: FGFR1−, HR+), (gp 4: FGFR1−, HR−). Pt selection was performed according to FISH/CISH for FGFR1 (cut-off ≥ 6 gene copies). Dovitinib (500 mg) was administered once daily on a 5-day on/ 2-day off schedule. The primary endpoint was RECIST best overall response rate in pts with measurable disease per external radiology review. Results: As of January 2011, 81 pts were treated, with data for 77 pts available (gp 1 = 21, gp 3 = 34, gp 4 = 22). Prior therapy in the metastatic setting: a median of 2 chemotherapy lines (all pts) and 2 endocrine therapy lines (HR+ pts). 58% of pts had liver metastases (gp1: 81%; gps 3,4: 50%). Most common adverse events included: vomiting (75%; grade 3 [g3]: 6%), diarrhea (72%; g3: 6%), nausea (62%; g3: 5%), and asthenia (61%; g3: 17%). Median exposure was 1.7 (range, 0-8.2) months (mos), including 8 pts who received > 4 mos of therapy. For pts with measurable disease at baseline: gp 1, 2 (13%) had unconfirmed partial responses, and 7 (44%) pts had stable disease ≥ 4 mos (SD4); gps 3 and 4, SD4 was respectively noted in 8 (29%) and 2 (11%) pts. Conclusions: This is the first trial reporting efficacy of an FGFR1 inhibitor in pts with FGFR1−amplified BCs. Dovitinib showed antitumor activity in this heavily pretreated BC population with extensive visceral involvement. Activity was observed in HR+ pts with FGFR1−amplified disease with disease stabilization observed in other subgroups. FGFR1 is likely a relevant target in BC and FGFR1 amplification may define a molecular segment of dovitinib-sensitive disease. Further evaluation of dovitinib in pts with HR+ BC is planned.