Lucitanib for the treatment of HR+ HER2- metastatic breast cancer (MBC) patients (pts): Results from the multicohort phase II FINESSE trial

Abstract

Background Fibroblast growth factor receptor-1 (FGFR1) gene is amplified in about 15% of HR+ HER2- breast cancer (BC) pts. Lucitanib is an inhibitor of FGFR1 and VEGFR-1,2, and 3. Methods HR+ HER2- MBC pts received oral lucitanib in 3 centrally confirmed cohorts: 1) FGFR1 amplified, 2) FGFR1 non-amplified, 11q13 amplified, 3) FGFR1 and 11q13 non-amplified, until intolerable toxicity, disease progression or pt withdrawal. Main inclusion criteria included ECOG PS < 1, at least 1 line and no more than 2 lines of chemotherapy. Primary endpoint was ORR. The study used a Simońs 2-stage design: if > 2 pts responded among 21 pts, 20 additional pts could be enrolled in each cohort. FGFR1 copy number variations (CNV) were determined by FISH and ddPCR, while FGFR1 expression by IHC. Serum FGF23 was assessed by ELISA. Results 76 pts (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. 92% of pts had received >1 lines of chemotherapy. The most frequent AEs were hypertension (76% grade >3), hypothyroidism (45%), nausea (33%) and proteinuria (32%). ORR were 19% (95%CI: 9-35%), 0% (0-17%), 15% (6-33%) in cohorts 1, 2, 3 respectively. Clinical benefit rates (CR, PR and SD > 24 weeks) were 41% (25.52 - 57.7), 11% (3.10 - 32.8), 27% (13.70 - 46.1) respectively. Exploratory biomarker analyses suggested that pts with high FGFR1 amplification (FGFR1/centromere ratio >4 , n = 16) presented higher ORR than those without high level amplification (n = 37) (25% versus 8%). ORR in pts with FGFR1-high tumors (IHC, H-score >50) was 25% (n = 5/20) while ORR was 8% in FGFR1-low cancers. The 20 patients with FGFR1 membrane over-expression had in average 3-month longer PFS (212[165-NA] days) than other patients (109[57-158] days). Serum FGF23 levels after 14 days of lucitanib were significantly increased from baseline (p < 0.0001), suggesting an effective targeting on FGFR. Conclusions While the study was stopped prematurely based on a decision by the sponsor in relation to efficacy and safety signals, the FINESSE trial suggests that lucitanib has antitumor activity in pts with HR+ HER2- MBC. Biomarker analyses generates the hypothesis that pts with high FGFR1 expression could derive more benefit. This population deserves further exploration in large trial. Clinical trial identification NCT02053636 Protocol no.: BIG 2-13/CL2-80881-001