Abstract P1-09-11: A phase Ib study of oral administration of lucitanib in combination with fulvestrant in patients with HR+ metastatic breast cancer (mBC)
Authors: Campone M , Bachelot T , Penault-Llorca F , Pallis A , Agrapart V , Pierrat M-J , Poirot C , Paux G , Dubois F , Xuereb L , Robert R , Andre F 
Published: February 2018

Abstract
FGFR1 amplification could mediate resistance to endocrine therapy and FGFR1 inhibition reverses this resistance. This phase Ib seeks to evaluate whether the combination of lucitanib, a potent FGFR/VEGFR/PDFGR inhibitor, in combination with fulvestrant, an endocrine agent, reverses resistance to fulvestrant.
Eligible patients for this study were postmenopausal with ER+/HER2- mBC and have relapsed during or after treatment with fulvestrant. There were 2 parts in the study: a dose allocation to assess the tolerability of the combination in terms of DLTs and MTD using a modified Continual Reassessment Method (mCRM) [part I] and a dose expansion, with patients assigned to 2 different cohorts based on FGFR amplification, to further evaluate the tolerability of the combination and to identify the recommended phase II dose (RP2D) [part II]. Surrogate target hitting biomarkers were also dosed at baseline and on-treatment. The sponsor decided to halt the clinical development in mBC indication and the study was prematurely terminated after 18 patients (15 in part I and 3 in part II). The presentation will focus on these 18 patients.
Patients had ECOG PS 0 or 1 and median number of previous treatments in metastatic setting was 3. Two doses of lucitanib (10mg daily n=9 and 12.5mg daily n=6) in combination with 500 mg/month of fulvestrant were tested in part I. At the 10mg dose level, one patient experienced a DLT (grade 3 hypertension). Based on global lucitanib development program data, it was decided to start Part II with lucitanib 10mg daily. The most common related grade ≥3 toxicities occurring in more than 10% of patients were hypertension (78%) and asthenia (22%). All patients required at least one dose interruption mainly for toxicities, while 13 patients (72%) required at least a dose reduction for toxicities. Thirteen patients (72%) withdrew from the study for disease progression, 3 (17%) for adverse events (at 10mg) and 2 (11%) for non-medical reasons. Three patients achieved a confirmed partial response (as per RECIST v1.1), one at 10mg and two at 12.5mg. About 55% of the patients experienced clinical benefit with a median duration of the benefit of 39.6 weeks and a maximun duration of the benefit of 79.1 weeks for 1 patient (PR at Cycle 4). Biomarker modulations were consistent with lucitanib mode of action; targeting VEGFRs (significant increase of VEGFA, IL8, PlGF) and FGFR1 (significant increase of FGF23).
The combination is feasible but requires close patient monitoring and intensive management of adverse events. Those are in line with the anti-angiogenic activity of lucitanib.
10mg (N=12)12.5mg (N=6)All (N=18)Objective Response Rate (ORR)n(%) 11 (8.3)2 (33.3)3 (16.7) 95% CI 3[1.5;35.4][9.7;70.0][5.8;39.2]Clinical Benefit Rate (CBR)n(%) 24 (33.3)6 (100.0)10 (55.6) 95% CI 3[13.8;61.0][61.0;100.0][33.7;75.4]Duration of Clinical Benefitmedian (weeks)28.171.339.6 95% CI 3[27.9; 32.7][29.1; 79.1][27.9; 79.1]1: CR or PR 2: CR or PR or stabilization (SD or NonCR/NonPD) &gt;24 weeks or at end of cycle 6 3: 95% Wilson method of Confidence interval of the estimate
Citation Format: Campone M, Bachelot T, Penault-Llorca F, Pallis A, Agrapart V, Pierrat M-J, Poirot C, Paux G, Dubois F, Xuereb L, Robert R, Andre F. A phase Ib study of oral administration of lucitanib in combination with fulvestrant in patients with HR+ metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-11.