A phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer

Abstract

Purpose The primary objective of this multicentric dose allocation and dose expansion study was to determine the MTD and the DLTs of the lucitanib (a tyrosine kinase inhibitor of the FGFR/VEGFR/PDFGR pathways)/fulvestrant combination. Methods Postmenopausal women with ER+/HER2− mBC, who have relapsed during or after treatment with fulvestrant, were eligible. The study had a dose allocation part to assess the tolerability of the combination followed by a dose expansion part. Results Eighteen patients with ER+, mBC were enrolled; median age was 66 years, 50% had a PS: 0 and all had received previous endocrine treatment. The study was prematurely terminated after 18 patients (15 in part 1 and 3 in part 2) based on preclinical experiments that failed to confirm the hypothesis that addition of lucitanib would reverse sensitivity to endocrine treatments. Based on data of global lucitanib development, it was decided to stop the dose allocation at 12.5 mg and to start the dose expansion part at 10 mg/day. The most common grade ≥ 3 toxicities (> 10% of patients) were hypertension (78%) and asthenia (22%). All patients required at ≥ 1 interruption, 13 patients (72%) required ≥ 1 dose reduction. Three patients (72%) withdrew from the study for AEs (at 10 mg). Three patients achieved a confirmed PR (10 mg n = 1; 12.5 mg n = 2). Conclusion Although the combination is feasible it requires close monitoring of the patients for the management of adverse events. Further investigation is required to better understand the potential role of FGFR inhibition in reversing resistance to endocrine treatment.

Lucitanib for the Treatment of HR+/HER2− Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study

“…Preclinical studies in cell lines and xenografts have demonstrated more effective inhibition of tumor cell growth with combined blockade of FGFR1 and ER using both lucitanib and fulvestrant (28). The efficacy of lucitanib in combination with fulvestrant in a small study showing CBR of 55.6% in patients with metastatic HR þ / HER2 À breast cancer with unselected FGFR1 status appeared to be numerically higher than monotherapy lucitanib in our study (48). Given the role of FGFR1 aberrations in the development of endocrine resistance, it may be useful to explore the combination of lucitanib and fulvestrant as a potential treatment for HR þ /HER2 À FGFR1-amplified breast cancers after resistance to first-line endocrine therapy.…”

FGFR1 amplification or overexpression and hormonal resistance in luminal breast cancer: rationale for a triple blockade of ER, CDK4/6, and FGFR1

“…Single-agent FGFR1-inhibitors do not show sufficiently high activity in advanced HR+ breast cancer to warrant further development [24,29,30]. Combinations of a hormonal agent and an FGFR1inhibitor show variable activity [26,27]. Our results advance in the task of finding a therapeutic scenario and a patient sub-population where FGFR inhibitors would deserve clinical investigation: HR+ breast cancer patients with amplification and/or overexpression of FGFR1 upon progression to aromatase inhibitors.…”

“…Selective FGFR inhibitors (1)(2)(3)(4) have shown activity in tumors with FGFRs mutations, amplifications, or fusions [19,[22][23][24][25]. The role of FGFR inhibitors in breast cancer, however, is yet unclear [26][27][28][29]. Preclinical and clinical data suggest limited single-agent efficacy [24,29,30].…”

“…Preclinical and clinical data suggest limited single-agent efficacy [24,29,30]. There is considerable preclinical evidence regarding the additive effects in combination with hormonal blockade [17,20], but this evidence has not translated into strong clinical activity [26,27]. With the current number of available options for advanced HR+ breast cancer [31][32][33][34][35][36][37][38], the development of FGFR inhibitors will be challenging unless a biomarker that narrows down the population that will benefit from FGFR1 blockade and a specific therapeutic niche are determined.…”

Treatment of Luminal Metastatic Breast Cancer beyond CDK4/6 Inhibition: Is There a Standard of Care in Clinical Practice?

“…Among patients in the MONALEESA-2 study, FGFR1 amplification detected in ctDNA was associated with a shorter PFS under ribociclib [56]. Initial studies failed to demonstrate a significant activity of the FGFR1-3 inhibitors lucitanib [57] and dovitinib [58] in combination with fulvestrant in endocrine-resistant patients. Clinical development is now focusing on novel FGFR inhibitors, such as erdafitinib, which is currently being investigated in combination with palbociclib and fulvestrant in CDK4/6i-pretreated patients (Table 1).…”