Phase Ib Trial of Fulvestrant, Palbociclib, and Erdafitinib, a pan-FGFR Tyrosine Kinase Inhibitor, in HR+/HER2- Metastatic Breast Cancer

Abstract

Purpose: We report herein a phase Ib trial to determine the safety, tolerability, and antitumor activity of erdafitinib, a pan-FGFR tyrosine kinase inhibitor, with fulvestrant and palbociclib in patients with hormone receptor-positive/HER2-negative metastatic breast cancers (NCT03238196).

Patients and methods: Thirteen patients were enrolled on the escalation phase in a traditional 3 + 3 trial design to determine the maximum tolerated dose (MTD). Subsequently, 22 patients were treated at the established MTD during the expansion phase. All patients had received prior treatment with cyclin-dependent kinase-4/6 inhibitors and endocrine therapy, and 29 showed FGFR pathway alterations in their tumors.

Results: The MTD of erdafitinib was 6 mg taken orally once daily when combined with palbociclib and fulvestrant. The triple combination showed clinically manageable tolerability. Most common adverse events were neutropenia, likely attributable to palbociclib, and oral mucositis and hyperphosphatemia, attributable to erdafitinib. Three patients showed a partial response, one of them lasting more than 2.5 years, despite lacking detectable FGFR1 to FGFR4 somatic alterations. FGFR1 amplification was not associated with response to FGFR inhibition, but high FGFR1 protein expression, measured by IHC, correlated with longer progression-free survival within the FGFR1-amplified cohort. There was no correlation between FGFR1 copy number and FGFR1 protein levels in specimens from metastatic sites, potentially highlighting the need for a more recent metastatic tumor biopsy for biomarker evaluation.

Conclusions: The trial endpoint was met establishing the MTD of erdafitinib at 6 mg. Whereas the triplet regimen may pose tolerability challenges, alterative doublets with selective FGFR1 inhibitors in patients with FGFR1-dependent tumors, possibly administered in sequence, are worthy of further investigation.

Figure 1:

Consort diagram

Figure 2:. Response to the combination of fulvestrant, palbociclib and erdafitinib.

Swimmers plot showing time on treatment, start of response (if any), reason for end of treatment. Patients are color coded by FGFR1-4 amplification status. Star (*) indicates patient with FGFR1, 2 and 3 amplification bearing tumor. Arrows correspond to follow-up after treatment discontinuation.

Figure 3:. Response to fulvestrant, palbociclib and erdafitinib combination according to FGFR1 gene status and protein expression.

A) Kaplan-Meier curve stratified by A) FGFR1-4 amplification status (n=31), and B) FGFR1:CEP8 ratio by FISH for the FGFR1 amplified sub-cohort (n=22). High FGFR1 amplification was defined as FGFR1:CEP8 ≥5 based on the cut-off set on previous publications. We also explored cut-off of FGFR1:CEP8 ≥10 on Supplemental Figure 2. PFS: progression free survival. C) Representative images of FGFR1 IHC categorized as 3+ (top), 2+ (middle) and 1+ (bottom). D) Kaplan-Meier curve stratified by FGFR1 protein expression by IHC for the FGFR1 amplified sub-cohort (n=21). E) Correlation between FGFR1 CN by FISH and FGFR1 membranous H-score by IHC (n=28). Coloring represents site of sample evaluated. Primary breast cancer samples (cyan circles n= 17) were used for biomarker analysis when metastatic site samples (pink triangles n=12) were unavailable. Black dotted line represents cut-off for amplification and 2+/3+ IHC categories.