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

PURPOSE

We report herein a phase Ib trial to determine safety, tolerability and anti-tumor activity of erdafitinib, a pan-FGFR tyrosine kinase inhibitor, with fulvestrant and palbociclib in patients with HR+/HER2-negative metastatic breast cancers (NCT03238196).

EXPERIMENTAL DESIGN

Thirteen patients were enrolled on escalation phase in a traditional 3+3 trial design to determine maximum tolerated dose (MTD). Subsequently, twenty-two patients were treated at the established MTD during the expansion phase. All patients had received prior treatment with CDK4/6 inhibitors and endocrine therapy, 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 over 2.5 years, despite lacking detectable FGFR1-4 somatic alterations. FGFR1 amplification was not associated with response to FGFR inhibition, but high FGFR1 protein expression, measured by immunohistochemistry, 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 of a more recent metastatic tumor biopsy for biomarker evaluation.

CONCLUSIONS

The trial endpoint was met establishing the MTD of erdafitinib at 6 mg. While 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.