Erdafitinib Demonstrates Promising Efficacy in FGFR-Altered Solid Tumors: NCI-MATCH Subprotocol K2 Results

Authors: Jun Gong, MD; Alain C. Mita, MD; Zihan Wei, MS; Heather H. Cheng, MD; Edith P. Mitchell, MD; John J. Wright, MD, PhD; S. Percy Ivy, MD; Victoria Wang, PhD; Robert C. Gray, PhD; Lisa M. McShane, PhD; Larry V. Rubinstein, PhD; David R. Patton, MS; P. Mickey Williams, PhD; Stanley R. Hamilton, MD; James V. Tricoli, PhD; Barbara A. Conley, MD; Carlos L. Arteaga, MD; Lyndsay N. Harris, MD; Peter J. O’Dwyer, MD; Alice P. Chen, MD; Keith T. Flaherty, MD.

Introduction:

FGFR pathway alterations, including gene mutations, copy-number amplifications, and gene rearrangements or fusions, are found in approximately 5-10% of all human cancers. Erdafitinib was the first FGFR inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma, and other FGFR inhibitors have been approved for patients with cholangiocarcinoma and myeloid/lymphoid neoplasms. This study aimed to evaluate the activity of erdafitinib in a broader spectrum of FGFR-altered solid tumors.

Design:

• The NCI-MATCH subprotocol K2 was a phase II, single-arm study evaluating the efficacy of the oral FGFR1-4 inhibitor erdafitinib in patients with solid tumors harboring FGFR1-4 mutations or FGFR1-3 fusions, excluding urothelial carcinoma.
• Of the 35 patients enrolled, 25 had centrally confirmed FGFR alterations and were included in the primary analysis.
• The majority of patients (52%) had received 3 or more prior lines of therapy, and the most common tumor types were intrahepatic cholangiocarcinoma (20%), glioblastoma (16%), and endometrioid endometrial adenocarcinoma (12%).
• The primary endpoint was objective response rate (ORR), with key secondary endpoints of safety, progression-free survival (PFS), and overall survival (OS).

What We Learned:

In the primary analysis cohort of 25 patients with centrally confirmed FGFR alterations, the ORR was 16% (4 out of 25 patients), meeting the study’s primary endpoint. An additional seven patients experienced stable disease as the best confirmed response. Notably, responses were observed in patients with intrahepatic cholangiocarcinoma, adenoid cystic head and neck cancer, gynecologic cancer, and IDH1-/2-wildtype brain tumors. The median PFS and OS were 3.6 months and 11.0 months, respectively.

Key Highlights:

• Erdafitinib demonstrated a centrally confirmed ORR of 16% and a clinical benefit rate of 32% across a spectrum of solid tumors.
• Responses were observed in patients with FGFR2 or FGFR3 alterations, including fusions, in tumor types such as cholangiocarcinoma, adenoid cystic head and neck cancer, and a malignant Brenner tumor of the ovary.
• Four patients, including those with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma, experienced prolonged PFS of more than 168 days.
• Exploratory analyses suggested that co-occurring mutations in BAP1 were associated with positive predictors of benefit, while mutations in TP53, PTEN, and PIK3CA were associated with a lack of benefit.
• Erdafitinib was generally well-tolerated, with no new safety signals observed, and no treatment-related grade 4-5 adverse events were reported.

Key Takeaway Messages:

• This study supports the potential of erdafitinib to treat FGFR-altered malignancies, particularly those with FGFR2/3 fusions, in a tumor-agnostic fashion.
• The findings suggest that better patient selection based on specific FGFR alterations, such as FGFR2-3 fusions, may be warranted to optimize the clinical benefit of FGFR-targeted therapies.
• The identification of predictive biomarkers, such as co-occurring mutations, could help guide patient selection for FGFR-targeted therapies.
• Further investigation of erdafitinib and other FGFR inhibitors in larger, biomarker-driven trials is warranted to fully explore their potential in treating a broader range of FGFR-altered solid tumors.

Summary by Amalya Sargsyan, MD

Phase II Study of Erdafitinib in Patients With Tumors With Fibroblast Growth Factor Receptor Mutations or Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K2