Study on the Efficacy of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions

This academic report is based on the scientific paper “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,” and introduces the study’s academic background, purpose, methods, results, and conclusion.

Academic Background

The fibroblast growth factor receptor (FGFR) family consists of four receptor tyrosine kinases (FGFR1-4) that are activated by over 20 known fibroblast growth factor (FGF) ligands, initiating signaling cascades crucial for cell proliferation, survival, angiogenesis, and differentiation. Aberrations in FGFR1-4, including gene mutations (such as single nucleotide variants (SNVs)), copy number amplifications, gene rearrangements or fusions, have been found in approximately 5%-10% of all human cancers. Erdafitinib, discussed in this paper, is the first FGFR inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR3 gene mutations or FGFR2/FGFR3 gene fusions. In addition to Erdafitinib, two other FGFR inhibitors, Pemigatinib and Infigratinib, have also been approved for patients with locally advanced or metastatic cholangiocarcinoma.

Paper Origin

This paper is co-authored by multiple scholars from renowned research institutions such as Cedars-Sinai Medical Center, Dana Farber Cancer Institute, and University of Washington. It was published in JCO Precision Oncology, a journal under the Journal of Clinical Oncology, and released on April 11, 2024.

Research Methods

Patient Selection

The study included adult patients with any solid tumors, excluding urothelial carcinoma, lymphoma, or multiple myeloma. Patients needed to have progressed on standard treatment or have no standard treatment options available. Detailed inclusion criteria required appropriate hematological, liver, and kidney function parameters and central confirmation of tumor FGFR1-4 mutations or FGFR1-3 fusions. Patients who had not received previous FGFR-targeting inhibitors were included in this study.

Tumor Characterization

Tumor features were evaluated using the Oncomine Cancer Panel, and 4066 predefined gene variants were detected and reported using Ampliseq chemistry and PGM sequencers. The study employed a next-generation sequencing panel containing 143 genes, including SNVs, indels, amplifications, and selected fusions. Central testing tried to confirm all patients deemed eligible by external laboratories.

Study Design and Evaluation

Patients were assigned via a defined informatics rules algorithm, MATCHBox. Erdafitinib was administered orally at a fixed dose of 8mg daily, with each cycle lasting 28 days. On the 15th day of the first cycle, the dose was increased to 9mg daily if serum phosphate levels were less than 5.5mg/dl and no significant toxicity was observed. Treatment effects were evaluated using RECIST version 1.1 criteria every two cycles until disease progression. Toxicity was assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0.

Statistical Considerations

The primary analysis included patients who met eligibility and received treatment, excluding those included based on external testing results but not confirmed by MATCH testing. 90% two-sided confidence intervals were calculated for overall response rate (primary endpoint) and the proportion of patients surviving and progression-free within 6 months of treatment initiation (secondary endpoint).

Research Results

Patient and Tumor Characteristics

From July 3, 2018, to July 15, 2019, 35 patients were enrolled, with 25 patients included in the primary efficacy analysis. The median age was 61 years, and 52% of patients had received three or more lines of prior treatment. Peripheral blood samples were confirmed by the central MATCH test.

Efficacy

As of the data cut-off date in June 2022, all 25 patients had discontinued study treatment. The primary efficacy analysis showed a confirmed objective response rate of 16% (4 out of 25 cases, 90% CI 5.7 to 33.0). Additionally, 7 patients experienced stable disease (SD) as the best confirmed response. The median progression-free survival (PFS) was 3.6 months, and the overall survival (OS) was 11 months. Erdafitinib was manageable, with no new safety signals observed.

Safety

34 patients treated with Erdafitinib were evaluated for safety. The most common grade 1-2 adverse events included dry mouth (52.9%), diarrhea (50%), fatigue (47.1%), and anemia (32.4%). Common grade 3 adverse events included mucositis (14.7%) and fatigue (2.9%). No treatment-related grade 4 or 5 adverse events were reported.

Predictive Biomarkers

Exploratory analyses found that co-occurrence of BAP1 mutations was associated with Erdafitinib efficacy, while TP53, PTEN, and PIK3CA mutations were associated with poorer efficacy.

Conclusion

This study confirms that Erdafitinib has therapeutic potential in multiple solid tumor types with FGFR1-3 mutations or fusions, supporting its use in progressively intractable solid tumors and potential extension to unapproved indications.

Study Highlights

1. Key Findings: Erdafitinib shows anti-tumor activity across different solid tumors, with a notable effect in FGFR2/3 fusion tumors.
2. Innovations in Study Methods and Processes: Advanced tumor characterization methods, such as the Oncomine Cancer Panel, were used, and precise patient assignment was achieved through the MATCHBox algorithm.
3. Application Value: Provides novel insights for combating tumor resistance with Erdafitinib in future treatments.

This study further clarifies the efficacy of FGFR inhibition in various cancers, providing robust data support for personalized treatment strategies.