Phase II Study of Erdafitinib in Patients with FGFR Amplifications: A Detailed Report

Background

Dysregulation of Fibroblast Growth Factor Receptor (FGFR) family signaling pathways is widely recognized to be associated with cancer development, progression, and treatment resistance. This study primarily investigates tumors with FGFR1-4 amplifications, despite FGFR inhibitors being approved for specific types of tumors carrying FGFR rearrangements or genetic mutations—FGFR gene amplification is the most prevalent. Therefore, the study aims to evaluate the anti-tumor effects of the oral FGFR1-4 inhibitor erdafitinib in patients with tumors carrying FGFR1-4 amplifications.

Study Source

The study was authored by Jun Gong, Alain C. Mita, Zihan Wei, Heather H. Cheng, Edith P. Mitchell, and others from institutions like Cedars-Sinai Medical Center, Dana Farber Cancer Institute, University of Washington, etc. The study was published on April 11, 2024, in the Journal of Clinical Oncology Precision Oncology.

Study Design and Methods

Study Process

This study was an open-label, single-arm, Phase II clinical trial, enrolling tumor patients confirmed to have FGFR1-4 amplifications, excluding those with urothelial carcinoma. The study process was as follows: 1. Patient Screening and Enrollment: From August 20, 2018, to April 30, 2019, 35 patients were recruited. Ultimately, tumors from 18 patients were confirmed to have FGFR amplifications, comprising the primary efficacy analysis population. 2. Treatment Regimen: Enrolled patients received erdafitinib, starting at a dose of 8mg daily, adjusted to 9mg based on phosphate levels, until disease progression or intolerable toxicity.

Data Analysis and Methods

1. Efficacy Evaluation: The primary endpoint of the study was the Objective Response Rate (ORR), with secondary endpoints including a 6-month Progression-Free Survival (PFS6), Overall Survival (OS), and safety.
2. Statistical Methods: A 90% two-sided confidence interval was used to assess the efficacy of the ORR. If an ORR ≥ 16% was observed, the drug would be considered to have potential clinical activity, warranting further investigation.

Study Results

Patient and Tumor Characteristics

Of the 35 patients, FGFR amplification was confirmed in 18, forming the primary analysis group. Among them, 12 were female, with an average age of 60 years, and 78% had received ≥3 prior treatments. The main tumor types included breast cancer, gastrointestinal cancer, and uterine mixed malignant tumors.

Efficacy Analysis

In the primary analysis population, no confirmed responses were observed, and 5 patients achieved stable disease (SD). The median Progression-Free Survival (PFS) was 1.7 months, and the median Overall Survival (OS) was 4.2 months.

Safety and Adverse Events

The toxicity of erdafitinib was evaluated in 33 patients. Common 1-2 grade treatment-related adverse events (AEs) included dry mouth (45.5%), hyperphosphatemia (30.3%), fatigue (30.3%), and diarrhea (24.2%). One case of grade 5 liver failure related to the treatment was reported.

Discussion

Significant Findings

1. Low Efficacy: Erdafitinib’s ORR in this patient population was 0%, failing to meet the primary endpoint. This contrasts with previous preclinical data and may be attributed to higher dose treatment, lower levels of FGFR amplification, and concomitant other mutations.
2. Tumor Heterogeneity: The study highlighted differences in treatment responses among various FGFR amplification types. High FGFR2 amplification showed better treatment response, while FGFR1 amplification responded poorly, potentially due to low protein expression consistency.
3. Potential for Combination Therapy: The study suggests that future might require more specialized FGFR2 inhibitors or combination therapy strategies, such as using PI3K, mTOR, or ER pathway inhibitors, to enhance efficacy.
4. Toxicity Management: The study found that erdafitinib was generally well-tolerated in most patients, although severe adverse events occurred in a few.

Significance and Value of the Study

This study provides clinical evidence of the insensitivity of FGFR1-4 amplified tumors to erdafitinib treatment. These findings offer important references for future clinical trials, particularly in selecting appropriate patients and devising optimized treatment strategies. Additionally, the study underscores the necessity of testing FGFR inhibitors under higher amplification conditions and developing new combination therapy plans to address co-existing oncogenic pathways.

Conclusion

Although erdafitinib failed to demonstrate satisfactory efficacy in patients with FGFR1-4 amplified tumors, this trial enhanced the understanding of FGFR1-4 amplifications in tumor treatment. It suggests careful patient selection and the need for potentially combined treatment methods in future research. This study provides critical guidance for both future clinical research and practical applications.