Erdafitinib (Balversa, Janssen Biotech) was approved by the Food and Drug Administration on January 19, 2024, for adult patients with FGFR3 genetic changes who have locally advanced or metastatic urothelial carcinoma (mUC). Patients who have had their disease get worse after receiving at least one prior systemic therapy are eligible for this approval, according to an FDA-approved companion diagnostic test. Erdafitinib is not advised for treating patients who are eligible for and have not undergone prior PD-1 or PD-L1 inhibitor therapy. This approval changes the original use for people with metastatic urothelial carcinoma (mUC) who have certain mutations in the FGFR3 or FGFR2 genes and have already been treated with platinum-containing chemotherapy.
Study BLC3001 Cohort 1 looked at how well it worked. It was a randomized, open-label trial with 266 people who had metastatic urothelial carcinoma (mUC) and certain FGFR3 mutations. These patients had undergone 1-2 previous systemic therapies, which included a PD-1 or PD-L1 inhibitor. Participants were randomly assigned in a 1:1 ratio to either receive erdafitinib or the investigator’s preferred chemotherapy option, which could be docetaxel or vinflunine. Stratified randomization was conducted based on area, performance status, and the occurrence of visceral or bone metastases. In 75% of patients at a central laboratory, therascreen FGFR RGQ RT-PCR kit (Qiagen) detected FGFR3 mutations in tumor tissue, with the remaining patients having local next-generation sequencing studies find the mutations.
The primary efficacy measure was overall survival (OS). Investigator-evaluated progression-free survival (PFS) and objective response rate (ORR) were supplementary outcome metrics.
There were statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) when erdafitinib was used instead of chemotherapy. The median overall survival was 12.1 months (95% CI: 10.3, 16.4) for patients treated with erdafitinib and 7.8 months (95% CI: 6.5, 11.1) for those who received chemotherapy. The hazard ratio (HR) was 0.64 (95% CI: 0.47, 0.88) with a p-value of 0.0050. The median progression-free survival was 5.6 months (95% CI: 4.4, 5.7) for patients treated with erdafitinib and 2.7 months (95% CI: 1.8, 3.7) for those who received chemotherapy. The hazard ratio was 0.58 (95% CI: 0.44, 0.78) with a p-value of 0.0002. The confirmed objective response rate (ORR) was 35.3% (95% CI: 27.3, 43.9) for patients who were treated with erdafitinib and 8.5% (95% CI: 4.3, 14.6) for those who received chemotherapy (p-value<0.001).
The most frequent adverse reactions, occurring in more than 20% of cases, included elevated phosphate levels, nail issues, diarrhea, inflammation of the mouth, elevated alkaline phosphatase levels, reduced hemoglobin levels, elevated alanine aminotransferase levels, elevated aspartate aminotransferase levels, reduced sodium levels, increased creatinine levels, dry mouth, reduced phosphate levels, skin condition affecting the palms and soles, altered sense of taste, fatigue, dry skin, constipation, reduced appetite, increased calcium levels, hair loss, dry eyes, elevated potassium levels, and weight loss.
The suggested erdafitinib dosage is 8 mg taken orally once a day, with a potential increase to 9 mg once daily after 14 to 21 days depending on tolerability, particularly hyperphosphatemia. Continue treatment until disease worsens or side effects become intolerable.
Targeting FGFR4 and CD276 with CAR T-cells demonstrates a strong antitumor impact against children rhabdomyosarcoma
Chimeric antigen receptor (CAR) T-cells that specifically target Fibroblast Growth Factor Receptor 4 (FGFR4), a surface tyrosine receptor that is extensively expressed in rhabdomyosarcoma (RMS), are now undergoing clinical research. However, the effectiveness of these CAR T-cells may be hindered by tumor heterogeneity and inadequate activation. In this study, we present a method to enhance the co-stimulatory and targeting characteristics of a FGFR4 CAR through an optimization process. We substituted the hinge and transmembrane domain of CD8 as well as the 4-1BB co-stimulatory domain with the corresponding domains of CD28. The CARs produced exhibit heightened anti-tumor efficacy in multiple RMS xenograft models, with the exception of the RMS559 cell line, which is known for its aggressive nature.
