Johnson & Johnson's Janssen Pharmaceuticals announced the preliminary results of Valvesa's (Erdafitinib)'s key Phase II RAGARO trial (NCT04083976) (Abstract #3007) in the form of an oral presentation.
Previously, on April 12, 2019, the U.S. FDA approved erdatinib for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who carry FGFR2/3 mutations or fusions and develop disease progression during or after platinum chemotherapy (including within one year of neoadjuvant chemotherapy or adjuvant chemotherapy).
The FGFR kinase inhibitor Balversa is on the brink
Balversa is an FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. Erdatinib can also bind to RET, CSF1-R, PDGFRA, PDGFRB, FLT4, KIT and VEGFR2.
Fibroblast growth factors (FGFs) and their receptors (FGFRs) can activate the downstream signaling pathways regulated by them, and play an important role in biological processes such as promoting division (embryogenesis, growth and development, etc.) and non-division promotion (neuromodulation, metabolic regulation, etc.), and participate in regulating cell proliferation and migration.
FGF/FGFR signal path
FGFR is a highly similar family of receptors, including FGFR1-4. FGFR abnormalities are common in patients with solid tumors, accounting for about 7.1% of all solid tumor patients. According to Frost & Sullivan, the cancers most commonly affected by FGFR abnormalities include bladder cancer (31.7%), cholangiocarcinoma (25.2%), hepatocellular carcinoma (20.0%), breast cancer (17.5%) and stomach cancer (6.7%).
Specific FGFR abnormalities are common in specific cancer types: FGFR1 gene amplification is more common in breast cancer, lung squamous cell carcinoma, ovarian cancer, and urethral epithelial carcinoma. FGFR2 fusion is common in cervical and gastric cancers and cholangiocarcinomas; FGFR3 mutations are common in urethral epithelial cancer; The FGFR4 pathway is common in overactivation in hepatocellular carcinoma.
Inhibitor drugs that target FGFR can inhibit abnormal activation of the FGF/FGFR signaling pathway, which in turn can inhibit tumor development.
RAGNAR trial data disclosure
RAGNAR (NCT04083976) is a Phase II clinical study evaluating the efficacy and safety of Balversa in patients with advanced or metastatic solid tumors and specific types of FGFR gene alterations, independent of tumor location or histology.
The interim analysis was based on 178 patients with 32 different solid tumor histology. The most common types of tumors are cholangiocarcinoma (n=31), high-grade glioma (tumor of the brain or spinal cord) (n=29), breast cancer (n=14), pancreatic cancer (n=13), and squamous non-small cell lung cancer (n=11). The study also included tumors that occur less frequently in the real world, such as salivary adenocarcinoma and parathyroid carcinoma (rare endocrine malignancies), as well as tumors of unknown origin.
The primary endpoints of the trial were objective response rates (ORRs) assessed by an Independent Review Committee (IRC), with secondary endpoints including duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), plasma concentrations of erdatinib, adverse events, and changes in health-related quality of life.
RAGNAR study design
Among all patients, the overall objective response rate (ORR) assessed by the Independent Review Committee (IRC) was 29.2% and the ORR assessed by the investigators was 26.4%.
Efficacy of erdatinib in pan-tumor species
Responses were observed in all 14 different tumor types, including 100% orr for salivary adenocarcinoma (n=5), 31% for pancreatic cancer (n=4), and 21% for glioblastoma (n=6).
Efficacy of erdatinib in different tumor types
In addition, the disease control rate (DCR) was 72.5%; The median duration of response (DOR) was 7.1 months, and at the data cut-off, 24 patients (51.1%) who responded to treatment continued to show remission. Median progression-free survival (PFS) was 5.2 months and median overall survival (OS) was 10.9 months.
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The RAGNAR trial showed that the safety of erdatinib in metastatic urothelial carcinoma is consistent with the known safety profile. In addition, 44.9% of patients with tumor types reported adverse reactions of grade 3 or higher, which could be managed by interruption of supportive care and treatment or dose reduction if necessary.
7.3% of patients discontinued the drug due to drug-related adverse reactions.
Safety analysis of erdatinib in the RAGNAR study
brief summary
This interim analysis of the Phase II RAGARO trial showed that erdafitinib has good efficacy and safety in patients with solid tumors with various FGFR mutations.
"The development of FGFR gene mutation diagnosis has opened up targeted therapies that do not distinguish between tumor types," said Dr. Yohann Loriot, principal investigator of the trial, "and the results of the RAGNAR trial show that by targeting the inhibition of FGFR receptors, we may be able to provide more appropriate treatment for patients with advanced FGFR-driven tumors, regardless of tumor location and histological type." ”
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