Efficacy of erdafitinib in adults with advanced solid tumors and non-prespecified fibroblast growth factor receptor mutations in the phase 2 RAGNAR trial: Exploratory cohort.
Authors: Lugowska Iwona A. , Schuler Martin H. , Loriot Yohann , Carranza Omar , Iyer Gopa , Doi Toshihiko , Qin Shukui , Tabernero Josep , Reardon David A. , Massard Christophe , Arnold Dirk , Gutierrez Martin , Winter Helen , Sweiti Hussein , Xia Karen , Najmi Saltanat , Hammond Constance , Thomas Shibu , Triantos Spyros , Pant Shubham 
Published: June 2024

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Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. Primary analysis of the RAGNAR study Broad Panel Cohort (BPC) demonstrated tumor agnostic efficacy with an objective response rate (ORR) of 30% in pts with solid tumors harboring predefined susceptible FGFR mutations ( FGFRmut) or fusions (Pant 2023). Here we report on efficacy results in the RAGNAR exploratory cohort investigating erdafitinib in pts with other FGFRmut that were not predefined as potentially susceptible FGFRmut. Methods: Pts with advanced non-urothelial solid tumors harboring non-predefined FGFRmut, who had disease progression after ≥1 line of systemic therapy and who exhausted standard therapy options received oral erdafitinib 8 mg daily with optional up-titration until disease progression or intolerable toxicity. Eligible pts had FGFRmut that were not predefined as potentially susceptible. Objective was to evaluate efficacy of erdafitinib based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) objective response rate (ORR), duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS). Results: At data cutoff, 53 pts received erdafitinib. Median age was 62 years (range 24-80). Most common histologies were cholangiocarcinoma (n=10), breast cancer (n=7), endometrial cancer (n=6), squamous cell head and neck cancer (n=5), ovarian cancer (n=4), soft tissue sarcoma (n=4); 94% of patients had visceral metastases. Pts had a median of 3 prior lines of systemic therapy. Pts had mutations in FGFR1 (17%), FGFR2 (17%), FGFR3 (30%), and FGFR4 (38%). ORR was 4%; DCR 45%; and CBR 17%. Median PFS was 0.94 months (95% CI 0.49, not evaluable); median OS was 1.79 months (95% CI 0.92, not evaluable). Most common adverse events (AE) were hyperphosphatemia (79%), diarrhea (53%), dry mouth (45%), stomatitis (42%), decreased appetite (38%), fatigue (32%), and increased alanine transaminase levels (32%). 49% of pts had serious treatment-emergent AEs. No treatment-related deaths were observed. Conclusions: In contrast to tumor-agnostic efficacy of erdafitinib reported in pts with predefined FGFR alterations (mutations or fusions), clinical activity was limited in tumors with FGFRmut not predefined as potentially susceptible. These findings further validate the predictive FGFRbiomarker panel, studied in the RAGNAR BPC in pts with advanced solid tumors and highlight the importance of careful FGFRmut selection for targeted FGFR inhibition. Clinical trial information: NCT04083976 .