51P Toxicity profile in early clinical trials with fibroblast growth factor receptor (FGFR) inhibitors (FGFRi): 10-years experience of a drug development unit

FGFRi have been in clinical development for over 10 years, with recent approvals in patients (pts) with cholangiocarcinoma and urothelial tumors with FGFR alterations. Management of toxicity is still challenging with 10-20% of pts experiencing at least one dose reduction, especially hyperphosphatemia. The purpose of our work was to evaluate biomarker inclusion and toxicity profile of pts treated with FGFRi. FGFRi-naïve pts included in early clinical trials with FGFRi in VHIO´s Early Drug Development Unit were included in the analysis. Adverse events were evaluated using CTCAE 4.03. A total of 72 eligible pts were treated between 2012-2022 with 6 different FGFRi. Median age was 56y, 73% female, main tumor types were breast cancer(37%) and colorectal cancer(14%). Most pts(85%) were included based on a biomarker (47% FGFR amplification, 4% FGFR mutation, 3% FGFR fusion and 22% FGFR overexpression/ligand overexpression). Most common alterations occurred in FGFR1(40%), FGFR2(19%), FGFR3(7%), FGFR4(1.7%) and 2.7% with two or more isoforms. Pts treated with panFGFRi (1-4) (76%) had statistically higher % of G2-3 toxicity than pts treated with FGFR1-2-3i(56%)(p<0.01). The commonest ≥G2 toxicity in both groups was hyperphosphatemia (7% G3 and 43% G2), fatigue (17%;G2-3), skin and nail changes (10%;G2-3), ocular/corneal toxicity(8%;G2-3) and diarrhea(6%;G2-3). 40% of pts experiencing G2-3 hyperphosphatemia needed at least 1 dose reduction, and 51.5% had to interrupt treatment. The % of G3 toxicity was statistically superior in pts treated at doses >RP2D than at doses ≤RP2D (p<0.01). Among 16 pts that received doses >RP2D, 68% exhibited G3 toxicity, 75% underwent a dose interruption, and 50% needed dose reduction. Among 56 pts treated at ≤RP2D doses 20% exhibited G3 toxicity, 25% had at least 1 dose interruption and 23% needed dose reduction. Toxicity management with FGFRi remains challenging with a high proportion of pts requiring dose reductions or interruptions even at the RP2D. FGFRi that spare FGFR4 were associated with lower G3 toxicity. The impact of hyperphosphatemia highlights the potential role of more specific inhibitors.