Purpose: Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor. Patients and Methods: Patients age !18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 doseescalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested. Results: The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were <10%. Conclusions: Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Expanded clinical experience with patients taking antiangiogenic compounds has come with increasing recognition of the renal adverse effects. Because renal histology is rarely sought in those patients, the renal consequences are underestimated. Antiangiogenic-treated-cancer patients, who had a renal biopsy for renal adverse effects from 2006 to 2013, were included in the current study. Clinical features and renal histologic findings were reviewed. Our cohort was 100 patients (58 women) with biopsy-proven kidney disease using anti-vascular endothelial growth factor (VEGF) therapy with a mean age of 59.8 years (range, 20–85 yr). Patients were referred for proteinuria, hypertension, and/or renal insufficiency. Kidney biopsy was performed 6.87 ± 7.18 months after the beginning of treatment. Seventy-three patients experienced renal thrombotic microangiopathy (TMA) and 27 patients had variable glomerulopathies, mainly minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS). MCN/cFSGS-like lesions developed mainly with tyrosine-kinase inhibitors, whereas TMA complicated anti-VEGF ligand. Thirty-one percent of TMA patients had proteinuria up to 1 g/24 h. Half of TMA cases are exclusively renal localized. Pathologic TMA features are intraglomerular exclusively. MCN/cFSGS glomeruli displayed a high abundance of KI-67, but synaptopodin was not detected. Conversely, TMA glomeruli exhibited a normal abundance of synaptopodin-like control, whereas KI-67 was absent. Median follow-up was 12 months (range, 1–80 mo). Fifty-four patients died due to cancer progression. Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents. No patient developed severe renal failure requiring dialysis. Drug continuation or reintroduction resulted in a more severe recurrence of TMA in 3 out of 4 patients requiring maintenance of anti-VEGF agents despite renal TMA. In conclusion, TMA and MCN/cFSGS are the most frequent forms of renal involvement under anti-VEGF therapy. Careful risk-benefit assessment for individual patients should take into account risk factors related to the host and the tumor.