3206 - Hyperphosphatemia due to Erdafitinib (a Pan-FGFR Inhibitor) and Anti-tumor Activity Among Patients (Pts) with Advanced Urothelial Carcinoma (UC)

Background

Erdafitinib (Erda), a pan-FGFR tyrosine kinase inhibitor, recently received accelerated approval by US FDA for treatment of post-platinum advanced UC pts with certain FGFR3 or 2 alterations. Erda induces dose dependent hyperphosphatemia via inhibition of PO4 excretion.

Methods

Ph1 data and PK/PD modeling identified a serum PO4 level of ≥ 5.5 mg/dL as a PD target with acceptable tolerability. In a ph2 study (NCT02365597) pts started Erda at 8mg/day, serum PO4 was assessed every cycle, and Cycle 1 Day 14 (C1D14). Up-titration on C1D15 to 9mg/day occurred if serum PO4 was < 5.5 mg/dL and pts had no significant investigator assessed toxicity. Objective response rate (ORR) and disease control rate (DCR) were assessed by logistic regression analysis; progression free survival (PFS), and overall survival (OS) were calculated by Cox regression methods.

Results

99 patients started 8 mg Erda and 41% were up-titrated to 9 mg based on C1D14 PO4 levels. The ORR and DCR were higher (42.7% and 85.3%) when maximum PO4 levels were >5.5 mg/dL as compared to below (34.8% and 65.2%, respectively). Median OS and PFS were prolonged with levels >5.5 mg/dL as compared to below with hazard ratio of 0.35 (median not reached vs 6.7 months) and 0.68 (5.6 vs 3.8 months), respectively. Among patients that could not be up-titrated due to concurrent toxicities, ORR was 27.3% (n = 22; 95% CI- 8.7%, 45.9%) as compared to 48.8% (n = 41; 95% CI-33.5%, 64.1%) for patients who were up-titrated. Logistic regression analysis (ORR, DCR), and Cox regression (PFS, OS) showed that maximum phosphate levels positively correlated with ORR, DCR, PFS, and OS (Table).Table:

932P ORR, DCR, PFS, OS and maximum on-treatment serum PO4*

The median time to maximum = 1.3m. Note: a. variable in model. b. odds ratio c. Pearson’s chi-square p-value e. Pearson’s chi-square p-value f. derived from first row using OR^0.43 and HR^0.43, based on PKPD simulations predicting average 0.43 mg/dL increase in maximum PO4 from 8 to 9 mg at steady state.

Conclusions

Hyperphosphatemia in Erda treated pts is associated with improved outcomes, supporting optimization of Erda dosing via uptitration based on serum PO4.

Clinical trial identification

NCT02365597, February 19, 2015.

Editorial acknowledgement

Himabindu Gutha (SIRO Clinpharm Pvt. Ltd.) writing assistance, Dr. Harry Ma (Janssen Research & Development, LLC) additional editorial support.

Legal entity responsible for the study

Janssen Research & Development.

Funding

Janssen Research & Development.

Disclosure

S.T. Tagawa: Advisory / Consultancy: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi; Research grant / Funding (institution): Lily, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merc; Travel / Accommodation / Expenses: Sanofi, Immunomedics, Amgen. A.O. Siefker-Radtke: Advisory / Consultancy: Janssen, Threshold Pharmaceuticals, Merck, National Comprehensive Cancer Network, Eisai, Genentech, Vertex, AstraZeneca, EMD Serono, Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Genentech; Research grant / Funding (self): National Institutes of Health, Genentech, Janssen Pharmaceuticals, Millennium, Michael and Sherry Sutton Fund for Urothelial Cancer. A. Dosne: Full / Part-time employment: Janssen Research and Development. B. Zhong: Full / Part-time employment: Janssen Research and Development. W.S. Shalaby: Full / Part-time employment: Janssen Research and Development. A. O’Hagan: Full / Part-time employment: Janssen Research and Development. K. Qi: Stockholder / Stock options, Full / Parttime employment: Janssen Research and Development. P. De Porre: Full / Part-time employment: Janssen Research and Development. P. Mahadevia: Full / Part-time employment: Janssen Research and Development. Y. Loriot: Advisory / Consultancy: Astellas Oncology; AstraZeneca; Ipsen; Janssen; MSD; Roche; Sanofi; Research grant / Funding (self): Sanofi (Inst); Travel / Accommodation / Expenses: AstraZeneca; MSD; Roche. All other authors have declared no conflicts of interest.