Abstract 3206
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*
ORR | DCR | PFS | OS | |
---|---|---|---|---|
ORb, (95% CI), p-valuec | ORb, (95% CI), p-valuec | HR, (95% CI), p-valuee | HR, (95% CI), p-valuee | |
Prognostic variablea | ||||
Maximum PO4: per 1 mg/dL increase | 1.25, (0.86, 1.81), 0.247 | 2.31, (1.31, 4.08), 0.004 | 0.78, (0.63, 0.96), 0.021 | 0.58, (0.43, 0.80), 0.001 |
Simulated outcomes via PK/PD modeling of up-titrating from 8 mg to 9 mg QDf | 1.10 (0.93, 1.29), - | 1.43 (1.12, 1.83), - | 0.90 (0.82, 0.98), - | 0.79 (0.70, 0.91), - |
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 OR0.43 and HR0.43, 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.
Resources from the same session
5056 - Phase 2 study of 2 dosing regimens of cemiplimab, a human monoclonal anti–PD-1, in metastatic cutaneous squamous cell carcinoma (mCSCC)
Presenter: Danny Rischin
Session: Poster Display session 3
Resources:
Abstract
5710 - Avelumab for advanced Merkel cell carcinoma in the Netherlands; a nationwide survey
Presenter: Sonja Levy
Session: Poster Display session 3
Resources:
Abstract
3152 - Health-related quality of life in patients with metastatic Merkel cell carcinoma receiving second-line or later avelumab treatment: 36-month follow-up data
Presenter: Sandra D'Angelo
Session: Poster Display session 3
Resources:
Abstract
5715 - A Phase 2, Randomized Study of Nivolumab (NIVO) and Ipilimumab (IPI) versus NIVO, IPI and Stereotactic Body Radiation Therapy (SBRT) for Metastatic Merkel Cell Carcinoma (MCC, NCT03071406) – a preliminary report.
Presenter: Sungjune Kim
Session: Poster Display session 3
Resources:
Abstract
2854 - Real-world impact of immune checkpoint inhibitors in metastatic uveal melanoma
Presenter: Kalijn Bol
Session: Poster Display session 3
Resources:
Abstract
2928 - Immune checkpoint inhibitors in a cohort of 206 metastatic uveal melanomas patients
Presenter: Mathilde Saint-Ghislain
Session: Poster Display session 3
Resources:
Abstract
1235 - Incidence and survival of Uveal Melanoma occurring as single cancer versus its occurrence as a first or second primary neoplasm
Presenter: Ahmad Alfaar
Session: Poster Display session 3
Resources:
Abstract
3615 - Validation of a Clinicopathological and Gene Expression Profile (CP-GEP) Model for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma
Presenter: Evalyn Mulder
Session: Poster Display session 3
Resources:
Abstract
1793 - External validation of the 8th Edition Melanoma Staging System of the American Joint Committee on Cancer (AJCC) using the Surveillance, Epidemiology and End Results (SEER) Program
Presenter: Angelina Tjokrowidjaja
Session: Poster Display session 3
Resources:
Abstract
4278 - Clinical factors and overall survival (OS) associated with patterns of metastases (mets) in melanoma patients (pts).
Presenter: Ines Pires da Silva
Session: Poster Display session 3
Resources:
Abstract