Yung Lyou1, Petros Grivas2, Jonathan E Rosenberg3, Jean Hoffman-Censits4, David I Quinn5, Daniel P Petrylak6, Matthew Galsky7, Ulka Vaishampayan8, Ugo De Giorgi9, Sumati Gupta10, Howard Burris11, Jessica Rearden12, Ai Li12, Hao Wang12, Maribel Reyes12, Susan Moran12, Siamak Daneshmand13, Dean Bajorin3, Sumanta K Pal14. 1. City of Hope Comprehensive Cancer Center, Duarte, CA, USA. 2. University of Washington, Seattle, WA, USA. 3. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. 5. USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 6. Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT, USA. 7. Mount Sinai School of Medicine, New York, NY, USA. 8. Wayne State University, Detroit, Ml, USA. 9. lstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 10. Huntsman Cancer Institute-University of Utah Health Care, Salt Lake City, UT, USA. 11. Sarah Cannon Research Institute, Nashville, TN, USA. 12. QED Therapeutics, San Francisco, CA, USA. 13. USC/Norris Comprehensive Cancer Center Department of Urology, Los Angeles, CA, USA. 14. City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address: spal@coh.org.
Abstract
BACKGROUND: Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition. OBJECTIVE: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. INTERVENTION: Oral infigratinib 125 mg/d for 21 d every 28 d. DESIGN, SETTING, AND PARTICIPANTS: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical outcomes were compared in groups with/without hyperphosphatemia. RESULTS AND LIMITATIONS: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. CONCLUSIONS: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. PATIENT SUMMARY: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.
BACKGROUND:Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition. OBJECTIVE: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. INTERVENTION: Oral infigratinib 125 mg/d for 21 d every 28 d. DESIGN, SETTING, AND PARTICIPANTS: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical outcomes were compared in groups with/without hyperphosphatemia. RESULTS AND LIMITATIONS: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. CONCLUSIONS: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. PATIENT SUMMARY: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.
Authors: Iris R Hartley; Kelly L Roszko; Xiaobai Li; Karen Pozo; Jamie Streit; Jaydira Del Rivero; M Teresa Magone; Michaele R Smith; Roo Vold; Carl L Dambkowski; Michael T Collins; Rachel I Gafni Journal: JBMR Plus Date: 2022-07-22
Authors: Yung Lyou; Jonathan E Rosenberg; Jean Hoffman-Censits; David I Quinn; Daniel Petrylak; Matthew Galsky; Ulka Vaishampayan; Ugo De Giorgi; Sumati Gupta; Howard Burris; Jessica Rearden; Ai Li; Cindy Xu; Corina Andresen; Susan Moran; Siamak Daneshmand; Dean Bajorin; Sumanta K Pal; Petros Grivas Journal: Clin Genitourin Cancer Date: 2021-10-13 Impact factor: 3.121