Abstract 751P
Background
To identify markers of intrinsic resistance to FGFR inhibition, plasma samples from a phase 2 study (BLC2001, NCT02365597; Loriot Y, et al. N Engl J Med. 2019) of erdafitinib (ERDA) in patients (pts) with mUC and FGFR2/3 alterations (mutations/fusions) were tested using next-generation sequencing for ctDNA.
Methods
Pretreatment plasma samples from 82 pts with mUC treated with 8 mg/d ERDA were assessed for alterations in 73 genes by Guardant360 ctDNA test. Mutation data were filtered for driver events using OncoKB and CancerHotspots.org knowledge bases. No filtering was applied to fusion/amplification calls. Relationship between altered genes in pretreatment plasma and best overall response (BOR) of progressive disease (PD) in response to ERDA was assessed by Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) distributions were analyzed by Cox proportional hazards model. p Values were adjusted to control false discovery rate (q).
Results
EGFR (n = 10, 12%), CCND1 (n = 11, 13%), or BRAF (n = 7, 9%) alterations were observed in 21% (17/82) of pts. Amplifications were predominant; 8/10 (80%), 11/11 (100%), and 6/7 (86%) pts had amplification in EGFR, CCND1, and BRAF genes, respectively. No genes were significantly associated with BOR of PD in response to ERDA. Shorter median PFS was seen in pts with alterations vs pts without alterations in EGFR (2.8 vs 5.7 mos; HR, 4.3; 95% CI, 2.1-8.9; q = 0.0026), CCND1 (2.8 vs 5.7 mos; HR, 3.6; 95% CI, 1.8-7.1; q = 0.0041), and BRAF (2.8 vs 5.6 mos; HR, 3.6; 95% CI, 1.6-8.2; q = 0.024). Pts with EGFR alterations also had shorter median OS vs pts without EGFR alterations (4.7 mos vs 14.2 mos; HR, 3.9; 95% CI, 1.7-9.0; q = 0.045).
Conclusions
In pts with mUC and FGFR alterations treated with ERDA, presence of EGFR, CCND1, and BRAF alterations at baseline correlated with shorter PFS, and EGFR with shorter OS. Further studies assessing the prognostic vs predictive value of these genes in pts with mUC and FGFR3 alterations are needed to provide insight into developing better combination and therapeutic sequencing strategies for this disease.
Clinical trial identification
NCT02365597.
Editorial acknowledgement
Sally Hassan, PhD, CMPP, of Parexel International provided editorial assistance for this abstract.
Legal entity responsible for the study
Janssen Research & Development, LLC.
Funding
Janssen Research & Development, LLC.
Disclosure
A.O. Siefker-Radtke: Advisory/Consultancy: Merck, Bavarian Nordic, Seattle Genetics, Genentech, Janssen, Mirati, AstraZeneca, Nektar Theraputics, Pfizer; Speaker Bureau/Expert testimony: Janssen. Y. Loriot: Honoraria (self): Roche, Astellas, Janssen, Seattle Genetics, AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Sanofi, Ipsen; Research grant/Funding (institution), Clinical Trial: Roche, Bristol Myers squibb, AstraZeneca, MSD, Pfizer, Seattle Genetics, Astellas, Janssen, Clovis, Incyte, Sanofi; Research grant/Funding (institution), Research Grant: MSD, Sanofi, Janssen. A. Necchi: Honoraria (self): Roche, Merck, AstraZeneca, Janssen, , BMS, Foundation Medicine; Advisory/Consultancy: Merck, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, Glaxo Smith Kline (GSK), Ferring; Research grant/Funding (institution): Merck, AstraZeneca, Ipsen; Travel/Accommodation/Expenses: Roche, Merck, AstraZeneca, Janssen, Rainier Therapeutics. R.A. Huddart: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Nektar; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Bayer; Full/Part-time employment: Cancer Centre London. E.F. Burgess: Shareholder/Stockholder/Stock options: Gilead Sciences, Exelixis, Clovis Oncology, Calithera Biosciences; Honoraria (self): Bayer, Exelixis. A. Rezazadeh: Shareholder/Stockholder/Stock options: ECOM Medical; Advisory/Consultancy: Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, Bristol Myers Squibb, EMD Serono; Speaker Bureau/Expert testimony: Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, Bristol Myers Squibb, Amgen, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas; Research grant/Funding (institution): Genentech, Exelixis, Janssen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Macrogenics, Astellas Pharma, Beyond Spring, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, Epizy; Travel/Accommodation/Expenses: Genentech, Prometheus Laboratories, Astellas Medication, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, AstraZeneca. A. O'Hagan: Full/Part-time employment: Janssen Pharmaceuticals; Shareholder/Stockholder/Stock options: Johnson & Johnson. P. De Porre: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Pharmaceuticals. A. Avadhani: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Pharmaceuticals. M. Monga: Full/Part-time employment: Janssen. Y. Cherkas: Full/Part-time employment: Janssen; Shareholder/Stockholder/Stock options: Johnson & Johnson. C.H. Moy: Full/Part-time employment: Janssen. A. Santiago-Walker: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen.