5763 - cfDNA is an acceptable but insufficient means of characterizing FGFR3 mutation in patients with metastatic urothelial cancer (mUC)

Background

Previous studies indicate that genomic alterations (GAs) in cell-free (cf)DNA are found in > 90% of patients (pts) with mUC [Agarwal et al Cancer 2018]. The ease of collection of cfDNA makes it an attractive alternative to tumor tissue-based screening, but the equivalency of cfDNA and tumor tissue for biomarker testing has yet to be defined in a prospective trial in mUC. We examine this in a phase Ib trial of infigratinib (BGJ398), a potent and selective FGFR1–3 inhibitor, in pts with mUC bearing FGFR3 alterations [Pal et al Cancer Discovery 2018].

Methods

Eligible pts had mUC with activating FGFR3 mutations/fusions and prior platinum-based chemotherapy, unless contraindicated. Pts received infigratinib 125 mg orally daily (3 wks on/1 wk off). Comprehensive genomic profiling (CGP) was performed on FFPE tissues in a CLIA-certified lab (Foundation Medicine; Cambridge, MA), and blood was collected for cfDNA analysis using a 600-gene panel on an Illumina HiSeq 2500 sequencer. Patients were monitored for their best overall response rate (ORR) based on radiological imaging.

Results

67 pts were enrolled; ORR was 25.4% and disease control rate was 64.2%. Blood for cfDNA was collected in 53 pts at the time of screening; collection occurred at a mean of 8.8 days (range 0–37 days) prior to therapy initiation. In contrast, tumor tissue was collected a mean of 520 days (range 28–2315 days) prior. GAs in cfDNA were found in all pts; 38 pts (68%) had detectable FGFR3 mutation. FGFR3 alterations were concordant in 30/38 (79%) of tumors with both tumor tissue and cfDNA at screening. Other commonly encountered alterations were found in KDM6A (30%), KMT2D (20%) and TP53 (20%). In this cohort, all 11 pts with progressive disease (PD) as a best response had detectable FGFR3 in cfDNA at screening, while this was found in only 7/12 responders (58%).

Conclusions

cfDNA identified FGFR3 mutations in 79% of pts whose mutations were previously identified in tumor tissue, suggesting that cfDNA is a secondary screening option for trials assessing FGFR3-directed therapies. The paradoxically higher rate of PD in pts with detectable FGFR3 mutations in cfDNA warrants further study.

Clinical trial identification

NCT01004224.

Editorial acknowledgement

Lee Miller (Miller Medical Communications Ltd).

Legal entity responsible for the study

QED Therapeutics.

Funding

QED Therapeutics.

Disclosure

S.K. Pal: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Research grant / Funding (self): Medivation; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aveo; Advisory / Consultancy: Myriad Pharmaceuticals; Advisory / Consultancy: Genentech; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai. D.F. Bajorin: Honoraria (self): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Fidia Farmaceutici S. p. A.; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Urogen pharma; Advisory / Consultancy: Pfizer; Advisory / Consultancy: EMD Serono; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Seattle Genetics/Astellas; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Genentech/Roche. J.H. Hoffman-Censits: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self): Clovis Oncology; Advisory / Consultancy: Foundation medicine; Advisory / Consultancy: AstraZeneca; Research grant / Funding (self): Sanofi. D.I. Quinn: Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Seattle Genetics; Full / Part-time employment: University of Southern California. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Johnson & Johnson; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (self): Millennium; Advisory / Consultancy, Research grant / Funding (self): Medivation; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tyme; Advisory / Consultancy, Research grant / Funding (self): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Lilly; Speaker Bureau / Expert testimony: Celgene; Research grant / Funding (self): Progenics; Research grant / Funding (self): Endocyte; Research grant / Funding (self): Genentech; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Agensys; Research grant / Funding (self): Innocrin Pharma; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Sotio; Research grant / Funding (self): Seattle Genetics; Research grant / Funding (self): Clovis Oncology. M.D. Galsky: Advisory / Consultancy: BioMotiv; Advisory / Consultancy, Research grant / Funding (institution): Janssen Oncology; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Lilly; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Incyte; Advisory / Consultancy: Aileron Therapeutics; Advisory / Consultancy: Dracen; Advisory / Consultancy: Inovio Pharmaceuticals; Advisory / Consultancy: NuMab; Licensing / Royalties, Methods and Compositions for Treating Cancer and Related Methods: Mount Sinai School of Medicine; Advisory / Consultancy: Genentech; Shareholder / Stockholder / Stock options: Rappta Therapeutics. U.N. Vaishampayan: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Honoraria (self): Janssen; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Exelixis; Advisory / Consultancy, Research grant / Funding (self): Astellas Pharma; Honoraria (self): Genentech. U. De Giorgi: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche. S. Gupta: Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Viralytics; Research grant / Funding (institution): Hoosier Cancer Research Network; Research grant / Funding (institution): Rexahn Pharmaceuticals; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): LSK; Spouse / Financial dependant: Keryx; Spouse / Financial dependant: Salarius Pharmaceuticals. H.A. Burris: Advisory / Consultancy, Research grant / Funding (institution): Mersana; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Forma Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): TG Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: HCA Healthcare / Sarah Cannon; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Tarveda Therapeutics; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): Moderna Therapeutics; Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Verastem; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): BioMed Valley Discoveries; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Vertex; Research grant / Funding (institution): eFFECTOR Therapeutics; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Valent Technologies; Research grant / Funding (institution): BioAtla; Research grant / Funding (institution): CicloMed; Research grant / Funding (institution): Harpoon therapeutics; Research grant / Funding (institution): Jiangsu Hengrui Medicine; Research grant / Funding (institution): Revolution Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): H3 Biomedicine; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Regeneron; Research grant / Funding (self): Sanofi. H.S. Soifer: Shareholder / Stockholder / Stock options, Full / Part-time employment: bioTheranostics; Shareholder / Stockholder / Stock options, Full / Part-time employment: QED Therapeutics. G. Li: Full / Part-time employment: QED Therapeutics. C.L. Dambkowski: Full / Part-time employment: QED Therapeutics. S. Moran: Full / Part-time employment: QED Therapeutics. H. Wang: Full / Part-time employment: QED Therapeutics. J.E. Rosenberg: Honoraria (self): UpToDate; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Medscape; Honoraria (self): Vindico; Honoraria (self): Peerview; Honoraria (self): Chugai Pharma; Advisory / Consultancy: Lilly; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merck; Advisory / Consultancy, Research grant / Funding (institution): Agensys; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: AstraZeneca/MedImmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Inovio Pharmaceuticals; Advisory / Consultancy: BioClin Therapeutics; Advisory / Consultancy: QED Therapeutics; Advisory / Consultancy: Adicet Bio; Advisory / Consultancy: Sensei Biotherapeutics; Advisory / Consultancy: Fortress Biotech; Advisory / Consultancy: Pharmacyclics; Advisory / Consultancy: western oncolytics; Research grant / Funding (self): Incyte; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Oncogenex; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Viralytics; Shareholder / Stockholder / Stock options: Illumina; Licensing / Royalties, Institution: Predictor of platinum sensitivity. All other authors have declared no conflicts of interest.