Clinical utility of plasma ctDNA sequencing in metastatic urothelial cancer.

Background: Genomic stratification may help improve the management of patients with metastatic urothelial cancer (mUC), given the recent identification of targetable alterations. However, the collection of tissue samples remains challenging. Here, we assessed the clinical utility of plasma circulating tumour DNA (ctDNA) sequencing in these patients.
Methods: Patients with mUC were prospectively enroled in the STING trial (NCT04932525), in which ctDNA was profiled using the Foundation One Liquid CDx Assay (324 genes, blood tumour mutational burden [bTMB], microsatellite instability status). Each genomic report was reviewed by a multidisciplinary tumor board (MTB).
Results: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. The median time to obtain the assay results was 20 days ((confidence interval) CI95%: [20,21]). The ctDNA analysis reproduced the somatic genomic landscape of previous tissue-based cohorts. Concordance for serial ctDNA samples was strong (r = 0.843 CI95%: [0.631-0.938], p < 0.001). At least one actionable target was detected in 63 patients (45%) with a total of 35 actionable alterations, including bTMB high (≥10 mutations/Mb) (N = 39, 21.1%), FGFR3 (N = 20, 10.8%), and Homologous recombination deficiency (HRD) alterations (N = 14, 7.6%). MTB recommended matched therapy in 63 patients (45.0%). Eight patients (5.7%) were treated, with an overall response rate of 50% (CI95%: 15.70-84.30) and a median progression-free survival (PFS) of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with a shorter PFS in patients treated with immunotherapy.
Conclusion: Overall, we demonstrated that genomic profiling with ctDNAs in mUC is a reliable and feasible approach for the timely initiation of genotype-matched therapies.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C. Helal: None declared; C. Pobel: None declared. A. Bayle: Personal fees: Sanofi (Advisory Board), Pfizer (Travel); As part of the Drug Development Department (DITEP) = Principal/sub-Investigator of Clinical Trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, AgiosPharmaceuticals, Amgen, Argen-X Bvba, AstexPharmaceuticals, Astra Zeneca Ab, Aveo, BasileaPharmaceutica International Ltd, Bayer Healthcare, Ag, BbbTechnologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, NektarTherapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, Xencor; Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. D. Vasseur: None declared. C. Nicotra: None declared. F. Blanc-Durand: Financial Interests: Eisai (Inivited speaker, Pesonal), Cureety (Member of Board of Directors, Personal), AZ (Research Grant, Institutional, Financial Interest), GSK (Travel). N. Naoun: Merck (Travel Fees). A. Bernard-Tessier: Honorarium: Astellas, Bayer, Orion, Hoopika; Consulting or Advisory role (Hoopika, Novartis, Janssen, MSD, AstraZeneca). A. Patrikidou: Financial Interests: Amgen (Congress Subscription), Basilea (Advisory Board);. Other: Janssen (Congress expenses). E. Colomba: None declared. R. Flippot: Astellas, Bayer, Janssen, Ipsen, BMS, MSD. A. Fuerea: None declared; N. Auger: None declared; M. Ngo Camus: None declared. B. Besse: Sponsored Research at Gustave Roussy Cancer Center: Abbvie, Amgen, AstraZeneca, Chugai pharmaceutical, Daiichi-Sankyo, Ellipse pharma, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, Pharmamar, Roche-Genentech, Sanofi, Socar research, Tahio Oncology, Turning Point Therapeutics. L. Lacroix: None declared. E. Rouleau: Sponsored Research / Presentation for Gustave Roussy Cancer Center: Amgen, AstraZeneca, MSD, GSK, BMS, Roche Diagnostic, Clovis. S. Ponce: Sponsored Research at Gustave Roussy Cancer Center: Amgen, AstraZeneca, Genmab, IPSEN, Astellas, MSD, Pharmamar, Roche-Genentech, Sanofi. A. Italiano: None declared. Y. Loriot: Honoraria: Janssen, MSD, Pfizer, Merck, KGaA, BMS, Astellas, AstraZeneca, Gilead;. Travel: Roche, Astellas, Pfizer, Merck, KGaA, MSD, BMS, Janssen.
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