Abstract
Immune checkpoint inhibitors (ICIs) improve overall survival in patients with metastatic urothelial cancer (mUC). To identify predictive markers of response, whole-genome DNA (n=70) and RNA-sequencing (n=41) were performed using fresh metastatic biopsies prior to treatment with pembrolizumab. PD-L1 combined positivity score failed, while tumor mutational burden and APOBEC mutagenesis modestly predicted response. Using gene expression analysis, we defined the T cell-to-stroma enrichment (TSE) score, a signature-based metric that captures the relative abundance of T cells and stromal cells. Patients with a positive and negative TSE score show progression free survival rate at 6 months of 67% and 0%, respectively. The significant predictive value of the TSE score was validated in two independent ICI treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS). The TSE score represents a clinically applicable marker that may select patients with metastatic and primary UC who do not benefit from ICI treatment.
Competing Interest Statement
Martijn P. J. Lolkema has received research support from JnJ, Sanofi, Astellas and MSD, and consultancy fees from Incyte, Amgen, JnJ, Bayer, Servier, Roche, INCa, Pfizer, Sanofi, Astellas, AstraZeneca, Merck Sharp & Dohme, Novartis, Julius Clinical and the Hartwig Medical Foundation (all paid to the Erasmus MC Cancer Institute). Debbie G.J. Robbrecht has received research support from Treatmeds and consultancy fees from Bristol-Myers Squibb, Bayer, AstraZeneca, Merck, Pfizer (all paid to the Erasmus MC Cancer Institute). Ronald de Wit has received consultancy fees from Sanofi, Merck, Astellas, Bayer, Hengrui and Orion, speaker fees from Sanofi and Astellas, research support from Sanofi and Bayer (all paid to the Erasmus MC Cancer Institute). Astrid A.M. van der Veldt has received consultancy fees from for BMS, MSD, Merck, Novartis, Roche, Sanofi, Pierre Fabre, Ipsen, Eisai, Pfizer (all paid to the Erasmus MC Cancer Institute). Michiel S. van der Heijden has received research support from Bristol-Myers Squibb, AstraZeneca and Roche, and consultancy fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Seattle Genetics and Janssen (all paid to the Netherlands Cancer Institute). Joost L. Boormans has received research support from Decipher Biosciences and Merck Sharp & Dohme, and consultancy fees from Merck Sharp & Dohme, Eight Medical, Ambu, APIM therapeutics, Bristol-Myers Squibb, Astellas Roche and Janssen (all paid to the Erasmus MC Cancer Institute). Niven Mehra has received research support from Astellas, Janssen, Pfizer, Roche and Sanofi Genzyme, and consultancy fees from Roche, MSD, BMS, Bayer, Astellas and Janssen (all paid to the Radboud University Medical Center). Hans M. Westgeest has received consultancy fees from Roche and Astellas (all paid to the Amphia hospital, Breda), Paul Hamberg has received consultancy fees from Astellas, Merck Sharp & Dohme, Pfizer AstraZeneca, Bristol-Myers Squibb and Ipsen. Maureen J.B. Aarts has received advisory board / consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer, research grants from Merck-Pfizer, and not related to current work and paid to Maastricht UMC+ Comprehensive Cancer Center. Geert J.L.H. van Leenders has received research grants from Roche and AstraZenaca, and has been member of advisory boards of Roche and Merck. Maud Rijnders, J. Alberto Nakauma-Gonzalez, Alberto Gil-Jimenez and Jens Voortman declare no competing interests.
