A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma

• Published in: British journal of cancer Vol. 122; no. 4; pp. 555 - 563
• Main Authors: Nassar, Amin H., Mouw, Kent W., Jegede, Opeyemi, Shinagare, Atul B., Kim, Jaegil, Liu, Chia-Jen, Pomerantz, Mark, Harshman, Lauren C., Van Allen, Eliezer M., Wei, Xiao X., McGregor, Bradley, Choudhury, Atish D., Preston, Mark A., Dong, Fei, Signoretti, Sabina, Lindeman, Neal I., Bellmunt, Joaquim, Choueiri, Toni K., Sonpavde, Guru, Kwiatkowski, David J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2020; Nature Publishing Group
• Subjects: 692/4028/67/589/1336; 692/53/2423; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological - therapeutic use; B7-H1 Antigen - antagonists & inhibitors; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Cancer Research; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - immunology; Drug Resistance; Epidemiology; Female; Genomics; Humans; Immune checkpoint inhibitors; Lymphocyte Count; Lymphocytes; Male; Metastases; Metastasis; Middle Aged; Molecular Medicine; Neutrophils - immunology; Oncology; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Taxanes; Tumors; Urologic Neoplasms - drug therapy; Urologic Neoplasms - genetics; Urologic Neoplasms - immunology; Urothelial carcinoma
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-019-0686-0

Background
In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC.
Methods
Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.
Results
Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01–1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01–0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006–0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.
Conclusions
This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.