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

• DOI: 10.1038/s41416-019-0686-0
• Publication Date: 2019-12-20T00:02:54Z
• Authors: Amin H. Nassar; Kent W. Mouw; Opeyemi Jegede; Atul B. Shinagare; Jaegil Kim; Chia-Jen Liu; Mark Pomerantz; Lauren C. Harshman; Eliezer M. Van Allen; Xiao X. Wei; Bradley McGregor; Atish D. Choudhury; Mark A. Preston; Fei Dong; Sabina Signoretti; Neal I. Lindeman; Joaquim Bellmunt; Toni K. Choueiri; Guru Sonpavde; David J. Kwiatkowski
• Keywords: Adult; Aged, 80 and over; Male; Carcinoma, Transitional Cell; Urologic Neoplasms; 0303 health sciences; Neutrophils; Programmed Cell Death 1 Receptor; Middle Aged; Article; B7-H1 Antigen; 3. Good health; 03 medical and health sciences; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Humans; Female; Lymphocyte Count; Aged

Abstract 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.