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

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.

Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade

“…The predictive value of NLR was recently formally assessed in a cohort of mUC patients, in which associations between candidate biomarkers and clinical benefit were investigated comparing a cohort treated with anti-PD-1/anti-PD-L1 to a cohort treated with taxanes. A NLR <5 and a high single nucleotide variant count were proposed as independent predictors of treatment response for ICIs ( 72 ).…”

A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors

“…Multiple clinical prognostic tools have been developed in patients with aUC treated with chemotherapy to identify prognostic factors to guide practice and inform clinical trial enrollment and risk stratification [9][10][11][12][13][14][15][16][17]. Two prominent tools, developed by Bajorin et al [9] and Bellmunt et al [10], have been used for prognostication of patients receiving first-line and salvage treatment, respectively.…”

Predicting immune checkpoint inhibitor response in urothelial carcinoma: another step in personalised medicine?

“…These factors may have biased the results of this study. 7 Another relevant finding of this study 7 is that in the era/age of "big data" on sophisticated molecular parameters detected in cancer tissues the importance of basic clinical parameters should not be ignored. The clinical parameters identified here are hypothesis-generating as well, as they may point at "host factors" influencing immune responses.…”

“…5 Even worse, some non-responders may experience/ suffer deterioration by hyper-progressive disease. 6 In this context, Nassar et al 7 present their data on both clinical and genomic parameters to predict response towards ICI in UC. They analysed retrospectively a cohort of 62 metastatic UC patients treated with ICI in whom not only clinical, but also genomic characteristics (by targeted gene sequencing using an institutional customised gene panel 8 ) had been assessed.…”

“…Biomarker studies are usually performed on primary tumour tissue, as in this study. 7 However, as in other malignancies, biological parameters of UCs may differ between primary lesions and metastases and may be altered significantly by systemic therapies. 10,11 The authors do address this concern arguing that analysing the primary untreated lesion instead of new metastatic lesions "reflects common practice".…”