Novel predictive biomarkers of response to immune checkpoint blockade in the TITAN-RCC trial
Biomarker analyses from the phase II TITAN-RCC trial identified various immune cell-related parameters that are associated with increased or poor therapeutic efficacy in renal cell carcinoma (RCC) patients which are currently investigated in multi-marker models. These parameters may represent novel predictive biomarkers for response to nivolumab with or without ipilimumab in clear cell RCC.
Despite promising therapeutic efficacy of immune checkpoint inhibitors in renal cell carcinoma (RCC), response varies significantly between individual patients. Therefore, predictors of response are urgently needed. To identify novel predictive biomarkers, Grimm et al. explored the characteristics of blood-circulating immune cell subsets within the population of the TITAN-RCC trial applying a tailored approach with nivolumab (NIVO) and ipilimumab (IPI).
In the phase II TITAN-RCC trial, 207 patients with intermediate and high International Metastatic RCC Database Consortium (IMDC) risk metastatic or locally advanced clear cell RCC (ccRCC) started NIVO Q2W induction. Patients were either untreated or pretreated with one prior tyrosine kinase inhibitor. Upon early progressive disease (PD, week 8) or non-response (stable disease or PD) at week 16, patients received two to four NIVO+IPI “boost” cycles. Responders (complete or partial response) to NIVO induction continued with maintenance but could receive NIVO+IPI for later PD. Blood samples for biomarker analyses were taken at baseline, during NIVO induction and prior to each NIVO+IPI boost cycle. Samples from 198 RCC patients (105 first-line, 93 second-line) were analysed by multi-parametric flow cytometry for frequency and phenotype of T-cell, monocyte, myeloid-derived suppressor cell (MDSC) and dendritic cell (DC) subsets. Baseline data were associated to response upon NIVO induction and data from samples taken prior to first boost to response to NIVO+IPI. Uni- and multivariable logistic regression modelling were used to investigate the association between treatment response and immune parameters. Here we report on single marker models, adjusted for age and gender.
Median age of study participants was 65 years, 71% were male and half of them received treatment in first-line. In the intention-to-treat population, 71% and 25% of patients were intermediate or poor risk by IMDC, respectively. In total, 137 patients received boost cycles and the baseline characteristics of these patients were similar.
Responders to NIVO induction are characterised by a higher proportion of 4-1BB- or LAG-3-expressing T-cells at baseline. This was evidenced by the higher percentages of blood-circulating 4-1BB+ CD4+ T-cells (adjusted odds ratio (ORadj) 1.05, 95% CI: 1.02-1.08), 4-1BB+ CD8+ T-cells (ORadj[95%CI]: 1.03[1.01-1.07]) and LAG3+ CD4+ T-cells (ORadj[95%CI]: 1.03[1.01-1.05]) that were found in responders as compared to non-responders. In contrast, response to NIVO+IPI boosts is associated with higher proportions of PD-L1-expressing myeloid cells and plasmacytoid dendritic cells (pDC). In patients receiving NIVO+IPI boosts, a higher proportion of PD-L1+ CD14+ monocytes (ORadj[95%CI]: 1.22[1.06-1.58]), PD-L1+ early-stage myeloid-derived suppressor cells (ORadj[95%CI]: 1.14[1.02-1.41]) and PD-L1+ plasmacytoid DC (ORadj[95%CI]: 1.08[1.01-1.17]) was observed in responders compared to non-responders.
Investigators identified various immune cell-related parameters that are associated with increased efficacy in patients with advanced or metastatic ccRCC. For patients only receiving nivolumab induction, higher proportions of 4-1BB- or LAG-3-expressing T-cells correlated with treatment response. For patients receiving NIVO + IPI boosts, higher percentages of PD-L1 expressing myeloid cells and pDC are associated with a better response. These immune cell parameters may represent novel predictive biomarkers for the response to nivolumab and/or nivolumab plus ipilimumab therapy in ccRCC.
Grimm M-O, et al. Novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC phase 2 trial. Presented at ASCO GU 2022; Abstract 367