ASCO GU 2022: Novel Predictive Biomarkers of Response to Immune Checkpoint Blockade with Nivolumab ± Ipilimumab in the TITAN-RCC Phase 2 Trial

( The 2022 GU ASCO Annual meeting included a renal cell carcinoma (RCC) session featuring work from Dr. Marc-Oliver Grimm and colleagues presented results of novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC phase 2 trial. Despite the promising therapeutic efficacy of immune checkpoint inhibitors in RCC, response varies significantly between individual patients. Therefore, predictors of response are urgently needed. To identify novel predictive biomarkers, Dr. Grimm and colleagues explored the characteristics of blood-circulating immune cell subsets within the population of the TITAN-RCC trial (NCT02917772) applying a tailored approach with nivolumab and ipilimumab.

In TITAN-RCC, patients with intermediate and poor-risk advanced clear cell RCC started nivolumab Q2W induction. Upon early progressive disease (week 8) or non-response (stable disease or progressive disease) at week 16, patients received 2-4 nivolumab + ipilimumab “boost” cycles. Responders (complete or partial response) to nivolumab induction continued with maintenance but could receive nivolumab + ipilimumab for later progressive disease. Blood samples for biomarker analyses were taken at baseline, during nivolumab induction and nivolumab + ipilimumab “boost” cycles. The trial design for TITAN-RCC is as follows: 

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Samples from 198 RCC patients (105 first line, 93 second line) were analyzed by multi-parametric flow cytometry for frequency and phenotype of T cell, monocyte, myeloid-derived suppressor cell, and dendritic cell subsets. Baseline data were associated with response upon nivolumab induction and data from samples taken prior to first “boost” to response to nivolumab + ipilimumab. Univariable and multivariable logistic regression modeling was applied to investigate the association between treatment response and immune parameters. At GU ASCO 2022, Dr. Grimm reported on single marker models (adjusted for age and gender).

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 1.03, 95% CI 1.01-1.07) and LAG3+ CD4+ T cells (ORadj 1.03, 95% CI 1.01-1.05) were found in responders to nivolumab induction compared to non-responders:

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Furthermore, in patients receiving nivolumab + ipilimumab “boosts”, a higher proportion of PD-L1+ CD14+ monocytes (ORadj 1.22, 95% CI 1.06-1.58), PD-L1+ early-stage myeloid-derived suppressor cell (ORadj 1.14, 95% CI 1.02-1.41) and PD-L1+ plasmacytoid dendritic cell (ORadj 1.08, 95% CI 1.01-1.17) was observed in responders compared to non-responders:

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Dr. Grimm concluded this presentation of novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC study with the following concluding statements:

  • This study identified various immune cell-related parameters that are associated with increased or poor therapeutic efficacy in RCC patients which are currently investigated in multi-marker models
    • Nivolumab induction: higher proportions of 4-1BB- or LAG-3 expressing T cells correlated with treatment response
    • Nivolumab + ipilimumab “boosts”: higher percentages of PD-L1-expressing myeloid cells and plasmacytoid dendritic cells are associated with a better prognosis
  • These parameters may represent novel predictive biomarkers for response to nivolumab + ipilimumab in clear cell RCC

Presented by: Marc-Oliver Grimm, Department of Urology, Jena University Hospital, Jena, Germany

Co-Authors: Miriam Kesselmeier, Katharina Leucht, Ulrike Schumacher, Antje Tunger, Nadja Röber, Karsten Conrad, Ulrich Sommer, Gustavo Bruno Baretton, André Scherag, Laurence Albiges, Emilio Esteban, Philippe Barthélémy, Manuela Schmidinger, Jonas Busch, Begoña Pérez-Valderrama, Guillermo de Velasco, Ignacio Duran, Marc Schmitz, Rebekka Wehner 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022 

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