Intratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial.
Authors: Sayed Matar, Opeyemi Jegede, Thomas Denize, Fatme Ghandour, Yasmin Nabil Laimon, Nourhan El Ahmar, Aseman Bagheri Sheshdeh, Varunika Savla, Razan Assaad Mohanna, Paul J. Catalano, David A. Braun, Maxine Sun, Saurabh Gupta, Sai Vikram Vemula, Gordon J. Freeman, Robert J. Motzer, Michael B. Atkins, David F. McDermott, Toni K. CHOUEIRI, Sabina Signoretti
Journal: Journal of Clinical Oncology (2024)

4536 Background: We have previously shown that levels of antigen-experienced but not terminally exhausted CD8 + TILs (i.e. CD8 + PD1 + TIM3 - LAG3 - TILs) are associated with improved clinical outcomes in patients (pts) with metastatic clear cell RCC (mccRCC) treated with nivolumab monotherapy within three independent clinical trials (CheckMate-010, CheckMate-025, HCRN GU16-260). Here, we aimed to evaluate the performance of this biomarker in patients with mccRCC treated with nivolumab plus ipilimumab (Nivo+Ipi) versus sunitinib (Sun) as part of the CheckMate-214 (CM-214) clinical trial. Methods: Pre-treatment, formalin fixed paraffin embedded (FFPE) tumor samples from the CM-214 clinical trial were stained with a multiplex immunofluorescence (mIF) assay and the density of CD8+PD1+TIM3-LAG3- TILs (mIF biomarker) was quantified using Halo image analysis software. The correlation between the mIF biomarker and clinical outcomes, including progression-free survival (PFS), and objective response rate (ORR), was evaluated using Cox proportional hazards and logistic regression models. The significance level was set at 5% (2-sided). Results: Following quality control, mIF data were obtained for 255 intermediate-and poor-risk patients (Nivo+Ipi= 136, Sun= 119). A comparison between patients with mIF biomarker data available and those without, showed no imbalance with regards to ORR and PFS in the Nivo+Ipi group. However, in the Sun group, pts with mIF biomarker data showed a higher ORR compared to pts without available data (33% vs 24%). In Nivo+Ipi-treated pts, the mIF biomarker measured as continuous variable showed a trend for a positive association with ORR (OR = 1.23, p = 0.1162) but no association with PFS (HR 0.97, p = 0.688). In Sun-treated pts, the mIF biomarker measured as continuous variable showed a trend for a positive association with ORR (OR = 1.32, p = 0.0726) and a significant positive association with PFS (HR= 0.78, p = 0.004. However, given that Sun-treated pts with available mIF data were enriched for responders, results obtained in the Sun group should be interpreted with caution. Conclusions: In contrast to Nivo monotherapy, pre-treatment levels of CD8+ PD1+ TIM-3-LAG-3- TILs were not associated with improved clinical outcomes to Nivo+Ipi. These results suggest that the baseline levels of intratumoral T-cell inflammation do not represent a strong determinant of response to anti-CTLA4-based therapy in mccRCC, which is consistent with the knowledge that anti-CTLA4 therapy (Ipi) can recruit new T cells into the tumor. The association between CD8+ PD1+ TIM-3-LAG-3- TILs and outcomes on sunitinib needs further investigation.