Abstract A020: Tumor-infiltrating lymphocytes and peritumoral tertiary lymphoid structures as biomarkers of response to first-line nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma enrolled in the COSMIC 313 trial

Abstract Background: Nivolumab plus ipilimumab (nivo+ipi) is an approved first-line therapy for metastatic clear cell renal cell carcinoma (mccRCC). However, only a subset of patients (pts) achieves long term benefit, highlighting the need for biomarkers of response. We previously showed that high baseline levels of non-terminally exhausted tumor infiltrating lymphocytes (NTE TIL) defined as CD8+PD-1+TIM-3-LAG-3- cells (Pignon 2019; Ficial 2021; El Ahmar 2023) and peritumoral tertiary lymphoid structures (pTLS) (El Ahmar 2025) were associated with improved outcomes to nivolumab monotherapy. Here, we evaluated both biomarkers, alone and in combination, in pts receiving first-line nivo+ipi in the COSMIC-313 clinical trial. Methods: Pre-treatment tumor samples from patients treated with nivo+ipi were analyzed by multiplex immunofluorescence and image analysis algorithms to determine the density of NTE TIL and pTLS (≤1000 μm from the tumor margin). NTE TIL density was obtained for 198 pts and pTLS density was obtained for 176 pts. The natural log of the densities was calculated and associations with progression-free survival (PFS) and objective response rate (ORR) were assessed using univariable Cox proportional hazards and logistic regression models, respectively. The Contal and O'Quigley method with PFS was used to obtain optimized cutoffs. Binary splits of the individual biomarkers were used to create a combined biomarker. Results: Both the density of NTE TIL and the density of pTLS, measured as a continuous variables, were positively associated with ORR (OR: 1.37 [95% CI: 1.11-1.69], p=0.004 for NTE TIL; OR: 1.27 [1.04-1.54], p=0.018 for pTLS) and PFS (HR: 0.81 [0.71-0.92], p=0.001 for NTE TIL; HR: 0.83 [0.73-0.95], p=0.006 for pTLS). At an optimized cutoff, pts with high (n=53/198, 27%) vs. low density of NTE TIL had higher ORR (60.4% vs. 37.9%, OR: 2.49 [1.31-4.75], p=0.005) and longer median PFS (not reached (NR) vs. 9.3 months, HR: 0.42 [0.25-0.71], p=0.001). Similarly, pts with high (n=126/176, 71.6%) vs. low density of pTLS had higher ORR (52.4% vs. 24.0%, OR: 3.48 [1.67-7.28], p=0.001) and longer median PFS (NR vs. 4.4 months, HR: 0.41 [0.27-0.63], p<0.001). Densities of NTE TIL and pTLS were weakly correlated (Spearman r = 0.13). The combination of the two biomarkers stratified patients in four groups with significantly different outcomes: (i) High pTLS/High TIL (n=33): ORR, 72.7%; median PFS, NR; (ii) High pTLS/Low TIL (n=89): ORR, 46.1%; median PFS, 14.0 months; (iii) Low pTLS/High TIL (n=11): ORR, 36.4%; median PFS, 12.0 months; (iv) Low pTLS/Low TIL (n=35): ORR, 20.0%; median PFS, 4.4 months. Conclusions: In line with what was observed in the setting of nivolumab monotherapy, baseline levels of both NTE TIL and pTLS were positively associated with improved response to nivo+ipi in pts with mccRCC. The novel combination of these two biomarkers further improved the ability to stratify patient outcomes. Citation Format: Mohamed Farghaly, Berkay Simsek, Samuel M. Niman, Nourhan El Ahmar, Gabriel Roberti. De Oliveira, Yasmin Nabil . Laimon, Andrew Delcea, Maxwell D. Seager, Liliana Ascione, Wanling Xie, David A. Braun, Maxine Sun, Eddy Saad, Jad El Masri, Gordon J. Freeman, Andrew Simmons, Dana Aftab, Robert J. Motzer, Michael B. Atkins, David F. McDermott, Toni K. Choueiri, Sabina Signoretti. Tumor-infiltrating lymphocytes and peritumoral tertiary lymphoid structures as biomarkers of response to first-line nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma enrolled in the COSMIC 313 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A020.