CD8+/PD-1+ TILs Predict Better Response to Nivo/Ipi in Metastatic Clear Cell RCC

Tumor-infiltrating leukocytes (TILs) with CD8 and PD-1 positivity but not expressing TIM-3 or LAG-3 (CD8+ PD-1+ TIM-3– LAG-3–) were associated with improved clinical outcomes in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with anti–PD-1 combination therapy, representing a potential biomarker of response for further investigation.¹

In an analysis of the phase 3 COSMIC-313 trial (NCT03937219),² investigators used multiplex immunofluorescence to analyze pretreatment tumor samples of 198 patients treated with first-line nivolumab (Opdivo) plus ipilimumab (Yervoy) for mccRCC. Findings of this analysis were presented by Berkay Şimşek, MD, Brigham and Women’s Hospital of Harvard Medical School, at the 2025 European Society for Medical Oncology Congress in Berlin, Germany.

The analysis initially revealed that the density of CD8+ PD-1+ TIM-3– LAG-3– TILs was positively associated with both objective response rate (ORR) (odds ratio [OR], 1.37; 95% CI, 1.11-1.69; P = .004) and progression-free survival (PFS) (HR, 0.81; 95% CI, 0.71-0.92; P = .001).

“After seeing this, we wanted to further explore the value of this biomarker as a possible biomarker of response to nivolumab plus ipilimumab therapy,” explained Şimşek in his mini oral session presentation.

Dichotomizing patients by density at an optimized cutoff, the 27% of patients (n = 53) who were classified as having high density of these TILs had a higher ORR (60.4% vs 37.9%; OR, 2.49; 95% CI, 1.31-4.75; P = .005) and longer median PFS (not reached vs 9.3 months; HR, 0.42; 95% CI, 0.25-0.71; P = .001) compared with the remaining 83% of patients with low density (n = 145).

“In line with what we observed previously in the nivolumab monotherapy [setting], the levels of CD8+ PD-1+ TIM-3– LAG-3– TILs were associated with improved outcomes, this time in the nivolumab plus ipilimumab setting in mccRCC,” Şimşek concluded. “Our exploration of this biomarker in combination with other tissue-based biomarkers is still ongoing.”

Pending further validation of these findings, measuring CD8+ PD-1+ TIM-3– LAG-3– TIL density may inform future biomarker-driven treatment strategies aimed at tailoring treatments and enhancing clinical outcomes.

Previous Evidence and Rationale

Previous findings demonstrated that high density of CD8+ PD-1+ TIM-3– LAG-3– TILs was associated with improved clinical outcomes to anti–PD-1 monotherapy. These associations were observed and validated in previously treated patients across 3 clinical trials: the phase 2 CheckMate-010 (NCT01354431) trial, phase 3 CheckMate-025 trial (NCT01668784), and phase 2 HCRN GU16-260 trial (NCT03117309).

Şimşek noted the biological plausibility and rationale for conducting this analysis in patients who received anti–PD-1 combination therapy. “It is also worth noting that our findings are not only reproducible, but also biologically makes sense, as CD8-positive TILs that are expressing PD-1 but lacking additional checkpoints like TIM-3 or LAG-3 are thought to represent antigen-experienced but not terminally exhausted cytotoxic TILs that…can be effectively rejuvenated by anti–PD-1 monotherapy,” he said.

REFERENCES

1. Şimşek B. Identifying biomarkers of response to first-line nivolumab plus ipilimumab therapy in patients with metastatic clear cell renal cell carcinoma (mccRCC) enrolled in the COSMIC 313 trial. Presented at: ESMO 2025 Congress; October 17–21, 2025; Berlin, Germany. Abstract 2613MO.

2. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). ClinicalTrials.gov. Updated September 10, 2025. Accessed November 6, 2025. https://clinicaltrials.gov/study/NCT03937219