irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial

Abstract

Purpose: Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1). Experimental Design: Endpoints based on RECISTv1.1 [objective response rate (ORR)/progression-free survival (PFS)] or irRECIST [immune-related ORR (irORR)/immunerelated PFS (irPFS)] were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing. Results: Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 !1% had longer median irPFS and higher irORR. High percentage of CD8 þ tumor-infiltrating cells (TIC) that are PD-1 þ TIM-3 À LAG-3 À (% CD8 þ PD-1 þ TIM-3 À LAG-3 À TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8 þ PD-1 þ TIM-3 À LAG-3 À TIC identified three groups of patients for which irPFS and irORR were significantly different. Conclusions: Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8 þ TIC may predict outcome on nivolumab in mccRCC.

Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

“…High levels of CD8+ PD1+ TIM3- LAG3- TIC were associated with an activation of the inflammatory response. Interestingly, the combination of PD-L1 expression on tumor cells with the density of CD8+ PD1+ TIM3- LAG3- TIC improved the predictive value, confirming previous results from Pignon et al [ 43 , 44 ].…”

Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma

“…The endpoints defined by RECISTv1.1 could potentially impair the identification of predictive biomarkers. For instance, in the CheckMate 010 phase II trial, tumour cell PD-L1 expression was not associated with PFS or ORR defined by RECISTv1.1, but was associated with a longer median irPFS and higher irORR using irRECIST [54]. A high level of T cells with the CD8+ PD-1+ TIM3- LAG3- phenotype, corresponding to T cell activation, was associated with longer median irPFS and higher irORR.…”

“…The expression of PD-1 in tumour-infiltrating lymphocytes was not associated with poor clinical outcomes [61]. If not reported alone as a biomarker in metastatic ccRCC, PD-1 was described in association with other markers to define a T cell activation phenotype correlated with the response to nivolumab [54].…”

The Evaluation of Response to Immunotherapy in Metastatic Renal Cell Carcinoma: Open Challenges in the Clinical Practice

“…Recently, a secondary analysis of the CheckMate 010 trial [8] was published, aimed at investigating the irRECIST criteria for the evaluation of biomarkers of response to nivolumab in mRCC patients. The different endpoints assessed according to RECIST 1.1 and irRECIST criteria were compared and the results showed that immune-related PFS (irPFS) was significantly longer than median PFS per RECIST 1.1 (5.5 versus 3.3 months), unlike ir-ORR that did not significantly differ from ORR per RECIST 1.1 (22.8% versus 21%), even though PD according to RECIST 1.1 overestimated the irPD (35.3% versus 24.6%) [58].…”