ASCO 2020: Evaluation of Predictive Biomarkers for Nivolumab in Patients with Metastatic Clear Cell Renal Cell Carcinoma from the CheckMate-025 Trial

( Checkmate 025 was a large open-label phase 3 study that compared nivolumab vs everolimus for patients with pretreated metastatic RCC.1 72% of patients had 1 line of prior anti-angiogenic regimen and 28% had 2 prior lines of therapy. This study met its primary endpoint with a median overall survival of 25 months for patients receiving nivolumab compared with 19.6 months for patients receiving everolimus. The objective response rate (ORR) for nivolumab was 25% compared with 5% for everolimus. Following this study, the FDA approved nivolumab for the second-line treatment of patients with mRCC. The authors of this study sought to validate prior biomarker showing that the levels of CD8+ tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+TIM3−LAG3−) were associated with response to nivolumab with the CM025 dataset.

Tumor tissue from 116 patients on the nivolumab arm and 107 on the everolimus arm were analyzed with multiplex immunofluorescence. RNA-seq was performed on a subset of patients (n=71) and data was analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA) and gene signature scores.

Analysis showed that the density of CD8+ PD1+TIM3−LAG3− tumor-infiltrating cells was associated with objective response and clinical benefit (CB, as defined as CR/PR and PFS≥12 months).


When CD8+ PD1+TIM3−LAG3− tumor-infiltrating cell density was combined with tumor cell PD-L1 expression, this further separated ORR, CB, and PFS in the nivolumab arm but not the everolimus arm. Patients who were PD-L1 high and high in TIC had the best outcomes.


The CD8+ PD1+TIM3−LAG3−tumor-infiltrating cell density biomarker, first described Pignon et al based on the CheckMate-010 trial, was validated here in Checkmate-025 and when combined with tumor cell PD-L1 expression, further separated the PFS curves for patients with mRCC.2 The treatment landscape of RCC has changed dramatically since CM-025, now that frontline therapy for patients involves immunotherapy-TKI combination or IO-IO combinations and these biomarkers should be examined with contemporary datasets to see if we can predict who might be more responsive to an IO-IO approach vs IO-TKI approach.

Presented by: Miriam Ficial, MD, BM, Research Fellow in Pathology, Brigham and Women's Hospital, Boston, MA 

Written by: Jason Zhu, MD. Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 


  1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2015;373:1803-13.
  2. Pignon J-C, Jegede O, Shukla SA, et al. 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. Clinical Cancer Research 2019;25:2174-84.