ASCO 2020: Single Agent PD-1 Inhibitor Biomarkers in Untreated and Previously Treated Advanced RCC: What Can Biomarkers Teach Us to Advance Clinical Care?

( Following two poster discussion presentations assessing predictive markers in patients with advanced renal cell carcinoma, “Evaluation of predictive biomarkers for nivolumab in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 (CM-025) trial” and “Association of gene expression with clinical outcomes in patients with renal cell carcinoma treated with pembrolizumab in KEYNOTE-427”, Dr. Katy Beckermann provided her perspective as a discussant on the value of biomarkers to advance clinical care of patients with advanced renal cell carcinoma. The data from the abstracts upon which this discussion was based will briefly be summarized. 

First, Dr. Miriam Ficial and colleagues utilized data from the randomized Phase III trial of nivolumab versus everolimus (evero) (CheckMate-025) and explored the association of the biomarker with transcriptomic profiles. The authors examined the density/percentage of CD-8+PD-1+TIM3LAG-3TIC evaluated by immunofluorescence (IF) and PD-L1 expression on tumor cells (TC) was evaluated by immunohistochemistry (IHC) and correlated these with clinical outcomes including objective response rate, clinical benefit, progression-free survival, and overall survival. They demonstrated that, among patients receiving nivolumab, high levels of CD-8+PD-1+TIM3LAG-3TIC predicted response.

Second, the Phase II KEYNOTE-427 study included patients with clear cell (n=110, cohort A) and non-clear cell (n=165, cohort B) renal cell carcinoma who received pembrolizumab. In the analysis presented at the 2020 ASCO Virtual Annual Meeting, Dr. David McDermott and colleagues assessed the association of baseline RNA-sequencing–based gene expression signatures and DNA alterations with response or resistance to pembrolizumab using RNA sequencing. They assessed a number of gene expression signatures (18-gene T-cell–inflamed gene expression profile [GEP]; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) and correlated these with objective response rate and progression-free survival. They found that in cohort A (i.e. those with clear cell histology), T-cell–inflamed gene expression profile (GEP) (n = 78) was statistically significantly associated with a better overall response rate (ORR) (P = 0.021; AUROC = 0.65) but not progression-free survival (PFS) (P = 0.116). No other tumor microenvironment (TME) canonical signatures showed a correlation with ORR or PFS.

Dr. Beckermann highlighted that PD-L1 status and tumor mutational burden (TMB) have, thus far, failed to provide significant predictive value. She then highlighted other emerging biomarkers including the regulation of endogenous retroviruses and immune-suppressive signatures including T-effector and myeloid signatures. Based on the data presented at the 2020 ASCO Virtual Annual Meeting, Dr. Beckermann highlighted the following points:

The data from CheckMate-025 confirm that a combined assessment of protein and gene expression is necessary to explain the T-cell function necessary for response to PD-1. Clinically, these may be useful to explain the extremes of response but are unlikely to distinguish patients with intermediate responses who represent the majority of patients.

From KEYNOTE-427, Dr. Beckermann highlighted that this was the first study assessing this question in patients with non-clear cell histology. It further confirms that the T-cell inflamed signature is an important marker of response in patients with clear cell histology. However, this approach is not yet readily available in practice and thus is not immediately translatable.

In summary, Dr. Beckermann highlighted the need for confirmation and ongoing utilization of multi-platform analysis to understand the complex tumor and immune interactions underpinning immunotherapy.

Presented by: Katy Beckermann, MD, PhD, Instructor of Medicine, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville, Tennessee

Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, Tennessee, Twitter: @WallisCJD, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020