RCC studies identify biomarkers of PD-1 inhibitor outcomes
medwireNews: Analyses of the CheckMate 025 and KEYNOTE-427 trials of nivolumab and pembrolizumab, respectively, have identified biomarkers associated with response to the individual agents in patients with advanced renal cell carcinoma (RCC).
Both studies were presented in a poster discussion session of the virtual 2020 ASCO Annual Meeting.
The first analysis sought to validate a biomarker that has previously been associated with nivolumab response in previously treated patients with metastatic clear-cell RCC, namely levels of CD8+ tumor infiltrating cells (TICs) expressing PD-1 but not TIM-3 and LAG-3 (CD8+PD1+TIM3−LAG3−).
The researchers used multiplex immunofluorescence to measure the density of CD8+PD1+TIM3−LAG3− TICs in tumor samples from 116 patients randomly assigned to receive nivolumab and 107 patients instead given everolimus in the phase 3 CheckMate 025 trial.
Among nivolumab-treated patients, the density of these TICs as a continuous variable was significantly associated with the objective response rate (ORR) and clinical benefit rate (CBR), which was defined as a complete or partial response and progression-free survival (PFS) of at least 12 months.
The results were similar when an optimal cutoff was used to delineate patients into high- and low-density groups, with significantly higher ORR (45.8 vs 19.6%), CBR (33.3 vs 14.1%), and PFS (median, 9.6 vs 3.7 months) for those with a high density of the biomarker.
No such associations between the biomarker and outcomes were observed in the everolimus treatment arm, said Miriam Ficial of Brigham and Women's Hospital in Boston, Massachusetts, USA.
Combining the biomarker with tumor cell PD-L1 expression allowed further stratification of nivolumab-treated patients into three groups with differing outcomes, such that patients with high levels of both the TIC biomarker and PD-L1 had the most favorable outcomes and those with low levels of both markers had the poorest outcomes.
“Further validation in the setting of first-line anti-PD-1 therapy is ongoing,” Ficial concluded.
The second study evaluated 11 gene expression profile (GEP) signatures in 78 patients with clear-cell RCC and 136 with non-clear-cell RCC who were enrolled in the single-arm phase 2 KEYNOTE-427 trial of first-line pembrolizumab and had available RNA sequencing data.
As reported by David McDermott (Dana-Farber Cancer Center, Boston), only the T-cell-inflamed GEP was significantly associated with ORR in both the clear-cell and non-clear-cell cohorts, and was also significantly linked to overall survival in the clear-cell cohort.
There was no significant association between any of the other signatures, such as those for angiogenesis, glycolysis, hypoxia, or proliferation, and response to pembrolizumab after adjusting for the T-cell-inflamed GEP and IMDC status.
“An integrative analysis of biomarkers from KEYNOTE-427 using immunohistochemistry, DNA, and RNA samples is underway,” concluded McDermott.
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This independent news story was supported by an educational grant from Pfizer and Merck KGaA