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Progress Made in Identifying Gene-Signature Biomarkers in Renal Cell Carcinoma


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A NEW ANALYSIS of the phase III IMmotion151 trial identified gene signatures in renal cell carcinoma that correlate with improved progression-free survival in patients treated with atezolizumab (Tecentriq) plus bevacizumab (Avastin) vs sunitinib (Sutent). These findings were presented at the European Society for Medical Oncology (ESMO) 2018 Congress.1

Brian Rini, MD

Brian Rini, MD

“We found clinical subsets that were characterized by gene expression. A consistent effect favoring atezolizumab was observed, notably in sarcomatoid tumors,” lead author Brian Rini, MD, of the Cleveland Clinic, told listeners.

Previously, the phase II IMmotion150 trial identified gene signatures associated with response to atezolizumab, which were then validated by Dr. Rini and colleagues’ analysis of IMmotion151. “It’s not often that we get a chance to validate gene-expression data like these in two different data sets. It is important that the gene signatures in IMmotion150 were validated in IMmotion151,” he commented.

Study Description

IMMOTION151 included 915 patients with treatment-naive advanced or metastatic renal cell carcinoma. In that trial, atezolizumab plus bevacizumab improved progression-free survival vs sunitinib in programmed cell death ligand 1 (PD-L1)–positive patients and in an intent-to-treat analysis. In PD-L1–positive patients, the median progression-free survival was 11.2 months vs 7.7 months (P = .02). In the intent-to-treat analysis of the overall study population, the median progression-free survival was 11.2 months vs 8.4 months, respectively. The analysis was based on 263 patients enrolled in IMmotion151.

A signature showing high expression of T-effector cells was associated with improved progression-free survival using atezolizumab plus bevacizumab vs sunitinib. Atezolizumab plus bevacizumab also achieved numerically superior progression-free survival in tumors with low expression of angiogenesis-related genes, whereas sunitinib did better in patients with tumors showing high expression of angiogenesis-related genes.

In the group with low expression of angiogenesis-related genes, the median progression-free survival was 8.94 months with atezolizumab plus bevacizumab vs 5.95 months with sunitinib. In the group with high expression of angiogenesis-related genes, the improvement in progression-free survival with the combination was not as robust: 12.45 months vs 10.2 months.

NEW ANALYSIS OF IMMOTION151

  • The study provided identification and validation of genetic signatures that correlate with progression-free survival associated with atezolizumab plus bevacizumab vs sunitinib in patients with advanced renal cell carcinoma.
  • The findings suggest that MSK risk group alone does not necessarily predict response and that genetic signatures are an important piece of the puzzle in the search for biomarkers.

In the subgroup with high expression of T-effector cells, the median improvement in progression-free survival was 12.45 vs 8.34 months, respectively. In patients with low expression of T-effector cells, a smaller increase in progression-free survival was seen with the combination vs sunitinib: 9.72 vs 8.41 months, respectively. Among sunitinib-treated patients, sunitinib was associated with a better median progression-free survival in the high vs low expression of angiogenesis-related genes (10.12 vs 5.95 months, respectively).

The investigators performed an analysis based on Memorial Sloan Kettering Cancer Center (MSK) risk groups and sarcomatoid histology to characterize the interaction between gene-expression signatures and these factors. They found that high expression of angiogenesis-related genes was more prevalent in MSK favorable–risk patients (74%) than in MSK intermediate/poor-risk patients (57%).

Patients with sarcomatoid tumors had a significant benefit with atezolizumab plus bevacizumab vs sunitinib. Only one-third of sarcomatoid tumors had high expression of angiogenesis-related genes vs two-thirds of nonsarcomatoid tumors. PD-L1 expression was higher in those with nonsarcomatoid tumors. T-effector gene expression was increased in sarcomatoid tumors vs nonsarcomatoid tumors: 54% vs 40%, with high expression of T-effector genes, respectively. Also, sarcomatoid tumors were more likely to be PD-L1–positive, “likely explaining the effect of atezolizumab in this subgroup,” he added. 

DISCLOSURE: The study was sponsored by F. Hoffmann-La Roche. Dr. Rini has received honoraria from Bristol-Myers Squibb; is a consultant/advisor with Novartis, Pfizer, Merck, and Roche/Genentech; has received institutional research funding from Pfizer, Roche/Genentech, Bristol-Myers Squibb, and Merck; and has received travel/accommodations/expenses from Pfizer.

REFERENCE

1. Rini BI, et al: Molecular correlates differentiate response to atezolizumab + bevacizumab vs sunitinib. ESMO 2018 Congress. Abstract LBA31. Presented October 20, 2018


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