Gene Expression Signature Correlates with Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Everolimus Alone or with a Vascular Disrupting Agent

Although the mTOR pathway has long been regarded as a promising therapeutic target in renal cell carcinoma, randomized clinical trials on mTOR inhibitors such as temsirolimus have shown modest activity in metastatic disease (mRCC). A recent clinical trial studying the efficacy of everolimus alone versus everolimus with a vascular disrupting agent (BNC105P) showed similar outcomes in both arms and no added benefit from BNC105P. In this work, we hypothesized that gene expression associated with everolimus benefit may provide the rationale to select appropriate patients.

We used tumor samples from patients enrolled in the phase I/II clinical trial and performed gene expression profiling through NanoString. Samples from the everolimus arm of a phase III trial (CheckMate 025) were used for validation. Clinical benefit (CB) was defined as response or stable disease for ≥6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC).

A total of 82 tissue samples, all from primary nephrectomies were obtained for patients of the phase I/II trial. 35 patients were treated with everolimus alone, and 47 patients were treated with the combination (everolimus + BNC105P). Most patients (84%) had received one prior line of tyrosine kinase inhibitors (TKI). The median progression-free survival was 4.9 months for the discovery cohort. The validation cohort consisted of 130 patients treated on the everolimus arm of CheckMate 025, with bulk RNA-seq data available. The median PFS was 3.7 months.

Using the Nanostring platform, gene expression profiling of 82 samples for 517 genes enabled the identification of a 4-gene expression signature (ASXL1, DUSP6, ERCC2, and HSPA6) that was associated with clinical benefit in the entire discovery cohort (82 patients). Among 37 patients with high expression of this 4-gene signature, 30 (81.1%) displayed clinical benefit, while among 45 patients with low expression, 7 patients (15.6%) displayed clinical benefit (AUC 86.9% [95%CI=79.2-94.7]). This was validated in 130 patients from CheckMate 025 treated with everolimus (AUC 60.2% [95%CI=49.7-70.7]). A comparison of the two arms of the phase I/II trial (everolimus +/- BNC105P) identified an 18-gene signature that correlated with better outcomes in the combination arm (10.4 vs 6.9 months, HR 0.49, 95% CI, 0.24-1.002, p=0.047).

In our retrospective analysis of prospective trial data, a four-gene signature was determined to have prognostic value for using everolimus alone or with BNC105P. Validation in an external cohort (CheckMate 025) had a suboptimal AUC (60.2%). Overall, this represents the first transcriptomic signature that correlates with clinical benefit in mRCC patients treated with everolimus. If further validated, this signature could be useful in patient selection for mTOR inhibitors after VEGF TKIs or immune checkpoint inhibitors.

Written by: Elio Adib,¹ Amin H. Nassar,² Guru P. Sonpavde,³ and Eddy S. Yang⁴

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital
Division of Pulmonary Medicine, Brigham and Women's Hospital
Department of Medical Oncology, Dana-Farber/Harvard Cancer Center
Department of Radiation Oncology, University of Alabama at Birmingham

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