Select Transcriptional Signatures in nccRCC May Have Clinical Potential, Research Shows

Pedro C. Barata, MD, MSc

Non-clear cell renal cell carcinoma (RCC) was found to have a strong correlation with the proliferative subtypes but showed a weak correlation with the angiogenic subtypes compared to clear cell RCC (ccRCC).¹

These findings suggest that understanding both subtypes is important for personalizing treatment for patients with nccRCC, according to a presentation given by Pedro C. Barata, MD, MSc, during the 2021 International Kidney Cancer Symposium: North America.

“Gene expression profiling reveals differential genomic signatures with the potential to optimize treatment selection for non clear cell renal cell carcinoma,” Barata, assistant professor of Medicine Hematology & Medical Oncology at Tulane University School of Medicine told Targeted Oncology™, in an interview.

In recent years, multiple therapeutic options have entered the RCC landscape after demonstrating activity against the disease. A new exploration into anti-angiogenic and immune signatures suggests new ways to treat the disease.

In the IMmotion151 (NCT02420821), which evaluated the combination of bevacizumab (Avastin) and atezolizumab (Tecentriq) compared with sunitinib (Sutent) in metastatic RCC (mRCC), patients who previously received anti-VEGF in combination with anti-PD-L1 therapy were the most likely to derive benefit. Further, in the JAVELIN Renal 101 (NCT02684006) of avelumab (Bavencio) plus axitinib (Inlyta) versus sunitinib in patients with advanced RCC, the combination showed significant improvement in OPFS among patients who were previously untreated.^2,3

Using gene expression profiling, investigators evaluated nccRCC samples to identify transcriptional signatures with the potential to offer clinical benefit for patients in the future.¹

To conduct the study, DNA/RNA next-generation sequencing was performed on the samples and confirmed diagnoses of nccRCC samples were made by central pathology review. The molecular subgroups were defined based on research from Motzer et al., 2020 as well as by a weighted average of gene expression levels.

A total of 657 patients' RCC samples were analyzed. The cohort had a median age of 62 years (range, 14-90), and the majority of patients were males (70.6%). In terms of histology, 9.6% had papillary nccRCC, 4.6% had chromophobe histology, 1.2% had medullary disease, 0.9% had collecting duct carcinoma, and the remaining 6.2% mixed had mixed nccRCC histology. Biopsies for assessment were collected from the kidney of 51.7% of the study population, but there were also samples from the lung (11.4%), bone (6.8%), lymph nodes (5.2%), liver (4.2%), and other metastatic sites (20.7%).

Fifty percent of the RCC samples were classified as angiogenic or angio/stromal at baseline. Less than < 10% nccRCC samples were classified as proliferative.

Results from the study showed that sarcomatoid and rhabdoid features were associated with T-effector/proliferative as well as stromal/proliferative. An increase in immune cell infiltration was also observed with the T-effector/proliferative subtype compared with other subgroups. The I-effector/proliferative subtype also led to an increased amount of pro-immune cell types was concurrent with high expression of immune checkpoint genes.

Immunosuppressive cell types were more abundant with the stromal/proliferative subtypes compared with the other, and endothelial cells showed up predominantly in the angiogenic and angio/stromal subtypes.

Based on these findings, the investigators noted that RCC tumors with sarcomatoid/rhabdoid have similar enrichment of the T-effector/proliferative subgroup, regardless of whether the disease is clear cell or non-clear cell.

It was also noted in the presentation that PD-L1-positive tumors were more common in the nccRCC tumors (range 16.7%-37.5%) compared with the ccRCC tumors. The highest rate of PD-L1 positivity was observed in RCC samples with medullary histology.

Rate of mismatch repair deficiency (dMMR), high microsatellite instability (MSI-H), and high tumor mutational burden (TMB-High) were observed most commonly in collecting duct carcinoma (33.3%). In the other histologic subgroups, dMMR, MSI-H, and TMB-High were seen in less than 3.5% of patients.

According to Barata, although the patient cohort was small, this research could offer insight into future treatment. However, prospective data around the predictive value of gene expression signatures are needed.

_References:

_{1. Barata PC, Gulati S, Elliott A, et al. Gene Expression Profiling (GEP) of non-clear cell renal cell carcinoma (nccRCC) identifies a unique spectrum of transcriptional signatures with clinical potential. Presented at the International Kidney Cancer Symposium: North America. November 5-6, 2021; Austin, TX.}

_{2. Rini BI, Atkin MB, Escudier B, et al. Abstract CT188: IMmotion151: updated overall survival (OS) and exploratory analysis of the association of gene expression and clinical outcomes with atezolizumab plus bevacizumab vs sunitinib in patients with locally advanced or metastatic renal cell carcinoma (mRCC). Can Res. 2021;81(13). doi: 10.1158/1538-7445.AM2021-CT188}

_{3. Choueri TN, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31(8):1030-1039. doi: 10.1016/j.annonc.2020.04.010.}