The Role of Biomarkers in the Prediction of Response to Therapeutics in Metastatic Renal Cell Carcinoma - Beyond the Abstract

This review summarizes the current treatment landscape for metastatic renal cell carcinoma (mRCC) prior to February 16th, 2019. It reviews the data from some of the most recent mRCC trials: CABOSUN, CheckMate 214, IMmotion151, and JAVELIN Renal 100. Additionally, there is a discussion the current state of biomarkers in renal cell carcinoma and their actionability, significantly associated genes found from the RECORD-3 trial, the value of PD-(L)1 as predictive/prognostic, and current understanding of the impact of the microbiome on therapy. It identifies next-generation sequencing of circulating tumor DNA can further inform treatment decisions for patients. 

The incidence and prevalence of mRCC have both been increasing, the former most likely due to improved imaging techniques and the latter because of improved treatment modalities. The pathogenesis and genomic alterations most commonly altered in mRCC are exploitable through VEGF inhibitors. Agents targeting VEGF have been very successful and flourished, but there have also been implications in the role of the immune system. Prior to VEGF directed therapies, immunotherapy (IO) in the form of IL-2 and interferon-alpha were the only treatments for mRCC. There has been a new influx of immunotherapy in the form of checkpoint inhibitors and specifically PD-1 and CTLA-4 inhibitors in the first-line treatment of mRCC. With both of these treatment strategies in mind, combining VEGF-IO has been very popular and slowly becoming mainstay after trials such as IMmotion151 and JAVELIN-100 Renal. The latter earning FDA breakthrough designation for the impressive ORR in phase Ib trial. 

Genomic-driven approaches have also become more popular and targeting mTOR pathway as well as identifying specific gene mutations that have prognostic implications have been strongly supported. For example, PBRM1 mutations have been implicated in predicting benefit to both VEGF inhibitors and IOs, while KDM5C, VHL, NF1, and TP53 mutations have been shown to be prognostic of outcome to VEGF inhibitors. Furthermore, The gene MET has been implicated in the papillary subtype of kidney cancer and targeting this mutation with MET inhibitors in patients with this alteration has been shown to significantly prolong progression-free survival. Analyzing the sequences of circulating tumor DNA from blood samples has also helped guide therapies for patients. Additionally, the ease of attaining blood samples has made monitoring ctDNAs and seeing temporal changes a very unique aspect that previously was not as feasible with repeated tumor biopsies. 

Predicting response based on the gut microbiome composition and resident bacterial species is also gaining prevalence in mRCC in the IO era. Although this is still a space in need for further investigation, efforts to increase the utility of microbiome data continues to thrive. 

The treatment landscape for mRCC continues to evolve at a rapid pace and various combinations of treatments are being tested to find the optimal regimen in distinct categories of patients. Biomarkers are still an elusive part of the treatment of mRCC, but as therapeutic strategies continue to progress with an increase in the number of VEGF-IO combination regimens in the foreseeable future, biomarkers will be pivotal in tailoring therapies to mRCC patients most likely to derive benefit. 

Written by: Jacob J. Adashek, BA,1; Meghan M. Salgia, BS2; Edwin M. Posadas, MD3; Robert A. Figlin, MD3; Jun Gong, MD3*
1. Doctor of Osteopathic Medicine Candidate 2019, Western University of Health Sciences, College of Osteopathic Medicine of the Pacific, Pomona, California, United States 
2. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California, United States
3. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States

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