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March 5, 2020

A New Therapeutic Era for Metastatic Renal Cell Carcinoma: Call for a New Prognostic Model

Author Affiliations
  • 1Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. Published online March 5, 2020. doi:10.1001/jamaoncol.2019.6862

The therapeutic landscape for metastatic renal cell carcinoma (mRCC) has evolved over 3 eras, including the cytokine, targeted therapy, and current immune checkpoint inhibitor (ICI) eras. The contemporary ICI era was introduced by the CheckMate 025 trial, which led to the US Food and Drug Administration approval of nivolumab for treating mRCC in 2015.1 Since then, the use of ICI has continued to markedly affect the treatment paradigm for mRCC.

In counseling patients on their predicted survival, clinicians frequently rely on validated prognostic risk models. The most commonly used models for mRCC include the Memorial Sloan Kettering Cancer Center (MSKCC) risk score,2 developed during the cytokine era, and, later, the International mRCC Database Consortium (IMDC) risk score,3 developed in the targeted therapy era (Table). These models are based on combined clinical and laboratory parameters to stratify patients into favorable, intermediate, and poor risk groups. Common adverse prognostic features shared between the 2 models include time-to-initiation of systemic therapy (<1 year from diagnosis), anemia, hypercalcemia, and poor Karnofsky performance status. The MSKCC model also includes elevated lactate dehydrogenase levels as an adverse factor, whereas the IMDC model includes neutrophilia and thrombocytosis as adverse factors. Recent efforts using genomic annotation have even been underway to help improve the accuracy of these relatively simple models in capturing the heterogeneity of mRCC.4

Table.  Commonly Used Prognostic Models for mRCC
Commonly Used Prognostic Models for mRCC

While these models have been generally reliable in predicting survival outcomes in patients treated with traditional systemic agents, their accuracy may be compromised as we increasingly use ICI to treat mRCC. For example, an analysis of the CheckMate 214 trial, which led to the first frontline approval of an ICI-based regimen (ipilimumab and nivolumab) for treating mRCC, revealed that patients classified as poorer risk per IMDC criteria exhibited a more robust relative response to ICI vs sunitinib compared with favorable-risk patients.5 Furthermore, post hoc analyses of recent ICI trials revealed that patients exhibiting sarcomatoid features, which have classically been associated with worse outcomes, respond well to ICI.6 Taken together, these emerging data should prompt us to reconsider the relevance of the MSKCC and IMDC risk models in our current ICI era, as poor-risk patients treated with targeted therapies may no longer be considered poor risk when treated with ICI.

Conceivably, this observation may be due, in large part, to the notion that tumors exhibiting a more inflammatory phenotype are inherently more aggressive and less responsive to targeted therapies, such as angiogenic inhibitors. However, mechanistically, these immunogenically “hot” tumors may respond more readily to ICI. In a preclinical study using patient-derived xenografts, Wang et al7 recently showed that at least 4 of the 6 IMDC variables, including thrombocytosis, anemia, neutrophilia, and low performance status, likely result from inflammation induced by the tumor. While tumors that exhibit more of these inflammatory features are less likely to respond to targeted therapies, the presence of these features may actually be associated with a better response to ICI.

Accurately predicting risk is important not only to counsel patients on their survival probability but also to better establish candidacy for multimodal treatment approaches, such as cytoreductive nephrectomy (CN). The role, candidacy, and timing of CN have been a moving target and rely on appropriate patient selection. As CN has been reserved for patients with more favorable risk scores, it is plausible that more patients may now derive benefit from consolidative surgery by introducing ICI into the therapeutic armamentarium. Future clinical trials combining CN with ICI will illuminate the role of CN in our contemporary era.

Indeed, as we gain further insight into the molecular predictors of therapeutic responsiveness, precision medicine will likely play an increasing role in stratifying patients to an appropriate first-line therapy (ie, angiogenic inhibitor, ICI, or a combination of the 2) that would maximize benefits. A novel approach to prognostication can then ensue, contingent on the class of therapy selected. While the IMDC criteria may be relevant for patients treated with antiangiogenic agents, a different, to my knowledge heretofore undefined, set of criteria is needed to better predict survival in patients treated with ICI.

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Article Information

Corresponding Author: Nirmish Singla, MD, MSCS, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (nirmish@gmail.com).

Published Online: March 5, 2020. doi:10.1001/jamaoncol.2019.6862

Conflict of Interest Disclosures: None reported.

References
1.
Motzer  RJ, Escudier  B, McDermott  DF,  et al; CheckMate 025 Investigators.  Nivolumab versus everolimus in advanced renal-cell carcinoma.  N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665PubMedGoogle ScholarCrossref
2.
Motzer  RJ, Bacik  J, Murphy  BA, Russo  P, Mazumdar  M.  Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.  J Clin Oncol. 2002;20(1):289-296. doi:10.1200/JCO.20.1.289PubMedGoogle ScholarCrossref
3.
Heng  DY, Xie  W, Regan  MM,  et al.  Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.  J Clin Oncol. 2009;27(34):5794-5799. doi:10.1200/JCO.2008.21.4809PubMedGoogle ScholarCrossref
4.
Voss  MH, Reising  A, Cheng  Y,  et al.  Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study.  Lancet Oncol. 2018;19(12):1688-1698. doi:10.1016/S1470-2045(18)30648-XPubMedGoogle ScholarCrossref
5.
Motzer  RJ, Tannir  NM, McDermott  DF,  et al; CheckMate 214 Investigators.  Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.  N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126PubMedGoogle ScholarCrossref
6.
Rini  BI, Plimack  ER, Stus  V,  et al.  Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study.  J Clin Oncol. 2019;37:4500-4500. doi:10.1200/JCO.2019.37.15_suppl.4500Google ScholarCrossref
7.
Wang  T, Lu  R, Kapur  P,  et al.  An empirical approach leveraging tumor grafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors.  Cancer Discov. 2018;8(9):1142-1155. doi:10.1158/2159-8290.CD-17-1246PubMedGoogle ScholarCrossref
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