Opinion Progress Toward Precision Medicine in Frontline Treatment VIEWPOINT of Metastatic Renal Cell Carcinoma Asmolecularunderstanding of cancer biology evolves, Cell Cancer (JAVELIN Renal 101; testing avelumab plus Nirmish Singla, MD, MSCS precision medicine will play a growing role in guiding axitinib, which is now US Food and Drug Administration\u2013 Department of Urology, therapy. This is certainly evident in the case of meta- approved as a frontline therapy), and A Study of Atezoli- University of Texas static renal cell carcinoma (mRCC), which is inherently zumab in Combination With Bevacizumab Versus Suni- Southwestern Medical a heterogeneous tumor type on both clinical and mo- tinib in Participants With Untreated Advanced Renal Cell Center, Dallas; and Urology Service, lecular levels. The treatment approach for mRCC has Carcinoma (IMmotion151; testing atezolizumab plus Department of Surgery, 7 evolved considerably over the past couple of decades, bevacizumab). The treatment paradigm for kidney can- Memorial Sloan since the original cytokine era of interleukin-2 and cer is evolving at an undeniably rapid pace as various in- Kettering Cancer interferon-\u03b1. The targeted therapy era for mRCC, which terclasstherapeuticpermutationsarebeingtestedandap- Center, New York, New York. dominated throughout most of the 2000s, was the proved. Although these options may be oncologically first foray into precision medicine. It capitalized on beneficial for patients, clinicians are left with the daunt- pathways implicated in tumorigenesis and disease pro- ingchallengeofstayingabreastofthesedevelopmentsand gression. Among the therapeutic classes introduced, integrating them into their care algorithms. angiogenic inhibitors emerged as the most promising When combining therapeutic classes, a logical next agents and defined the new standard of care for treat- question is whether the combined benefit is additive (by ing mRCC. The efficacy of these agents highlights the targeting separate mechanisms) or biologically synergis- unique biology underlying clear-cell renal cell carci- tic.TherationaletocombineICIandangiogenicinhibitors noma (ccRCC), the most common histologic subtype, in for mRCC is the potential transformation of a so-called which von Hippel\u2013Lindau gene (VHL) inactivation immunologically cold tumor, which may not respond to induces angiogenesis via the accumulation of hypoxia- ICI, to one that is immunologically hot via angiogenic inducible factors. Although encouraging, several inhibition. This strategy of therapeutically altering the patients with ccRCC have remained resistant to these microenvironment could theoretically increase ICI re- therapies, requiring novel approaches to treatment. sponsivenessviaimmunologicalpriming.However,asub- Theintroductionofimmunecheckpointinhibitors(ICI) set of patients with ccRCC who have benefited from into the clinician\u2019s therapeutic arsenal revolutionized the this approach may conceivably harbor heterogeneous, treatment paradigm across several immunogenic malig- mutually exclusive tumor clones that exhibit differential nant conditions, including mRCC. The landmark Study of responsiveness along a proposed ICI or antiangiogenic Nivolumab (BMS-936558) vs Everolimus in Pre-treated spectrum (Figure), amounting simply to an additive Advanced or Metastatic Clear-Cell Renal Cell Carcinoma effect\u2014that is, some clones may be pure antiangiogenic (CheckMate 025) trial, which led to the approval of the responders,whereasothercloneswithinthesametumor programmedcelldeathprotein1(PD-1)inhibitornivolumab maybepureICIresponders.Anotherpossibilityisthatpa- for patients with mRCC who had previously been treated tients may effectively respond to either class of therapy with antiangiogenic agents, brought mRCC into the con- alone (eg, those with shared features between pure temporaryICIerain2015.Soonthereafter,theNivolumab antiangiogenic-responder and pure ICI-responder tu- Combined With Ipilimumab Versus Sunitinib in Previ- mors), and the addition of another therapy is unneces- ously Untreated Advanced or Metastatic Renal Cell Carci- sary and increases both risk of toxic effect and cost. noma (CheckMate 214) trial, which demonstrated re- Thus, a more precise approach to inform treatment is markable clinical benefit in blocking both PD-1 and urgentlyneededbutwillbecomehardertostudyasmore cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) patients receive combination approaches upfront. pathwaystogether,ledtotheapprovalofcombinationICI Molecular correlates emerging from elegant pre- (ipilimumab plus nivolumab) as a frontline therapy. Since clinical and clinical studies have begun to lay a founda- then,aflurryofpractice-changingtrialshaveemergedthat tion for anticipating response along the ICI-anti- investigate various ICI combination regimens. Most re- angiogenic spectrum. In particular, the 3-arm phase 2 cently, the role of combining ICI with angiogenic inhibi- IMmotion150trial, whichincludedsunitinib(adrugwith tion was explored in 3 seminal phase 3 randomized clini- pure angiogenic inhibition), atezolizumab (a drug for caltrials,allofwhichwerepublishedin2019:theStudyto pure ICI), and atezolizumab plus bevacizumab (for com- Corresponding Evaluate the Efficacy and Safety of Pembrolizumab bination ICI and antiangiogenesis), highlighted the value Author: Nirmish Singla, (MK-3475) in Combination With Axitinib Versus Sunitinib of incorporating the genomic, transcriptomic, and im- MD, MSCS, Department Monotherapy in Participants With Renal Cell Carcinoma munohistochemical environments into therapeutic of Urology, University of Texas Southwestern (MK-3475-426\/KEYNOTE-426; testing pembrolizumab decision-making. Remarkably, the investigators found Medical Center, 5323 plus axitinib, which is now US Food and Drug Administra- that differential gene expression (characterized as an- Harry Hines Blvd, tion\u2013approved as a frontline therapy), A Study of Ave- giogenic, T-effector, and myeloid signatures) is associ- Dallas, TX 75390 (firstname.lastname@example.org). lumab With Axitinib Versus Sunitinib In Advanced Renal ated with response to therapy and may further corre- jamaoncology.com (Reprinted) JAMA Oncology January 2020 Volume 6, Number 1 25 \u00a9 \u00a9 2019 2019 American American Medical Medical Association. Association. All All rights rights rreserved. eserved. Opinion Viewpoint Figure. A Proposed Simplified Therapeutic Spectrum for Frontline Treatment Strategies for Clear-Cell Metastatic Renal Cell Carcinoma Pure ICI ICI + AI Pure AI Responder Clones Responder Clones Responder Clones PBRM1 mutation Additive vs synergistic High tumor mutational burden, high Candidate molecular biomarkers to High angiogenic gene expression Heterogeneous clones neoantigen burden expression assess treatment responsiveness are Low T-effector gene expression Shared features in same clone High human endogenous retrovirus annotated based on preclinical and Rich vascularity, low immune infiltrate Therapeutically alter environment expression, BAP1 mutation Low angiogenic gene expression clinical studies, although validation is High T-effector gene expression, necessary before they can be low myeloid expression clinically implemented. A subset of High immune infiltrate, high PD-L1 patients with clear-cell renal cell expression carcinoma will not respond to either immune checkpoint inhibitors (ICIs) or angiogenesis inhibitors (AIs) and Molecular Milieu Genome\/epigenome thus fall outside of this spectrum. Transcriptome BAP1 indicates BRCA1-associated Histology\/immunohistochemistry protein-1 gene; PBRM1, protein Tumor microenvironment polybromo-1 gene; Gut microbiome Metabolome PD-L1, programmed cell death protein 1. latewithsomaticmutations.Forexample,mutationsinthechromatin couraging insight into the biology and therapeutic responsiveness of remodeling protein polybromo-1 gene (PBRM1) were associated with renalcellcarcinomatumorsthroughnoninvasivemeans.However,de- higher angiogenesis and improved response to angiogenic inhibi- spite the unparalleled progress in identifying candidate biomarkers tors. In contrast, increased tumor mutational or neoantigen bur- toinformtreatment,nonehasyetbeenvalidatedorimplementedinto den, high T-effector expression, high human endogenous retrovi- routine clinical practice. Future studies are eagerly awaited to eluci- rus expression, and potentially mutations in BRCA1-associated date the value of these components in influencing patient care. protein-1 gene (BAP1) have been proposed as biomarkers of ICI re- Despite these advances, several questions remain. The subset sponse. These pivotal findings represent a milestone in advancing of patients with ccRCC (and with non-ccRCC) who fall outside of precision medicine in mRCC and form the basis for future studies of this arguably oversimplified therapeutic spectrum and do not re- treatment response. spond to approved regimens continue to request novel treatment Asidefromdrivermutations,geneexpressionsignatures,andpro- approaches. Ongoing and future trials will continue to explore the grammed cell death protein ligand 1 (PD-L1) immunohistochemical role of different drug combinations, including the 3-pronged expression, an even more comprehensive, multidimensional approach (ipilimumab, nivolumab, and cabozantinib) proposed approach that integrates tumor mutational burden, neoantigen bur- in the phase 3 Study of Cabozantinib in Combination With den, tumor clonality, major histocompatibility complex peptidome, Nivolumab and Ipilimumab in Patients With Previously Untreated T-cellreceptorrepertoire,tumormicroenvironment,metabolome,and Advanced or Metastatic Renal Cell Carcinoma (COSMIC-313) trial even possibly the gut microbiome may hold clues to stratifying pa- (NCT03937219). Integrating multimodal approaches (cytoreductive tients along the treatment spectrum. Furthermore, advances in nephrectomy,metastasectomy,andstereotacticablativeradiotherapy) imagingtechniques,suchasdynamiccontrast-enhancedultrasonog- into the treatment paradigm will remain paramount as systemic raphy, computed tomography, or magnetic resonance imaging, and therapiescontinuetoevolve.Undoubtedly,treatingmRCCisbecoming novel approaches in positron emission tomography, such as the use increasingly complex, but precision medicine may become a long- 89 9 of a Zr-labeled atezolizumab tracer, have begun to provide en- awaited reality to inform patient care. ARTICLE INFORMATION J Med. 2015;373(19):1803-1813. doi:10.1056\/ 7. Rini BI, Powles T, Atkins MB, et al; IMmotion151 NEJMoa1510665 Study Group. Atezolizumab plus bevacizumab Published Online: December 5, 2019. versus sunitinib in patients with previously doi:10.1001\/jamaoncol.2019.4716 4. Motzer RJ, Tannir NM, McDermott DF, et al; untreated metastatic renal cell carcinoma CheckMate 214 Investigators. Nivolumab plus Conflict of Interest Disclosures: None reported. (IMmotion151). Lancet. 2019;393(10189):2404-2415. ipilimumab versus sunitinib in advanced renal-cell doi:10.1016\/S0140-6736(19)30723-8 carcinoma. N Engl J Med. 2018;378(14):1277-1290. REFERENCES doi:10.1056\/NEJMoa1712126 8. McDermott DF, Huseni MA, Atkins MB, et al. 1. Ellis LM, Hicklin DJ. VEGF-targeted therapy. Nat Clinical activity and molecular correlates of 5. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Rev Cancer. 2008;8(8):579-591. doi:10.1038\/nrc2403 response to atezolizumab alone or in combination Investigators. Pembrolizumab plus axitinib versus 2. Rini BI, Atkins MB. Resistance to targeted with bevacizumab versus sunitinib in renal cell sunitinib for advanced renal-cell carcinoma. N Engl J therapy in renal-cell carcinoma. Lancet Oncol. carcinoma. Nat Med. 2018;24(6):749-757. doi:10. 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