Platinum Priority – Kidney CancerEditorial by Camillo Porta on pp. 1020–1021 of this issueA Phase 2 Trial of Sunitinib in Patients with Advanced Non–clear Cell Renal Cell Carcinoma
Introduction
Of the estimated 64 000 cancers of the kidney and renal pelvis that will be diagnosed in 2012 in the United States [1], approximately 80% will be clear cell renal cell carcinoma (ccRCC) and 20% will be non–clear cell renal cell carcinoma (nccRCC) subtypes. The most common of the nccRCCs is papillary renal cell carcinoma (pRCC), but histologies also include chromophobe RCC, renal medullary carcinoma (RMC), collecting-duct carcinoma (CDC), and other subtypes recently incorporated in the World Health Organization (WHO) classification. Each of these subtypes is morphologically unique and biologically distinct. Most of the recent clinical trials in RCC have either restricted enrollment to patients with ccRCC, or have reported small numbers of patients with nccRCC, often without differentiating among the heterogeneous group of non–clear-cell subtypes [2], [3], [4], [5], [6], [7], [8], [9]. Sunitinib was one of the first tyrosine kinase inhibitors (TKIs) to emerge in the treatment of RCC, and is currently a standard of care in the first-line setting. Retrospective series and expanded access data suggest that sunitinib may have efficacy in patients with nccRCC [10], [11].
By treating a histologically diverse population of nccRCC patients with a molecularly targeted agent, our aim was to provide a therapeutic framework to improve our disease classification and to set the stage for a deeper understanding of the molecular biology of these tumor subtypes.
Section snippets
Patients and methods
The trial, Sunitinib Malate in Patients With Non-Clear Cell Renal Cell Cancer (ClinicalTrials.gov identifier: NCT00465179), was approved by the institutional review board at MD Anderson Cancer Center (MDACC) and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. Patients provided written informed consent at enrollment.
Patient characteristics
The study opened for enrollment in April 2007. At the designated interim analysis, the study met criteria for continuation to full accrual. The study completed accrual in May 2010, with a total of 61 patients enrolled. Two patients were ineligible (one had urothelial carcinoma of the renal pelvis and one had ccRCC without sarcomatoid features); two patients (one with RMC and one with type 2 pRCC) withdrew consent and never received sunitinib. Fifty-seven patients received sunitinib and are
Discussion
The broad histologic diversity of nccRCC presents unique challenges. Emerging data suggest that several of the hereditary nccRCC entities are linked by defects in nutrient sensing and cellular energy metabolism; the role of angiogenesis as a driver and potential therapeutic target is less well defined. The activity of the targeted agents, standard in ccRCC, has not been well described in nccRCC, as patients with nccRCC have often been excluded from large studies. A concerted effort to define
Conclusions
The differential response of chromophobe RCC to sunitinib suggests that a therapeutically relevant biologic heterogeneity exists within nccRCC. The disappointing results in other nccRCC subtypes underscore the need to enroll these patients in clinical trials. In future trials of novel agents for nccRCC, in-depth characterization of the molecular features underpinning these subtypes will help identify rational therapeutic strategies targeting relevant pathways.
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2021, Clinical Genitourinary CancerCitation Excerpt :This may be in part because of the very low tumor mutational burden (between 0.1 and 1 mutation per megabase) seen in this histology.60 TKIs are also generally less effective against chRCC, but sometimes sunitinib (with which we have the most extensive prospective clinical experience to date) or cabozantinib can produce responses.14,15,46,61,62 There may be a mechanistic rationale for using regimens that include mTOR inhibitors such as everolimus in chRCC cases, particularly in tumors with TSC1, TSC2, or mTOR mutations,8,11,46,61 and the combination of lenvatinib + everolimus has demonstrated a hypothesis-generating signal of efficacy against chRCC,16 but this needs to be validated in further studies, and it is unclear how many of these patients had sarcomatoid dedifferentation.