Elsevier

European Urology

Volume 62, Issue 6, December 2012, Pages 1013-1019
European Urology

Platinum Priority – Kidney Cancer
Editorial by Camillo Porta on pp. 1020–1021 of this issue
A Phase 2 Trial of Sunitinib in Patients with Advanced Non–clear Cell Renal Cell Carcinoma

https://doi.org/10.1016/j.eururo.2012.06.043Get rights and content

Abstract

Background

Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non–clear cell renal cell carcinoma (nccRCC).

Objective

To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.

Design, setting, and participants

This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥20% sarcomatoid histology, performance status 0–2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.

Intervention

Patients received sunitinib 50 mg daily on a 4-wk on, 2-wk off schedule.

Outcome measurements and statistical analysis

Primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS).

Results and limitations

Fifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4–5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4–5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5–NA). Median OS for all patients was 16.8 mo (95% CI, 10.7–26.3). Treatment-emergent adverse events were consistent with sunitinib’s mechanism of action. The nonrandomized design and small number of patients are limitations of this study.

Conclusions

The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.

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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      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.

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