Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial

Summary

Background

Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma.

Methods

We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445.

Findings

Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8–11·4] vs 5·6 months [5·5–6·0]; hazard ratio 1·41 [80% CI 1·03–1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3–4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none).

Interpretation

In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors.

Funding

Novartis and Pfizer.

Introduction

Non-clear cell renal cell carcinomas are a genetically and histologically diverse set of cancers that arise from the kidney and includes types 1 and 2 papillary renal cell carcinoma, chromophobe renal cell carcinoma, translocation carcinoma, and many other rare subtypes, some of which remain histologically unclassified.1, 2 Non-clear cell renal cell carcinoma accounts for about 25% of all cases of renal cell carcinoma. However, in the metastatic setting, type 2 papillary and unclassified non-clear cell renal cell carcinomas are the most common subtypes, given their more aggressive disease course.1, 2

The optimum therapy for patients with metastatic non-clear cell renal cell carcinomas has not been determined. Data from single-arm trials and expanded access studies of VEGF receptor tyrosine kinase inhibitors sunitinib or sorafenib suggest up to 30% of patients achieve a radiographic response. Such patients' median progression-free survival ranges from 2–12 months, with notable heterogeneity linked to histological subtype, prognostic risk groups, and previous therapies.3, 4, 5 Data from a phase 3 trial6, 7 of the mTOR inhibitor temsirolimus versus interferon alpha suggested that patients with non-clear cell histologies had improved overall survival with mTOR inhibition. Similarly, activity of the oral mTOR inhibitor everolimus in patients with non-clear cell renal cell carcinomas has been shown in single-arm and randomised studies.8, 9 These collective data suggest that some patients with non-clear cell renal cell carcinomas might benefit from either an initial VEGF receptor inhibitor-based approach or an mTOR inhibitor-based approach. However, no randomised trials have addressed the optimum initial approach for these patients.

Biologically, chromophobe renal cell carcinoma is often found to have activating mutations in the PI3K-mTOR pathway and preclinical sensitivity to rapamycin analogues,10, 11 whereas patients with poor risk renal cell carcinoma have been shown to have improved survival with mTOR inhibitor therapy, particularly those patients with high concentrations of circulating lactate dehydrogenase.¹² These findings support the rationale of targeting the mTOR pathway in patients with these disease characteristics.

Research in context

Evidence before this study

We searched PubMed and American Society of Clinical Oncology abstracts using the search terms “non-clear cell renal cell carcinoma”, “RCC”, “papillary RCC”, or “chromophobe RCC”, with specific attention to prospective therapeutic trials of mTOR inhibitors (everolimus, temsirolimus) or VEGF inhibitors (sunitinib, sorafenib, bevacizumab, axitinib, pazopanib). We included open access datasets and retrospective analyses of datasets published between 1990 and 2015, and key historical data are included in the references cited. The only controlled study reported in abstract form in this population is the ESPN trial, which did not show superiority for progression-free survival with sunitinib or everolimus in a population of patients with non-clear cell renal cell carcinoma, although this study was smaller (n=73) than our study and permitted patients with clear cell renal cell carcinoma who showed sarcomatoid features; the complete study is yet to be published. Our study thus represents the largest controlled trial assessing front-line therapy in patients with non-clear cell renal cell carcinoma and provides evidence to suggest heterogeneity of clinical benefit in these patients according to prognostic risk group and histological subtype.

Added value of this study

Several key findings are of immediate clinical importance. First, sunitinib significantly improved progression-free survival compared with everolimus. Second, heterogeneity of outcomes was notable, particularly with respect to histological subtype and prognostic risk group. In exploratory, non-powered analyses, sunitinib was more effective in prolonging progression-free survival in patients rated as being at good or intermediate risk according to Memorial Sloan Kettering Cancer Center criteria and in patients with papillary or unclassified histologies, whereas everolimus was more effective in prolonging progression-free survival in patients at poor risk or with chromophobe histology. However, the treatment group by subgroups interactions were not tested because of small sample sizes, but the present data provide reasonable estimates of the median and the hazard ratio for effect sizes in these subgroups. Finally, we found no increase in unexpected toxic effects or differential quality of life with these agents in patients with non-clear cell renal cell carcinoma.

Implications of all the available evidence

Based on the present study and previous clinical studies, decisions on therapeutic choice between sunitinib and everolimus for patients with metastatic non-clear cell renal cell carcinoma should be based on prognostic risk criteria, histological subtype, and the known, expected side-effects. Future clinical trials in these patients should also consider this heterogeneity of outcome when assessing novel agents.

We designed a randomised, investigator-initiated, international trial to compare an initial VEGF receptor inhibitor-based strategy using sunitinib with an initial mTOR inhibitor-based strategy using everolimus in patients with metastatic non-clear cell renal cell carcinoma. The aims of this trial were to inform clinical practice about these treatments and to develop a biorepository to molecularly characterise this subset of rare cancers in the setting of prospective treatment of metastatic disease.