low enrolment

Two randomized trials in the cytokine era clearly showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC) increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs) including first-line sunitinib and pazopanib in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy.

Therefore it is unknown if similar survival benefit could be achieved without CN with these new targeted agents.

At the same time there is a need to better understand mechanisms of primary and secondary resistance to TKIs in mRCC patients and to identify eighter prognostic and predictive biomarkers to better define risk factors and potentially druggable targets.

Two randomized trials in the cytokine era clearly showed that CN had a role in mRCC increasing life expectancy. The survival benefit of TKIs including first-line sunitinib and pazopanib in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy.Therefore it is unknown if similar survival benefit could be achieved without CN with these new targeted agents.

At the same time there is a need to better understand mechanisms of primary and secondary resistance to TKIs in mRCC patients and to identify eighter prognostic and predictive biomarkers to better define risk factors and potentially druggable targets.

The hypothesis of this study is that CN followed by TKIs will improve overall survival (OS) when compared to TKIs alone in subjects with mRCC. Circulating blood biomarkers (CBBs) promise to become non-invasive real-time surrogates for tissue-based biomarkers. Circulating tumor cells (CTCs) shed from both primary tumors and metastases, and circulating tumor DNA (ctDNA) released into the bloodstream from dying tumor cells, are likely to capture the entire tumor heterogeneity providing a clear picture of the tumor genetic landscape. Moreover, CTCs fluctuations reflect and possibly anticipate treatment outcome. Through comparison of CBBs before and after disease becomes refractory to therapy, the investigators would be able to address challenging research questions regarding TKIs resistance mechanisms.

This study was designed to compare clinical benefit as measured by Overall Survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety provided by CN followed by TKIs vs upfront TKIs in mRCC subjects.To prospectively collect blood samples from patients at commencement of TKIs therapy and on development of resistance, with the purpose of analyzing CTCs and ctDNA mutational profile to highlight mechanisms underlying TKIs resistance. The investigators additionally aim to assess the role of CTCs as prognostic and pharmacodynamic biomarkers and prospectively collect demographic and clinical outcome data so that molecular and pathological analyses can be measured against clinical endpoints.

Rationale for TKIs treatment choice:

Pazopanib and sunitinib were compared to each other as a therapy for previously untreated patients with mRCC within the phase 3 non inferiority COMPARZ trial which represented the first-ever head-to-head comparison of first-line treatments for mRCC. Overall, the median PFS and OS with pazopanib compared to sunitinib were statistically non-inferior, showing that both agents are active and provide similar high quality care. For this reason the TKI will be assigned based on patients characteristics according to the guidelines of every single institution involved in the study.

Statistical plan:

The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and subjects randomized to receive TKIs (main study endpoint). A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of TKIs vs. CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a hazard ratio (HR) corresponds to an increase in the 5-year OS, from an anticipated value 10% for TKIs to 21.5% for CN followed by TKIs. The investigators estimate that approximately 270 patients (135 in each arm), recruited over 3 years and with a minimum follow up of 2 years, will be necessary to see the necessary number of deaths.

An interim analysis of OS based on O'Brien-Fleming stopping rules is planned at 96 deaths at approximately 34 months after randomisation.

Inclusion Criteria:

• Written informed consent
• ECOG Performance Status 0-1
• Favorable or intermediate MSKCC or Heng risk score
• Biopsy (primary tumour or metastases) confirming the diagnosis of predominantly clear cell RCC
• Resectable asymptomatic in situ primary (asymptomatic primary is defined as the absence of symptoms which can be exclusively assigned to the primary tumor such as flank pain and/or gross hematuria necessitating blood transfusion.)
• Tumour suitable to nephrectomy in the opinion of the urologist. Patients with Inferior vena cava thrombosis can be included
• Documented metastatic disease (CT scan or MRI)
• Life expectancy > or = 24 weeks
• Up to three different metastatic sites
• ≥ 3 metastatic lesions
• Platelets > 100,000/ml
• Haemoglobin > 9.0 g/dl
• neutrophils >1,500/mm3
• Bilirubin < or = 2 mg/dl, except for patients affected by Gilbert's syndrome
• AST and ALT < or = 2.5 times the UNL
• Serum albumin > the LNL
• Patients of childbearing age should use contraceptive methods during the study

Exclusion Criteria:

• Prior surgery or systemic treatment for mRCC

• Bilateral RCC

• Brain and liver metastases

• Non-clear-cell histology

• Poor prognosis as defined by MSKCC or Heng criteria

• Documented widespread disease (> or =4 metastatic organ sites)

• Oligometastatic disease suitable of metastasectomy (<3 lesions confined at one organ site)

• Symptomatic primary tumour at presentation

• High surgical risk in the opinion of the urologist

• Patients with > 3 of the following surgical risk factors are not eligible:

  • Serum albumin CTCAE v 4.0 grade 2 or worse
  • Serum LDH > 1.5 times upper limit of normal
  • Symptoms at presentation due to metastases
  • Clinical stage T4 disease
  • History of malabsorption syndrome

• Pregnant or breastfeeding women

• Concomitant cardiac disorders: cardiac failure NYHA> 2; Acute coronary syndrome or myocardial infarction or severe or unstable angina within the last 6 months as well as uncontrolled hypertension (sistolic>160, diastolic>90), arrhytmia requiring treatment (except for beta blockers or digossin)

• Uncontrolled diabetes

• Deep phlebitis not treated with LMWH or arterial thrombosis within the last 6 months

• HIV infection

• Active infections (> Grade 2 NCI-CTC v.3.0)

• Other cancer within the previous 5 years (except for in situ skin carcinoma, superficial bladder Ta, Tis, T1 and carcinoma of the cervix or every cancer with curative treatment within 5 years)