Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials

Abstract

What's known on the subject? and What does the study add? Targeted agents have greatly changed the therapeutic landscape in RCC. A substantial number of trials have been published in recent years. The current review summarises and analyses the available data to date. OBJECTIVE To estimate the effects of drugs with molecular targets on patients with advanced renal cell cancer (RCC). PATIENTS AND METHODS MEDLINE, EMBASE, and the Cochrane Collaboration Library were systematically searched on‐line through to June 2011 to identify eligible randomised trials. We also searched abstract reports from major oncology and urology meetings. We included randomised trials that tested a targeted agent and reported at least one outcome by allocation on an intent‐to‐treat basis. Completeness of ascertainment and risk of bias were assessed. Our primary outcome was progression‐free survival (PFS). RESULTS In all, 28 studies met our inclusion criteria and 10 were placebo‐controlled. Two studies were too small to assess, and five early studies used nonspecific anti‐angiogenic agents with poor activity. In all, 15 studies, in 5587 patients, tested anti‐vascular epithelial growth factor (VEGF) agents: bevacizumab (BEV), sorafenib, sunitinib, pazopanib, tivozanib, or axitinib. Three studies, in 1147 patients, tested the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors, and one tested the combination of temsirolimus plus BEV. In treatment‐naive patients with mostly good–moderate prognostic risk, in separate trials oral sunitinib (one trial) and intravenous BEV plus subcutaneousinterferon‐α (two trials) improved PFS compared with the previous standard of care interferon‐α within randomised phase III trials. Sorafenib did not improve PFS over interferon‐α in the first‐line setting and the addition of cytokines did not improve sorafenib efficacy. In poor‐risk patients, the mTOR inhibitor temsirolimus improved PFS and overall survival (OS). The studies of other VEGF inhibitors have used placebo controls no longer appropriate in this setting, although pazopanib is an approved option. Several trials examined agents in the second‐line setting. After cytokine therapy, sorafenib (one study) and pazopanib (one study) prolonged PFS over placebo. A preliminary report of the investigational VEGF receptorinhibitor axitinib gave superior PFS to sorafenib after either prior cytokine or prior sunitinib treatment. After cancer progression ≤6 months of sunitinib and/or sorafenib therapy, everolimusprolonged PFS. OS was marginally improved in several studies. A more substantial effect on OS may have been diluted by crossover from control therapy to the investigational arm and/or by other anti‐angiogenic agents after trial closure. Patient‐reported outcomes were considered unreliable in trials without ‘blinding’. A clear cell RCC (ccRCC) component was required for most trials, and information for non‐ccRCCs is consequently limited CONCLUSIONS Agents targ...

Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

“…The results of the sideby-side TKI studies determining potency, selectivity, and efficiency are shown in Table 1. The inhibitor names, along with structural features and clinical endpoints, are also shown (1,2,22).…”

“…axitinib | pazopanib | sorafenib | sunitinib | tivozanib T he VEGF receptor (VEGFR) tyrosine kinases (TKs) are the clinically validated drug target of four structurally diverse TK inhibitors (TKIs) that have been approved in the renal cell carcinoma (RCC) setting (1,2). The clear cell histology subtype of RCC is molecularly linked to the VEGF signaling axis by virtue of the ∼90% incidence of Von Hippel-Lindau (VHL) dysregulation.…”

“…Recent reports have analyzed similar RCC clinical studies across leading VEGFR TKIs for comparison purposes (1,2). Clear distinction in both efficacy and safety across the class is apparent in observations of hypertension and progression-free survival (PFS), endpoints specifically linked to VEGF blockade.…”

Cost effectiveness in practice and its effect on clinical outcomes

“…The reviewed studies were published during 2007-2011, including five full text articles, 24 research abstracts and one HTA report. [9]. b [10].…”

Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

“…23,24 Currently available treatment options for advanced RCC, that is, tyrosine kinase inhibitors (TKI) or mammalian target of rapamycin (mTOR) inhibitors, tackle disease stabilization without a curative intent. 25,26 In our model, carefully titrated T-cell infusions provided tumor-free survival without GVHD for more than 50% of the animals. High transplant-related mortality has limited to use of allogeneic HSCT for patients with RCC.…”