Practice and progress in kidney cancer: Methodology for novel drug development

Purpose: The minimal efficacy of standard therapy for metastatic renal cell carcinoma (RCC) has resulted in the evaluation of numerous novel agents. Some agents have shown promise in phase II trials and yet none have improved survival over standard therapy in phase III trials. We examined existing data relevant to standard therapy and clinical trial methodology in RCC to understand patient, disease and trial design factors that have impacted clinical trial outcome and drug evaluation. Furthermore, we describe new paradigms for the evaluation of novel agents to optimize the yield of clinical research in RCC. Materials and Methods: A comprehensive review of published retrospective analyses and phase II/phase III trials in patients with metastatic RCC was undertaken. Publications with patient selection and/or therapeutic implications in our judgment are presented and evaluated. Results: Patients with good performance status and access to centers with experienced staff may appropriately receive high dose interleukin-2 after consideration of the relative risks and benefits. Alternatively low dose, single agent cytokine regimens are acceptable. Novel agents may be tested in untreated and refractory RCC. Consideration of the prognostic factors of a given phase II cohort is essential when interpreting single arm clinical trial results. RCC histological subtypes continue to be distinguished biologically and treatment relevant to the vascular endothelial growth factor pathway is most appropriately targeted to clear cell RCC. Nephrectomy in metastatic RCC may impact evaluation of the tumor response and survival in metastatic RCC. Thus, consideration of nephrectomy status in phase II trials and stratification in phase III trials is warranted. Clinical trials that include patients with central nervous system metastases should have standardized treatment of these metastases prior to systemic therapy. Objective response rate as an end point should be used with caution, given its unreliable history in metastatic RCC. Novel trial designs using time to disease progression may allow for interpretation of the antitumor effect in the absence of tumor shrinkage. Conclusions: Metastatic renal carcinoma is a model disease for the design of clinical trials and testing of novel agents. Novel trial designs and end points should be considered to evaluate new agents in RCC. Phase III trials must be carefully performed with the most promising agents to impact survival in this disease.