Future Challenges for Drug Development in Renal Cell Carcinoma.

Therapeutics for metastatic renal cell carcinoma (mRCC) have been largely directed against the vascular endothelial growth factor (VEGF) pathway, with significant progress achieved. These approaches are based on the inherent biology underlying the vast majority of clear cell RCC tumors, in which inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene drives VEGF overproduction, leading to enhanced angiogenesis and tumor growth. Sunitinib, a small molecule that inhibits the tyrosine kinase portion of the VEGF receptor, has demonstrated clinical activity in mRCC and is a standard initial treatment option. It does not directly inhibit renal cell growth but rather inhibits the neovasculature. Innate or acquired resistance to the clinical effect of sunitinib is, however, inevitable. Attempts to understand and overcome the mechanism(s) of resistance have thus been vigorously investigated but without clinical benefit to date. Cabozantinib is also a small-molecule inhibitor of the VEGF receptor and, in addition, inhibits MET and AXL, receptors shown to be upregulated in VHL-deficient RCC cells and associated with resistance to VEGF-directed therapy in preclinical RCCmodels. Furthermore, cabozantinib has been shown to directly inhibit migration and invasion in RCC cell lines that have been stimulated with hepatocyte growth factor, the ligand for MET. Cabozantinib was approved by regulatory authorities on the basis of a randomized phase III trial in patients with mRCC previously treated with one to two VEGF-targeted agents, with demonstration of progression-free survival (PFS) and overall survival (OS) benefits compared with a mammalian target of rapamycin inhibitor, everolimus, which was commonly used in the refractory setting. Prior limited prospective data had supported the hypothesis that VEGF targeting would have a greater clinical effect compared with mammalian target of rapamycin inhibition in mRCC. Choueiri et al report on the results from a small, randomized trial—CABOzantinib versus SUNitinib (CABOSUN)—in treatmentnäıve patients with mRCC. This trial design allows hypothesis generation regarding the potential added clinical advantage of MET and AXL inhibition in addition to VEGF inhibition, a lingering question after the cabozantinib registration trial. This trial only enrolled patients whowere at intermediate risk (81%of patients; one to two risk factors) or poor risk (three or more risk factors) per International Metastatic Database Consortium (IMDC) criteria and demonstrated higher PFS in the cabozantinib arm. Choueiri et al are to be congratulated for completing this important trial within the cooperative group setting. These data, however, reveal a number of important considerations concerning the role of the randomized phase II trial in drug development. Phase II trials in general are exploratory and designed to identify active agents to move to definitive phase III testing. Randomized phase II trials were introduced in 1985 as a means of selecting new agents worthy of further development. Comparison between or among arms and formal statistical testing are discouraged in randomized phase II trials, in part because of the high chance of false-positive results. The desire to avoid such false positives is also reflected in the fact that a P value of less than . 005 (ie, an order of magnitude less than the traditional .05) has been suggested as being required to consider a randomized phase II trial convincing and reliable. Randomized phase II designs have proliferated in recent years for many purposes, including avoiding comparison with a historical control (as in a single-arm trial). Randomized phase II trials use the control arm to provide the context of a concurrently treated group of patients in which to interpret the results of the investigational arm. However, this only holds true if the control arm outcome is not substantially different to that of historical controls. Although provocative, there are several issues reflecting inherent limitations of the randomized phase II design that lessen the impact of the CABOSUN data on clinical practice. Namely, the PFS of 5.6 months for the sunitinib arm of CABOSUN was less than expected based on historical clinical trial data. In the registration trial for sunitinib, the PFS for patients in the intermediaterisk group (n 5 421) was 10.6 months. Although intermediate risk in the registration trial was defined by Memorial Sloan Kettering Cancer Center criteria, the IMDC and Memorial Sloan Kettering Cancer Center criteria overlap, and a majority of patients are categorized into the same risk group by either set of criteria. In addition, a large data set of patients with mRCC treated in sunitinib clinical trials, which included a similar number of patients without prior nephrectomy and with bone metastases compared with CABOSUN, reported a 9.2-month median PFS for intermediate-risk patients (n 5 517). This PFS occurred despite inclusion of patients with non–clear cell histology and despite patients receiving second-line treatment making up 26% of the intermediate-risk group, both of which would be expected to lower the median PFS. The null hypothesis in the CABOSUN protocol was 8 months, perhaps reflecting the investigators’ assumptions