For decades, physicians had a paucity of active agents for treating patients with advanced or metastatic renal cell cancer (RCC). It would have been unimaginable for those physicians practicing medicine in the 1980s and 1990s that the new millennium would see the approval of seven agents that could significantly benefit patients in this difficult disease setting. Identifying aberrant signal transduction and angiogenesis pathways that can be treated with drugs has heralded in a remarkable assortment of novel tyrosine kinase inhibitors (TKIs) to help manage this most refractory disease. The developmental process had also been a remarkably successful collaboration among academics, clinical researchers, industry advocates, and US Food and Drug Administration (FDA) officials to approve these agents so that everyone wins—industry, clinical investigators, treating physicians and, most importantly, our patients. Instrumental in this collaborative effort has been the FDA’s willingness to approve novel agents on the basis of improvements of progression-free survival (PFS) rates— often in the absence of meaningful benefit in overall survival (OS) rates. Implicit in this regulatory pathway to approval is a responsibility of the sponsors to provide welldesigned studies that measure PFS but, at the same time, do not jeopardize the inherent sanctity of OS, which is critical to the PFS approval compact. Sanctity in OS means that, in the absence of superiority, there is no ambiguity in the comparative interpretation of OS or in assuring that OS, which maybe not superior in the investigational agent, is not compromised. Such an approach has led to the timely approval of seven targeted agents including one that provided benefit in both PFS and OS (Table 1). In the article that accompanies this editorial, Motzer et al report the final results of the phase III study of tivozanib versus sorafenib as first-line therapy for patients with metastatic RCC. Tivozanib possesses some potential advantages over currently available TKIs in that it is a selective and potent inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3 at extremely low concentrations; it inhibits other kinases including c-Kit and PGFR; and it is administered orally, once daily. The phase III study design, however, had features that have made it difficult to fully appreciate the potential importance of this agent. The design compared, as first-line therapy, the investigational drug tivozanib to an already established and approved agent, sorafenib, in a head-to-head comparison of 517 patients (Fig 1). Though some aficionados may have argued that sunitinib may have been a more logical and robust comparator for first-line RCC therapy, at the time of study creation, sorafenib provided a very realistic and wholesome test of tivozanib activity. Indeed, the overall PFS was longer with tivozanib compared with sorafenib (11.9 v 9.1 months; P .042) in randomized populations that were otherwise balanced for Memorial Sloan-Kettering Cancer Center prognostic groups and other demographics. The investigator-assessed overall response rate did not differ between groups (35% v 31%; P .260) but on blinded independent review tivozanib fared better (33% v 23%; P .014). Both agents were tolerable, though each showed differing toxicities: hypertension and dysphonia were more common in the tivozanib group; hand-foot syndrome and diarrhea were more common in the sorafenib group, with no meaningful differences in health-related quality of life metrics. On the surface and based on the stated metrics, tivozanib was projected to join its seven compatriots in the wonderfully expanding armamentarium against metastatic RCC. Unfortunately, the study design was problematic in that the sanctity of OS was potentially compromised from the start. Conducted mainly in Eastern Europe, the study design is shown in Figure 1. Patients initially randomly assigned to the tivozanib arm were allowed access to second-line therapy at time of progression, but were only infrequently crossed over owing to a lack of availability of TKIs in Eastern Europe, where many of the patients were enrolled. In contrast, patients in the sorafenib group were allowed to cross-over to tivozanib at progression. Inherent in this unbalanced design was the real possibility that the groups were not comparable or, more precisely, the results from this imbalance would be difficult to interpret. In particular, differences in OS in favor of the sorafenib arm could not be adequately assessed because this study represents, in essence, a sequential trial of two agents (sorafenib 33 tivozanib) compared with one agent (tivozanib). This study design would have been predicted to pose a potential hurdle to overcome in the approval process for tivozanib. The results, which were a great disappointment to all constituencies involved, showed a worse overall survival in the tivozanib JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 30 OCTOBER 2