Discussion
tumor, papillary RCC, RCC, tumors, TRAEs
TUMOR, DISEASE, ADVERSE EVENT, TUMORS, RCC
This analysis of tivozanib in nccRCC suggests that tivozanib is an effective and well-tolerated therapeutic agent in this patient population. The responses to tivozanib were durable, and patients experienced a median PFS of 6.7 months. TRAEs were in accordance with what was seen in other studies of tivozanib. The adverse event profile is of note because although limited to patients with a clear cell component, the phase III TIVO-3 study completed subsequent to Study 201 demonstrated that tivozanib had better tolerability relative to the comparator VEGFR-TKI sorafenib.Owing to its histologic heterogeneity and relative scarcity, nccRCC has historically been fraught with a paucity of dedicated prospective phase III trials. Consequently, treatment algorithms have largely relied upon retrospective analyses, single-arms trials, and randomized phase II trials. At present, sunitinib is listed as a preferred regimen according to national guidelines.Another preferred agent is cabozantinib, a multi-kinase inhibitor that targets VEGFR 1-3, MET, KIT, AXL, and FLT3.Single-arm phase II studies exclusively including patients with nccRCC have showed encouraging ORR using cabozantinib in combination with either atezolizumab or nivolumab, or bevacizumab with atezolizumab.There are several limitations in this study. Our patient population included small individual RCC subtypes: 31 patients had mixed/unclassified tumors whereas only 11 had papillary RCC. Although tumor heterogeneity is common in nccRCC trials, the high proportion of mixed/unclassified tumors and paucity of papillary RCC deviates from the typical histologic distribution. Further, histologic classification was reported by the investigator, and was not confirmed centrally. Additionally, on account of these data being derived from an older trial, prior and subsequent therapies available to these patients are likely quite different compared to contemporary experiences. In the cited contemporary studies, few patients likely received prior interferon and more patients likely received novel tyrosine kinase inhibitors for refractory disease. Yet, the endpoints reported here such as ORR or PFS and not OS in this front-line study should not be impacted by access to contemporary therapies. Another limitation to our study is the randomized discontinuation design, which required censoring at 16 weeks for patients randomized to placebo. We observed that a good proportion of partial responders achieve their best response after 16 weeks. Therefore, it stands to reason that our PFS and ORR might be underestimated as the patients randomized to the placebo arm may have ultimately derived a more robust response were they to have continued on therapy.