Management of Favorable-risk Advanced Renal Cell Carcinoma: Is Dual Therapy the Answer?

Abstract

Dual therapy (immune checkpoint inhibitor [ICI]-ICI, ICItyrosine kinase inhibitor [TKI]) has changed the treatment landscape for patients with metastatic renal cell carcinoma (mRCC) [1–6]. While the overall survival (OS) benefits of dual therapy over sunitinib monotherapy have undoubtedly been proven for patients with International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, this benefit has not been demonstrated in the IMDC favorablerisk group [1–6]. In fact, not even progression-free survival (PFS) or complete response (CR) benefits were reported consistently across dual therapy in the IMDC favorable-risk group (Table 1) [1–6], although none of these trials was powered for subgroup analysis. Nevertheless, dual therapy (in particular pembrolizumab-axitinib [7,8], pembrolizumab-lenvatinib [8], avelumab-axitinib [8], and nivolumabcabozantinib [7,8]) was incorporated in established guidelines as a potential first-line treatment option for IMDC favorable-risk patients. There are no roles for atezolizumabbevacizumab [4] or nivolumab-ipilimumab [5] in the management of favorable-risk RCC, with the first trial failing to demonstrate an OS benefit across any RCC IMDC risk group and the second enrolling an IMDC favorable-risk group only for exploratory purposes [4]. While we agree with the overall recommendation to improve drug access, we are concerned about the potential risk of overtreatment if dual therapy is used as a straightforward intervention for this patient subgroup. Here, we address the urgent need to develop strategies to improve patient selection criteria for dual therapy in this subgroup. To understand the utility of dual therapy in IMDC favorable-risk RCC, we must first understand the limitations of the IMDC risk model. In a way, trials evaluating dual therapy have been using the IMDC risk model as a predictive tool for dual therapy efficacy rather than its originally intended use as a prognostic tool in the TKI era. The IMDC model holds true in its ability to prognosticate the three groups of patients with advanced RCC; however, the same model is predictive of dual therapy efficacy only in the intermediate-risk/poor-risk group, and not the