Recent large-scale multiplatform studies have shed light on the genomic landscape of renal cell carcinoma (RCC). Primarily focused on clear cell RCC (ccRCC), these studies have identified several driver mutations encompassing genes from several molecular pathways including chromatin regulation, angiogenesis and the mammalian target of rapamacyin pathways to name a few. ccRCC has been shown to be a highly heterogeneous entity, with a single tumor consisting of discrete subclones that demonstrate clonal evolution. Soutalti et al. (pp. 358–366) review the significant challenges to diagnosis, prognosis and treatment posed by intratumor heterogeneity in ccRCC.
Although ccRCC has been the focus of molecular and clinical studies, up to 25% of RCC patients exhibit nonclear cell histology. On the basis of subgroup analyses of phase III studies that included a small number of non-ccRCC patients as well as several phase II trials, targeted agents developed primarily for ccRCC have demonstrated limited efficacy in non-ccRCC. The histologic and molecular diversity of non-ccRCC adds further complexity to the evaluation and development of molecular therapies. The identification of actionable mutations, such as the alterations in MET in papillary RCC, holds promise for the development of targeted therapies in non-ccRCC, and indeed, MET inhibitors have shown early promise in clinical trials. Albiges et al. (pp. 367–373) provide an update of studies evaluating the therapeutic options for non-ccRCC patients.
The role of surgery continues to evolve in the era of targeted therapies. Level I evidence from the immunotherapy era solidified the role of cytoreductive nephrectomy in management of patients presenting with metastatic RCC (mRCC). However, given the introduction of more effective systemic therapies, the role of surgery in this patient population is unclear, reflected in the decline in utilization of cytoreductive nephrectomy over the past several years. Two randomized controlled trials due to report next year will provide answers regarding the role and sequence of cytoreductive nephrectomy Bex et al. (pp. 374–380). In addition to removal of the primary, there is increasingly compelling evidence that surgical resection of oligometastases can improve survival in selected patients. Given that targeted systemic agents rarely achieve a complete response, the multidisciplinary approach that includes surgical resection for isolated metastases is an important consideration (Karam et al. pp. 381–389).
Over the past decade, several targeted agents have been approved for mRCC, and the choice, sequence and timing of therapy continue to evolve. mRCC patients are a heterogeneous group, with some patients demonstrating indolent metastatic disease and slow progression. Thus, immediate therapy may not be necessary in all patients. Pickering et al. (pp. 390–394) review the evidence that suggests that deferred therapy (with freedom from the toxicity of systemic therapy) is an option for highly selected patients with low volume, asymptomatic metastatic disease. Regarding choice of first-line therapy, recent studies have provided some guidance with head-to-head comparisons of first-line agents. As discussed by Schmidinger et al. (pp. 395–401), these studies have come under scrutiny for methodological deficiencies. Physician experience and toxicity profile continue to be drivers of choice of agent in mRCC. After the development of resistance to first-line agents, sequential therapy with alternative agents is currently recommended. However, emerging evidence suggests that rechallenging at later lines of therapy with the same targeted agent can result in a clinical response in up to half of patients Oudard (pp. 402–410). Finally, among the most promising emerging therapies for mRCC are the T-cell checkpoint inhibitors. These agents that harness the immune response have demonstrated promising results in phase II studies, and the results of phase III studies are expected later in the year Grüenwald (pp. 411–415). Together, the articles in this section provide a comprehensive overview of the current state-of-the art and novel approaches to the management of mRCC.