First-Line Treatment Options

EP: 1.Overview of Non–Clear Cell Renal Cell Carcinoma

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EP: 2.First-Line Treatment Options

This segment of the Cancer Network Training Academy explores first-line treatment strategies for metastatic non–clear cell renal cell carcinoma (nccRCC). Following the initial discussion on diagnosis and classification, attention shifts to the complexities of therapeutic decision-making in the metastatic setting. Because nccRCC encompasses over 20 subtypes, treatment selection hinges on histological and biological characteristics. Available modalities include VEGF-targeting tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, mTOR inhibitors, and chemotherapy—used alone or in combination—depending on tumor profile.

Historically, early randomized trials like ASPEN and ESPN compared the efficacy of TKIs (eg, sunitinib) against mTOR inhibitors (eg, everolimus) by grouping all nccRCC subtypes together. These studies suggested that sunitinib had greater activity overall, though certain subsets—like those in the ASPEN trial—appeared to benefit more from everolimus. While informative, the broad grouping limited insights into subtype-specific efficacy. This has led to a shift toward histology-specific trials, such as PAPMET, which focused exclusively on papillary RCC. This study demonstrated that cabozantinib outperformed sunitinib in progression-free survival and response rate, setting a new standard in that subgroup.

Building on these findings, the field is now transitioning toward biomarker-driven and combination-based strategies. Immunotherapy, particularly PD-1 and PD-L1 inhibitors, is increasingly used alongside TKIs, similar to treatment paradigms for clear cell RCC—though the evidence base is less mature. This evolution marks a significant shift from monotherapy approaches toward more tailored and aggressive regimens, reflecting the complexity and heterogeneity of nccRCC. As trials increasingly focus on molecular drivers (eg, MET alterations), future care will likely be guided by even more precise biomarker stratification.