Overview of the Second-Line nccRCC Treatment Landscape
Panelists discuss the challenges of treating non–clear cell renal cell carcinoma (nccRCC) after first-line progression, emphasizing the limited second-line options, the emerging use of immunotherapy (IO) and combination regimens, the need for subtype-specific strategies, and the critical role of clinical trial enrollment to advance care in this heterogeneous disease.
Treating nccRCC after progression on first-line therapy remains a significant challenge. This group of cancers is highly heterogeneous with different biological behaviors, making it difficult to have a one-size-fits-all approach. Although major strides have been made in frontline therapy—doubling survival rates and tripling response rates—the options for patients who progress beyond first-line treatments are limited. Historically, second-line therapies mainly consisted of single-agent VEGF tyrosine kinase inhibitors (TKIs), which showed modest activity with response rates around 10% to 15%. This lack of highly effective options contributes to the complexity of managing refractory disease.
In current practice, patients who have not previously received IO are typically considered for IO-based combinations after progression. Although sometimes off-label, combining immunotherapy with TKIs appears to offer better outcomes than single agents alone, suggesting some synergistic benefit. Data from certain studies support this approach, with notable response rates even in the second-line setting. For specific subtypes like chromophobe RCC, mTOR inhibitors have shown promise, with some patients experiencing prolonged responses. Additionally, lenvatinib combined with everolimus is a treatment consideration for this subtype, especially when not previously used. Optimizing treatment based on the patient’s cancer biology and prior therapies is key in managing progressive disease.
Despite these strategies, the nccRCC field runs out of evidence-based treatment options more quickly compared with clear cell RCC. This scarcity highlights the critical importance of enrolling patients in clinical trials, including early-phase studies, to explore novel therapies and improve outcomes. Continued research and real-world evidence are essential to guide treatment decisions and expand the therapeutic landscape for this challenging and diverse group of kidney cancers.
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