Overview of the Second-Line ccRCC Treatment Landscape

EP: 1.Overview of the First-Line ccRCC Treatment Landscape

EP: 2.Treatment Management Strategies

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EP: 3.Overview of the Second-Line ccRCC Treatment Landscape

EP: 4.Clinical Experience in Treating ccRCC (Patient Case 1)

In the management of ccRCC following progression on first-line therapy, second-line treatment decisions are increasingly influenced by the initial regimen used. With the widespread adoption of immune checkpoint inhibitor (IO)-based combinations in the first line, second-line strategies now often shift toward TKIs or combination regimens targeting other pathways. Treatment goals evolve with disease progression; although first-line therapy might aim for durable responses or even treatment-free intervals, second-line therapy typically focuses more on disease control, symptom management, and maintaining quality of life.

Patient characteristics, initial response patterns, and disease biology help guide second-line choices. For example, patients with rapid progression on IO may benefit from switching to potent TKIs like cabozantinib or lenvatinib/everolimus. Conversely, those with limited oligoprogression may continue their current therapy with localized treatment to affected lesions. Importantly, clinical judgment is necessary, as validated biomarkers for treatment selection remain limited. Historical practices such as choosing sequential VEGF therapies based on prior response still influence decision-making but must be balanced with modern evidence and availability of newer agents.

Emerging combination strategies are generating interest in the refractory setting. Trials involving hypoxia-inducible factor inhibitors such as belzutifan, combined with VEGF TKIs, show promise for future standards of care. However, there is ongoing debate about optimal sequencing—whether to prioritize IO/IO or IO/TKI first—and a lack of definitive data continues to challenge clinicians. Despite this uncertainty, most experts now favor using the most effective available regimen up front rather than saving potent agents for later lines, acknowledging that many patients may never reach subsequent therapies due to disease progression. The field continues to evolve rapidly, with upcoming trial results likely to further reshape second-line strategies.

The acronym doesn't match the term here. Should this be "immune checkpoint inhibitor (ICI)-based combinations" or "immunotherapy (IO)-based combinations"? Please also confirm that this is corrected throughout this segment.