Over the past two decades, the treatment landscape for metastatic renal cell carcinoma (mRCC) has evolved significantly, leading to a quadrupling of patient survival rates. Modern systemic treatments include combinations of anti-PD-1 antibodies with either anti-CTLA-4 antibodies or antiangiogenic tyrosine kinase inhibitors (TKIs). The selection of first-line treatment is influenced by factors such as IMDC risk, functional status, side-effect profiles, sarcomatoid features, steroid use, and the need for rapid or durable responses. Notably, trials like Checkmate 9ER and Checkmate-214 have shown variations in patient demographics, with higher rates of multi-organ and liver metastases, indicating poorer prognoses. Dual immune checkpoint inhibitor (ICI) combinations, such as nivo + ipi, offer long-term progression-free survival (PFS) and overall survival (OS) benefits but come with challenges, including primary progressive disease in some patients. In contrast, ICI + TKI combinations provide faster responses and lower rates of refractory disease. Network meta-analyses suggest that nivo + cabo has the highest likelihood of OS benefit, while nivo + ipi offers durable complete responses (CR) and favourable long-term toxicity profiles. Quality of life (QoL) data, however, is challenging to interpret due to varying assessment methods and timing across trials. Sarcomatoid differentiation in mRCC is associated with aggressive disease and poor TKI response. ICI-based combinations, particularly nivo + ipi, have shown superior outcomes in these patients, with high objective response rates (ORR) and CR rates. Alternatives like pembro + axi, nivo + cabo, and pembro + lenva also show comparable efficacy and can be considered on a case-by-case basis. Overall, no single combination regimen is definitively superior, and treatment selection remains context-dependent. For second-line treatment, cabozantinib is highly effective, offering OS, PFS, and ORR benefits compared to everolimus. Axitinib, tivozanib, and lenvatinib + everolimus are also viable options, with varying toxicity profiles. Belzutifan, a novel agent, shows promise in the refractory setting with a favourable toxicity profile. Immunotherapy rechallenge is not supported by current data, and novel cellular therapies are under early investigation. In conclusion, the past decade has seen remarkable advancements in mRCC treatment, with ICI-based doublets becoming the first-line standard. Treatment selection relies on clinical factors, and future research into novel combinations and biomarker-driven approaches will continue to refine therapeutic strategies. Balancing efficacy, toxicity, and patient preferences remains crucial in advanced treatment stages.
First and second-line treatments in metastatic renal cell carcinoma
Reviewed by Asif H Ansari
First and second-line treatments in metastatic renal cell carcinoma.
