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Managing mRCC - The changing paradigms

Dr Brusabhanu Nayak

AIIMS, New Delhi

The management of metastatic renal cell cancer (mRCC) has undergone several advances in the recent past, both in the realm of cytroreductive surgery and the systemic therapy. Cytoreductive nephrectomy (CN) was once considered as the standard of care during the cytokine era. After the introduction of Tyrosine Kinase inhibitors (TKI), CN continued to be in practice based on large retrospective studies but its use gradually declined after 2006 (due to CN related morbidity and the inability of patients to receive TKI after CN). (1) The results of the CARMENA trial showed that sunitinib alone was non-inferior to CN followed by sunitinib with respect to overall survival in intermediate and poor risk patients. However, the predominant patient population were poor risk (selection bias), and the study was discontinued prematurely after an interim analysis.(2) Patient selection is of utmost importance to harness the benefits of CN and minimize surgical morbidity. IMDC poor risk patients are not candidates for CN whereas IMDC good risk patients should preferably undergo CN prior to systemic therapy. Among the intermediate risk group, patients with a single risk factor can undergo CN while systemic therapy is to be initiated in patients with two or more risk factors. Symptomatic tumors and tumors with venous thrombus should undergo CN if the patients are fit for surgery.

Systemic therapy in mRCC has also witnessed a dramatic evolution. TKIs were the standard of care (SOC) in mRCC prior to 2018. However, after the approval of nivolumab and ipilimumab (immune checkpoint inhibitors (ICI)) in 2018 the SOC has been shifted to include ICI for all patients with mRCC. The CheckMate 214 trial showed better PFS and OS compared to sunitinib in intermediate and poor risk patients receiving nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor).(3) After the success with combination of ICI, the combination of ICI with TKI was explored. The KEYNOTE 426 study compared axitinib / pembrolizumab combination against sunitinib. Better OS, PFS and complete response rates were seen with axitinib/pembrolizumab which led to its approval in mRCC by the FDA in 2019.(4) The CheckMAte 9ER study compared cabozantinib/nivolumab against sunitinib. The combination demonstrated better OS and PFS which led to its FDA approval.(5) Recently, the combination of cobozantinib/nivolumab/ipilimumab versus ipilimumab/nivolumab was investigated in the COSMIC 313 trial which showed better PFS but increased adverse events with the triple drug regimen.(6) The CLEAR study investigated lenvatinib/pembrolizumab vs lenvatinib/everolimus vs sunitinib alone in mRCC. The combination of lenvatinib/pembrolizumab demonstrated high response rates, PFS and complete responses compared to the other groups which led to its current use in patients with any IMDC risk category.(7) Thus, combinations of ICI/TKI like nivolumab/cabozantinib, pembrolizumab/axitinib or, pembrolizumab/lenvatinib are recommended as first line in IMDC good risk category patients. For intermediate and poor risk population, combination of ICI can be considered in addition to the abovementioned combinations (nivolumab/ipilimumab). In patients who cannot receive ICI, TKIs like sunitinib, pazopanib and cabozantinib (in poor risk) can be considered.

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