**5. Cytoreductive nephrectomy in the age of TKI**

**4.4. Sequencing of agents**

162 Evolving Trends in Kidney Cancer

**Trial Drug Number of** 

Nivolumab versus everolimus

Nivolumab plus ipilimumab (nivo+ipi) versus sunitinib

Nivolumab in combination with sunitinib or pazopanib

**Table 3.** Immunotherapy trials in metastatic renal cell carcinoma.

CheckMate 025 Motzer et al. [33]

CheckMate 214 Motzer et al. [16]

CheckMate 016 Amin et al. [35] **patients (n)**

**Image 2.** Pictorial representation of the mechanism of action of immunotherapy agents.

**Line of treatment**

subsequent

1096 First line Nivo+ipi 11.6

55 First line Nivolumab plus sunitinib 12.7

823 Second or

**Progression-free survival** 

**Overall survival (OS) (months)**

Nivolumab 25.0 Everolimus 19.6 HR 0.73 p = 0.002

Nivo+ipi-not reached Sunitinib 26.0 18 months of OS rate Nivo+ipi 75% sunitinib 60%

Nivolumab plus sunitinib not reached Nivolumab plus pazopanib 27.9

**(PFS) (months)**

Nivolumab 4.6 Everolimus 4.4 HR 0.88 p = 0.11

Sunitinib 8.4

Nivolumab plus pazopanib 7.2

The natural history of targeted agents in all cancers, and reflected here in RCC, is developing ultimate resistance. Therefore, a patient may undertake several lines of treatment. Both the European Society of Medical Oncology (ESMO) and National Comprehensive Cancer

> Historically, cytoreductive nephrectomy has been used in metastatic disease in a selected number of patients. It has been especially used in fit patients with asymptomatic, low burden of metastatic disease and troublesome local symptoms such as bleeding and pain [39]. However, publication of the CARMENA trial in 2018, where sunitinib versus cytoreductive nephrectomy plus sunitinib was evaluated, demonstrated non-inferiority of sunitinib alone [40]. The trial was designed to demonstrate non-inferiority and non-superiority of one investigational arm; however, it was noted that the median OS of sunitinib alone was 18.4 months versus 13.9 months as compared to sunitinib with nephrectomy [40]. Although further evaluation is required, and for symptomatic management, cytoreductive nephrectomy may still be beneficial in the metastatic setting, this new evidence has called into question the validity of this approach routinely used for patients in the contemporary systemic treatment setting.
