Ipilimumab was given intravenously every 3 weeks in doses ranging from 1?mg/kg to 3?mg/kg. the programmed cell death-1 receptor, as well as with the advent of new generation tyrosine-kinase receptor inhibitors. This article will review the new therapeutic options available for the treatment of advanced RCC, as well as the future potential molecular targets that are currently being investigated. conducted a phase III randomised trial (CheckMate 025 trial) of nivolumab versus everolimus in advanced clear cell RCC.23 In total, 821 patients previously treated with one or two regimens of antiangiogenic therapies were randomised to receive 3?mg/kg of nivolumab or a 10?mg/day of everolimus. The primary endpoint was OS. The secondary endpoints included the ORR and safety. Importantly, nivolumab prolonged OS as compared with everolimus. The median OS was 25.0 months (95%?CI 21.8?to?not estimable) with nivolumab and 19.6 months (95%?CI 17.6 to 23.1) with everolimus (HR 0.73, 98.5%?CI 0.57 to 0.93, p=0.002). The OS benefit was observed irrespective of the MSKCC group and number of prior antiangiogenic therapies. Similarly, the benefit with nivolumab over everolimus was seen regardless of PD-L1 tumour immunohistochemistry expression. Interestingly, the?median OS was consistently lower in the PD-L1 positive group irrespective of the treatment arm, which indicates a negative prognostic role of PD-L1 expression but do not support its role as a predictive marker of response to PD-1 blockade. The ORR was also significantly greater with nivolumab than with everolimus (25% vs 5%; OR 5.98, 95%?CI 3.68 to 9.72, p 0.001). The median PFS however was similar in both arms: 4.6 months (95%?CI 3.7 to 5.4) with nivolumab and 4.4 months (95%?CI 3.7 to 5.5) with everolimus PHTPP (HR 0.88, 95%?CI 0.75 to 1 1.03, p=0.11). Nivolumab safety profile was acceptable. The most common AEs with nivolumab were fatigue (33%), nausea (14%) and pruritus (14%). Nivolumab was better tolerated than everolimus, grade 3 or 4 4 treatment-related AEs occurring in 19% of the patients receiving nivolumab as compared with 37% with everolimus. Quality of life as measured by the Functional Assessment of Cancer Therapy- Kidney Symptom Index- Disease related Symptoms (FKSI-DRS) questionnaire was also significantly improved with nivolumab as compared with everolimus (p 0.05).23 The authors conclude PHTPP that this is the first study to show improvement in OS in advanced RCC since the publication of the pivotal trial of temsirolimus.5 Consequently, in November 2015 the FDA approved the use of nivolumab to treat patients with metastatic RCC who have previously progressed to one or two regimens of antiangiogenic therapy, becoming a new standard-of-care treatment option in that setting. Nivolumab was subsequently EMA-approved for RCC in February 2016. The main results of this clinical trial are summarised in table 1. The fact that OS but not PFS was prolonged in the phase III trial of nivolumab may be related to the intrinsic immunostimulatory mechanism of action of nivolumab. Immune?cell activation requires time to take place, and therefore tumour kinetics could initially surpass that time and show a transient progression TRIB3 before experiencing objective response. Moreover, tumour infiltration by immune?cell might increase the volume of tumour lesions and mimic progression, in what has been called pseudo-progression or flare phenomenon. Together, these events could lead to the observation of transient progression when using Response Evaluation Criteria In Solid Tumors (RECIST) criteria assessment that could lead to premature discontinuation of an active treatment affecting the assessment of PFS, but not necessarily OS. Similar findings have been observed with ipilimumab and nivolumab in patients with malignant melanoma and other immunotherapy agents in other tumour types. To address this issue, a modified version of RECIST, the immune-related response criteria, has been proposed to more adequately assess the delayed and mixed responses observed with new immunotherapy agents. Moreover, in order to deal with this issue, most clinical trials with PD1/PD-L1 inhibitors allow patients to continue PHTPP on study therapy beyond initial disease progression if there is clinical benefit and the side-effect profile remains acceptable. Finally, the recent approval of these three new treatment options (nivolumab, cabozantinib, lenvatinib plus everolimus) as second-line therapies has dramatically changed the landscape of advanced RCC. In view of the improvement in OS seen in large randomised phase III trials, both the National Comprehensive Cancer Network (NCCN) guidelines24 and the European Society for Medical Oncology (ESMO) guidelines25 now recommend nivolumab and cabozantinib as the new preferred second-line treatment options. Lenvatinib plus everolimus is also considered a PHTPP valid option with an OS benefit. Of note, only the NCCN guidelines have included this latter treatment combination as an option, while the ESMO guidelines have not included it yet, pending the.