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Superior overall survival of PD-1 blockade with nivolumab compared to everolimus has been shown in the phase III Checkmate-025 trial in metastatic clear cell carcinoma of the kidney in second line after progression under first line therapy with a tyrosine kinase inhibitor (TKI, sunitinib or pazopanib) (2). In addition, a phase II trial with nivolumab in 2nd or higher line had previously demonstrated clear activity in patients with non-clear cell kidney cancer (3). It seems that in subgroup analysis of the Checkmate-025 especially tumors with poor prognostic features have responded to PD-1 blockade with nivolumab. Despite the encouraging results of recent trials, only a minority of patients shows significant response to single agent immunotherapy with nivolumab (Overall response rate (ORR) around 20%) (2). Therefore, further investigations are urgently needed to improve the prognosis of patients with mRCC. Recent analyses of phase I trials in mRCC and also in non-small-cell lung carcinoma (NSCLC) patients as well as more advanced studies in melanoma patients have provided evidence that combination of immunotherapies can improve response rates and response duration (4). Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than as self and can be effectively attacked by an activated immune system. An effective immune response in this setting is thought to rely on immune surveillance of tumor antigens expressed on cancer cells that ultimately results in an adaptive immune response and cancer cell death (5). Meanwhile, tumor pro-gression may depend upon acquisition of traits that allow cancer cells to evade immunosurveillance and escape ef-fective innate and adaptive immune responses. Current immunotherapy efforts attempt to break the apparent toler-ance of the immune system to tumor cells and antigens by either introducing cancer antigens by therapeutic vaccina-tion or by modulating regulatory checkpoints of the immune system (6-8). T-cell stimulation is a complex process in-volving the integration of numerous positive as well as negative co-stimulatory signals in addition to antigen recognition by the T-cell receptor (TCR). Collectively, these signals govern the balance between T-cell activation and tolerance to antigens. PD-1 is a member of the CD28 fami-ly of T-cell co-stimulatory receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 signaling has been shown to inhibit CD-28- mediated upregulation of IL-2, IL-10, IL-13, IFN-ɤ and Bcl-xL. PD-1 expression has also been noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a negative regula-tory role of PD-1 comes from studies of PD-1 deficient mice, which develop a variety of autoimmune phenotypes. These results suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but these responses are variable and dependent upon various host genetic fac-tors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to selfantigens. Dys-functional T cells in cancer show an upregulation of inhibi-tory receptors (T cell exhaustion). Combined blockade of inhibitory receptors including CTLA-4 and PD-1 are con-sidered to act synergistically. Indeed, early trials in mRCC showed improved response rates and combinations have also demonstrated to be prolonging progression-free sur-vival in melanoma. While CTLA-4 is mainly involved in transmitting negative signals in T cells during priming in the lymph node, PD-1 is thought to mainly inhibit T cell cyto-toxicity within the tumor by engagement of ligands PD-L1 and PD-L2, which are upregulated by tumor cells and in-flammatory cells within the tumor microenvironment as shield against the immune attack. It is therefore reasonable to combine PD-1 blockade with CTLA-4 blockade and this has been tested with an intriguing doubling of ORR in a phase I trial in patients with mRCC (4). An important aspect of any combination therapy is the question of additional/ excessive toxicity. In that trial the combination of nivolumab 3mg/kg/q3w (cont.) and ipilimumab 1mg/kg/q3w (4 times) proved to be safe, efficacious and feasible (much Nivo and Ipi in mRCC Page 15 of 64 Version 2.0, 17.10.2017 SAKK 07/17 better safety profile in patients with mRCC compared to patients in melanoma trials). 78% of patients had any AE, but only 28% a grade 3-4 AE event. While diarrhea was quite common, only 4.8% had grade 3-4 diarrhea. Other treatment related immune-mediated AEs, especially endocrinopathy, pneumonitis, skin disorders were recorded at lower grades than 3. No deaths were reported for this combination. The overall response rate was 43% with du-rable responses of 78% in patients that had an initial re-sponse (durable responses). Moreover, recent variations of dosing schedules and strengths of the nivolumab-ipilimumab combinations have shown improvement of tox-icity rates with no loss of efficacy. For example, ipilimumab every 6 weeks at 1mg/kg was shown to be well tolerated in patients with non-small cell lung cancer when combined with nivolumab (9). Nivolumab has proven efficacy and a favorable toxicity profile as a 2nd line therapy in mRCC. It is therefore destined to become the standard therapy after a first line TKI therapy. However, only a minority of patients shows clear responses leaving plenty of room for im-provement. The addition of a further agent including block-ade of CTLA-4 that acts synergistically could improve the response rate and also extend the progression-free and overall survival in patients with mRCC. The addition of ipilimumab to nivolumab in order to increase response rates and induce more often durable remissions in patients is a reasonable next step and is currently tested in several randomized trials. However, at this point it is unclear which subgroup benefits most from the combination of CTLA-4 and PD-1 blockade and the optimal regimen/schedule re-mains unknown. To this end, this trial will test a combination of ipilimumab with nivolumab at an alternate schedule and a subsequent adaptation of the treatment regimen to the individual response with the aim to increase efficacy while reducing toxicity in mRCC patients. Ipilimumab is often used only in the first weeks of antineoplastic treatment for initial immune priming, allowing the presumption that it could be stopped after an initial priming phase. A phase I dose finding study is not needed, as experience with this dose (9) and even higher doses have been reported (4) and data are on file at Bristol-Myers Squibb (BMS). In addition, sequential biopsies and biomarker studies shall identify patients that benefit the most of a combination immunotherapy. In this trial, it was decided to have a nivolumab lead-in phase to be able to determine whether any acute side effect is nivolumab or ipilimumab related.