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%). 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.
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. Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to evade immunosurveillance and escape effective innate and adaptive immune responses. Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by modulating regulatory checkpoints of the immune system.
Dysfunctional T cells in cancer show an upregulation of inhibitory receptors (T cell exhaustion). Combined blockade of inhibitory receptors including CTLA-4 and PD-1 are considered to act synergistically. Indeed, early trials in mRCC showed improved response rates and combinations have also demonstrated to be prolonging progression-free survival 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 cytotoxicity within the tumor by engagement of ligands PD-L1 and PD-L2, which are upregulated by tumor cells and inflammatory 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. 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 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 durable responses of 78% in patients that had an initial response (durable responses).
Moreover, recent variations of dosing schedules and strengths of the nivolumab-ipilimumab combinations have shown improvement of toxicity 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.
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 improvement. The addition of a further agent including blockade 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 remains 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 and even higher doses have been reported 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.
