Nivolumab shows signs of superior response rate compared to standard chemotherapy in advanced melanoma

Preliminary data from a phase III trial suggest that the PD1 ‘checkpoint inhibitor’ nivolumab is well tolerated and leads to a sustained response in patients with advanced melanoma who progressed after ipilimumab therapy and a BRAF inhibitor when they were BRAFV600 mutation positive. In fact, nivolumab achieved superior response rates and a longer duration of response than standard chemotherapy in this patient population with limited treatment options.

Nivolumab is an antibody in a class of drugs called ‘checkpoint inhibitors’, that acts via relieving a critical brake placed on the immune system by the tumour itself. The drug then reinvigorates the patients’ anti-tumour immune response and promotes shrinkage of the tumour. In this first phase III trial of nivolumab among melanoma patients whose disease has progressed after treatment with ipilimumab (and a BRAF inhibitor in case of BRAFV600 mutation positivity), a total of 405 patients with unresectable metastatic melanoma were randomized in a ratio of 2:1 either to intravenous nivolumab (3 mg/kg) or the investigator’s choice of chemotherapy (ICC): dacarbazine (1000 mg/m2), or carboplatin AUC6 plus paclitaxel (175 mg/m2). The primary endpoints of the study were objective response rate (ORR) to treatment and overall survival (OS), but the study also evaluates the impact of treatment on secondary objectives of safety, progression-free survival (PFS), health-related quality of life (QoL) and expression of the programmed death-1 ligand (PD-L1), which is the ligand of PD-1 targeted by nivolumab.

Preliminary data from a subgroup of the nivolumab-treated patients in the open-label trial show that nivolumab has markedly higher clinical activity with a 32% response rate, as well as lower toxicity compared to the chemotherapy reference arm, with a 11% response rate. The median time to response with nivolumab was 2.1 months compared to 3.5 months with chemotherapy. A reduction of ≥ 50% in target lesion burden occurred in 82% of nivolumab responders and in 60% (3/5) of ICC responders. Treatment responses were longer-lasting in the nivolumab group compared to the chemotherapy group. The median duration of response for nivolumab was not reached with 95% of patients still in response (N=36), while the median duration of response for ICC was 3.6 months with 4 (80%) patients still in response.

Grade 3-4 treatment related adverse events were reported for 31% of the patients in the chemotherapy group compared to 9% incidence in the nivolumab group.

The differences in response rate and toxicity markedly favour the use of the PD-1 blocking antibody nivolumab compared to chemotherapy in patients that have failed ipilimumab. These new data suggest that there will be significant prolongation of progression-free and overall survival once the analysis of those data is mature. Following these results PD blockade can produce rapid and deep responses in advanced and bulky disease.

Reference

Weber J, Minor D, D’Angelo S et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) versus investigator's choice chemotherapy (ICC) in previously treated advanced melanoma. Presented at ESMO 2014; Abstract LBA3.