Nivolumab combined with ipilimumab delays disease progression in advanced melanoma, regardless of genetic status, age and disease stage

Patients with advanced melanoma survive longer without their disease progressing if they are treated with a combination of the immune checkpoint inhibitors ipilimumab and nivolumab rather than with ipilimumab or nivolumab monotherapy. Updated results of the Checkmate-067 study demonstrate that this benefit of the combination strategy is seen, regardless of age, disease stage, and the BRAF mutation status.

Nivolumab is an inhibitor of the programmed cell death protein 1 (PD-1), which functions as an immune checkpoint. Ipilimumab on the other hand inhibits the CTLA4 checkpoint, also playing an important role in the immune system. In the presented Checkmate-067 study, a total of 945 patients with advanced melanoma were randomly assigned to receive a combination of ipilimumab and nivolumab, or one of the drugs as monotherapy. The median progression-free survival (PFS) for patients receiving the combination was 11.5 months as compared to 6.9 months with nivolumab monotherapy (HR[95%CI]: 0.57[0.43-0.76]; p< 0.001) and 2.9 months with ipilimumab monotherapy (HR[95%CI]: 0.42[0.31-0.57]; p< 0.0001).

In a subgroup analysis of the PFS in function of the BRAF mutation status, the investigators noted a median PFS with the combination therapy of 11.2 months in patients without a BRAF mutation and 11.7 in patients with BRAF mutated tumors. This compared to 7.9 and 5.6 months with nivolumab alone and 2.8 and 4.0 months with ipilimumab alone. A similar pattern was seen when researchers looked at groups of patients according to the extent of the spread of the disease to other parts of the body, whether the patients were aged less than 65, between 65 and 75, or older than 75 years and whether they had elevated baseline lactate dehydrogenase (LDH) levels or not. For a complete overview of hazard ratios for the different subgroups analysed in this study, we refer to slide 1 attached to this report. In addition to this, the combination of nivolumab and ipilimumab was associated with a higher response rate than both agents as monotherapy. This benefit was also consisted among all investigated subgroups (slide 2).

Overall, drug-related grade 3/4 adverse events occurred in 55% of patients receiving the combination as compared to 16% with nivolumab alone and 27% with ipilimumab monotherapy. A similar pattern was seen in the different subgroups of patients. The most common adverse events were immune-related including diarrhoea, colitis and elevated levels of alanine aminotransferase. Of note, the majority of grade 3/4 adverse events resolved within 4 weeks with the use of immune modulators according to established guidelines.


Larkin J, et al. Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (MEL) (CheckMate 067). Presented at ECC 2015; Abstract 3303.

Speaker James Larkin


James M. Larkin, MD, PhD
Consultant Medical Oncologist, The Royal Marsden, London, UK

See: Keyslides

Back to Top