by ecancer reporter Clare Sansom

The incidence of melanoma, the most deadly form of skin cancer, is increasing with approximately 132,000 new cases now diagnosed worldwide every year.

It is easily curable if treated before it has spread, but many cases are only diagnosed after metastasis has occurred, and these are generally regarded as incurable.

About 60% of melanomas carry the V600E mutation in the proto-oncogene BRAF.

In recent years small-molecule inhibitors of BRAF and MEK, used alone or in combination, have made a significant difference to the survival of those patients whose melanomas carry this mutation, although resistance generally develops within about a year.

The options available for the 40% of patients who carry melanomas without this mutation are restricted to chemotherapy: dacarbazine, which is associated with a median survival time of about 6-8 months, is the most frequently prescribed drug.

Nivolumab is a monoclonal antibody that binds to the protein programmed cell death 1 (PD-1) and blocks its interaction with its ligand, PD-L1.

PD-L1 is an immunosuppressive protein that is found on the surfaces of some tumour cells, and blocking its interaction with PD-1 can enhance the anti-tumour activities of T cells.

A phase I trial of nivolumab in several solid tumour types, including metastatic melanoma, showed that it was relatively non-toxic and had some anti-tumour activity.

An open label Phase 3 trial has also shown it to be superior to chemotherapy in treating melanoma that is already resistant to another antibody, ipilimumab.

A large, international team led by Caroline Robert of Hôpital Saint André Centre Hospitalier Universitaire, Bordeaux, France has now conducted a double-blind, randomised Phase 3 trial of this antibody in previously untreated metastatic melanoma without BRAF mutations.

A total of 418 patients with previously untreated Stage III or IV melanoma were randomised in a 1:1 ratio to receive either 3 mg/kg of nivolumab every 2 weeks plus a dacarbazine-matched placebo every 3 weeks, or 1000 mg of dacarbazine per m2 of body surface area every 3 weeks plus a nivolumab-matched placebo every 2 weeks.

The randomisation was stratified according to PD-L1 expression status (positive, negative or indeterminate) and metastasis stage, and treatment continued until toxicity became unacceptable or the disease progressed.

Treatment was allowed to continue after disease progression if clinical benefit was observed and at the discretion of the investigator.

The primary endpoint of the trial was overall survival; secondary endpoints included progression free survival.

In June 2014, an interim safety review noted a potentially significant difference in overall survival in favour of the nivolumab group, so the study was unblended and the protocol changed to allow patients in the dacarbazine group to cross over to receive nivolumab.

At that time all randomised patients had been followed up for between 5.2 and 16.7 months, and 46.1% of patients in the nivolumab group but only 6.3% of patients in the dacarbazine group were still receiving the study treatment.

In both groups, the most common reason for discontinuing the study treatment was disease progression.

The overall survival rate after 1 year of treatment was 72.9% (95% CI (confidence interval) 65.5% to 78.9%) in the nivolumab group and 42.1% (95% CI 33.0% to 50.9%) in the dacarbazine group.

Results for progression-free survival followed the same pattern, with a median progression free survival of 5.1 months in the nivolumab group compared to 2.2 months in the dacarbazine group.

The hazard ratio for death or disease progression for nivolumab as compared to dacarbazine was 0.43 (95% CI, 0.34 to 0.56; P<0.001).

Both the objective response rate and the complete response rate were also significantly higher in the nivolumab group than in the dacarbazine group.

This significant difference in overall and progression-free survival in favour of nivolumab was seen in all defined subgroups including PD-L1 expression status, although the difference was larger in the patients with positive PD-L1 status.

Severe (grade 3 or 4) adverse events were relatively rare in all patients and occurred slightly less often in the nivolumab group than in the dacarbazine group.

Taken together, these results show that nivolumab is a relatively safe drug that is significantly superior to dacarbazine in treating patients with wild type BRAF metastatic melanoma who have not received previous therapies.

Reference

Robert, C., Long, G.V., Brady, B. and 25 others (2014). Nivolumab in Previously Untreated Melanoma without BRAF Mutation. New England Journal of Medicine, published online ahead of print 16 November 2014.