Nivolumab (OPDIVOO) BRAF V600 mutation-negative metastatic or inoperable melanoma: survival advantage.

Abstract

Existing drugs are poorly effective in patients with inoperable or meta- static melanoma without a mutation in the BRAF gene at position V600. The first-line treatment of choice for patients with BRAF V600-positive melanoma is a combination of dabrafenib (a BRAF inhibitor) and trametinib. Nivolumab is a human monoclonal antibody designed to block receptors for PD-1 (programmed cell death-1) and thus to enhance T lymphocyte activity, especially against tumour cells. Nivolumab has been authorised in Europe as monotherapy for patients with inoperable or metastatic melanoma, regardless of BRAFV600 status. Nivolumab has not been compared with the dabrafenib + trametinib combination in patients with BRAF V600-positive melanoma. A randomised double-blind trial ver- sus dacarbazine involved 418 patients with inoperable or metastatic BRAF V600-negative melanoma who had not yet received medication for this stage of the disease.The trial was halted prematurely when an unscheduled analysis showed an improvement in one-year survival with nivolumab compared to dacarbazne(73% versus 42%, p<0.0001). A double-blind trial compared first-line treatment with nivolumab, ipili- mumab or a combination of the two drugs.The mortality results are not yet available in mid-2016.The median time to melanoma aggravation or death was 6.9 months in the nivolumab group, 2.9 months in the ipilmumab group, and 11.5 months with the com- bination (p<0.001). A comparative, randomised, unblinded trial included 405 patients with metastatic or inoperable melanoma in whom at least one drug had failed. An interim analysis conducted after about two years showed no stat- istically significant difference in medi- an survival between patients who received nivolumab and those who received cytotoxic drugs. As expected, given its protein structure and mechanism, the adverse effects of nivolumab are mainly due to immunological mechanisms.They are numerous and affect many organs: skin rash and toxic epidermal necrolysis, thyroid dysfunction, hepatitis, pneumonia, colitis and encephalitis. Adverse effects were serious in 9% of patients, and a few cases were fatal. In practice, first-line nivolumab monotherapy was significantly more effective than dacarbazine in a trial in patients with BRAF V600-negative inoperable or metastatic melanoma. Although its evaluation must continue, nivolumab already seems to be a better option than dacarbazine and ipilimumab for treatment-naive patients, provided they receive detailed and balanced information on the uncertainties, efficacy and adverse effects of this new drug. For other patients, there is no evidence that nivolumab monotherapy represents an advantage over other available treatments.