Breakthrough treatment approved for advanced melanoma


Last December, FDA granted accelerated approval to nivolumab for treatment of unresectable or metastatic melanoma in patients with cancer that no longer responds to other therapies.

Kathryn WheelerLast December, FDA granted accelerated approval to nivolumab (Opdivo; Bristol-Myers Squibb Co.) for treatment of unresectable or metastatic melanoma in patients with cancer that no longer responds to other therapies. Nivolumab’s priority review is the result of the drug’s potential to offer patients improved safety or effectiveness in the treatment of a serious condition.

Nivolumab is a fully human monoclonal antibody that binds the human programmed death receptor-1 (PD-1) and blocks the inhibition of the anti-tumor immune response, which may decrease tumor growth. Because the manufacturer demonstrated that the drug may offer patients a substantial benefit compared to currently available therapies for a rare disease, FDA granted Opdivo status as a breakthrough therapy as well as an orphan drug.

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Efficacy of nivolumab was determined by the interim analysis of results from one multicenter, open-label, randomized trial. Participants included in the study experienced disease progression with ipilimumab therapy and a BRAF inhibitor if positive for BRAF V600 mutation. Patients with the following conditions were excluded from the study: autoimmune disease, ocular melanoma, and active brain metastasis, as well as patients requiring systemic immunosuppression, having experienced adverse reactions related to ipilimumab; and those who showed any grade 4 reaction or grade 3 reaction that remained unresolved or uncontrolled by 12 weeks.

Participants received either nivolumab 3 mg/kg every two weeks or investigator’s choice of chemotherapy (dacarbazine or paclitaxel and carboplatin).  Interim analysis of the results of the first 120 participants receiving nivolumab with at least 6 months of follow-up were assessed for objective response rate. Results demonstrated a 31.7% (95% CI, 23.5 – 40.8) objective response rate with nivolumab, compared to 10.6% (3.5 – 23.1) with chemotherapy.  Of those responding to therapy, 48% (38 – 56) of participants in the nivolumab group experienced 6-month progression-free survival, compared to 34% (18-51) in the chemotherapy group. Median progression-free survival for nivolumab and chemotherapy groups was 4.7 months (2.3 – 6.5) and 4.2 months (2.1 – 6.3), respectively.  

At interim analysis, evaluation of the intention-to-treat participants revealed no difference in progression-free survival. Enough data are expected by the end of 2015 to evaluate the overall survival analysis for nivolumab compared to chemotherapy. 

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Safety analysis was performed on 370 participants who had received at least one dose of nivolumab. The majority of participants in both groups experienced an adverse reaction; 68% of nivolumab and 79% of participants in the chemotherapy group. Fatigue, pruritus, and diarrhea were the most frequently reported adverse reactions among participants receiving nivolumab. Participants receiving chemotherapy most frequently reported nausea, fatigue, and alopecia. More severe reactions (grade 3 and 4) occurred more commonly among chemotherapy recipients than among nivolumab recipients (31% vs. 9%).  

Disease progression was the most common reason for treatment discontinuation in both groups. Toxic effects of the study drug led to the discontinuation of therapy in 3% of participants receiving nivolumab and 7% of participants receiving chemotherapy treatment.



Nivolumab is available in a 40-mg and a 100-mg single-use vial. Nivolumab is approved as a 3 mg/kg dose to be infused over 60 minutes every two weeks. On the basis of pharmacokinetic analysis, the manufacturer does not recommend altering the dosing of nivolumab due to renal or hepatic dysfunction.

Patients should be informed of the potential for the following immune-mediated adverse reactions: pneumonitis, colitis, hepatitis, nephritis or renal dysfunction, and hypo- or hyper-thyroidism. Nivolumab administration may be withheld or discontinued, and corticosteroid treatment may be required in these circumstances. 

All women of childbearing age should be informed of the potential for fetal harm and should be counseled to use contraceptive methods during and for five months after treatment with nivolumab. Antibodies can cross into human milk during lactation, so women should be advised against breastfeeding when taking nivolumab to avoid harm to the infant.

Patients should thoroughly read the FDA-approved Medication Guide and report all adverse events to a healthcare provider.

Kathryn Wheeler is an associate clinical professor of pharmacy practice at the University of Connecticut School of Pharmacy, Storrs, Conn.

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