Two phase 3 clinical trials recently published in the New England Journal of Medicine
compared 2 monoclonal antibodies – ipilimumab (Yervoy, Bristol-Myers Squibb) a human IgG1 monoclonal antibody against cytotoxic T-lymphocyte antigen 4 and nivolumab (Opdivo, Bristol-Myers Squibb), a human IgG4 monoclonal antibody against programmed death 1 (PD-1) – in 2 different populations of patients with advanced melanoma.
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. Melanoma is typically curable if managed in its early stages, but survival rates dramatically drop in its advanced stages. Five-year survival rates for advanced melanoma are about 15 – 20% and 10-year survival rates are in the 10-15% range.
The first study
was a head-to-head comparison between the 2 monoclonal antibodies as adjunct therapy for patients with resected stage IIIB, IIIC, or IV melanoma. The randomized, double-blind, phase 3 trial evaluated patients (≥15 years of age) undergoing complete resection of stage IIIB, IIIC, or IV melanoma received intravenous infusion of either nivolumab ( 3 mg/kg every 2 weeks; n=453) or ipilimumab (10 mg/kg every 3 weeks for 4 doses and then every 12 weeks; n=453).
The patients were treated for up to 1 year or until disease recurrence. The primary end point was recurrence-free survival. Results found that the 12-month rate of recurrence-free survival was 70.5% in the nivolumab group and 60.8% in the ipilimumab group (P
Nimvolumab also had a preferable safety profile. The study observed treatment-related grade 3 or 4 adverse events in 14.4% of the patients in the nivolumab group compared to 45.9% in the ipilimumab group. A staggering 42.6% of patients taking ipilimumab discontinued treatment due to adverse events compared to only 9.7% in the nivolumab group. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group.
A second study
conducted by Jeffrey Wolchok, M.D., Ph.D. and colleagues indicates nivolumab also performs much more successfully as a first-line treatment in advanced melanoma in comparison to ipimumab, confirmining that combining the 2 drugs would be most effective.
In the double-blind, phase 3 study, patients with untreated stage III or IV melanoma with known BRAF
V600 mutation status were randomized to receive nivolumab-plus-ipilimumab (n-314), nivolumab (n=316), and ipilimumab (n=315). Dosing was the same as stated in the other study.
Primary endpoints were overall survial and progression-free survival.
The study observed that median overall survival had not been reached in the nivolumab-plus-ipilimumab group. In the imilimumab group, overall survival was 37.6 months compared with 19.9 months in the ipilimumab group.
The median progression-free survival was 11.5 months in the nivolumab-plus-ipilimumab group. 6.9 months in the nivolumab group, and 2.9 months in the ipilimumab group.
Serious treatment-related adverse events (AEs) were reported in 59% of the patients in the nivolumab-plus-ipilimumab group, 21% in the nivolumab group, and 28% in the ipilimumab group.
All 3 treatments – ipimilumab, nivolumab, and the combination ipimulumab plus nivolumab – are approved orphan drug treatments for patients with advanced melamona.
Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. New Engl J Med.
Published online September 10, 2017. DOI: 10.1056/NEJMoa1709030
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. New Engl J Med
. Published online September 11, 2017. DOI: 10.1056/NEJMoa1709684
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