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Nivolumab superior to dacarbazine for untreated metastatic melanoma
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Patients with treatment-naive, BRAF wild-type metastatic melanoma treated with nivolumab demonstrated longer OS and PFS than those treated with dacarbazine, according to phase 3 study results presented at the Society for Melanoma Research International Congress.
Prior research showed nivolumab (Opdivo, Bristol-Myers Squibb) — a PD-1 immune checkpoint inhibitor — was associated with higher rates of objective response compared with chemotherapy in patients with ipilimumab (Yervoy, Bristol-Myers Squibb)-refractory disease.
In the current study, Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, and colleagues compared the efficacy of nivolumab vs. chemotherapy in 418 previously untreated patients.
Researchers assigned patients 3 mg/kg nivolumab every 2 weeks plus a dacarbazine-matched placebo, or 1,000 mg/m2 dacarbazine every 3 weeks plus a nivolumab-matched placebo.
OS served as the primary endpoint.
Robert and colleagues reported 1-year OS rates of 72.9% in the nivolumab arm and 42.1% in the dacarbazine arm. Overall, nivolumab significantly reduced the risk for death compared with dacarbazine (HR=0.42; 99.79% CI, 0.25-0.73).
Median PFS also was longer in the nivolumab arm (5.1 months vs. 2.2 months), and treatment with nivolumab was associated with a significant reduction in the risk for death or disease progression (HR=0.43; 95% CI, 0.34-0.56).
Researchers observed the survival benefits with nivolumab across prespecified patient subgroups, including those defined by PD-L1 expression.
Patients who received nivolumab were significantly more likely to demonstrate objective response to treatment compared with patients who received dacarbazine (40% vs. 13.9%; OR=4.06; P˂.001).
A higher percentage of patients who received dacarbazine experienced grade 3 or grade 4 adverse events (17.6% vs. 11.7%). The most common adverse events associated with nivolumab included fatigue, pruritus and nausea.
Disclosure: The study was funded by Bristol-Myers Squibb. See the study for a list of the researchers’ relevant financial disclosures.
Perspective
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Omid Hamid, MD
Recent approvals of nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) in patients with metastatic melanoma previously treated with ipilimumab (Yervoy, Bristol-Myers Squibb) and BRAF therapy has shifted focus toward the expanded role of PD-1 blockade in multiple solid tumors. Currently, breakthrough designation has been given for this these therapies in Hodgkin’s lymphoma, bladder cancer and lung cancer. This promise, along with the relative lack of toxicity and ease of administration, has naturally led investigators to ponder the utility of first-line therapy in multiple solid tumors in an effort to bring this utility to a greater number of patients.Robert and colleagues present results of a randomized phase 3 trial with the PD-1 immune-checkpoint inhibitor nivolumab vs. dacarbazine. This double blind trial enrolled 418 patients from 80 centers outside of the United States with untreated stage III or IV melanoma without BRAF mutation. Treatment with nivolumab significantly increased OS, PFS and objective response.
Although these remarkable data are the first presented in melanoma, dacarbazine is not clearly a first-line therapy in the United States. The question remains whether PD-1 therapy can provide improved benefit in OS in first-line therapy when compared with anti-CTLA-4 checkpoint blockade. We won’t have to wait long for these data, as two trials — pembrolizumab vs. ipilimumab (NCT01866319), and nivolumab vs. ipilimumab vs. the nivolumab–ipilimumab combination (NCT01844505) — have accrued. Additionally, trials looking at sequence of BRAF therapy and checkpoint blockade will help to clarify decision making in the BRAF-mutant subgroup.
The Holy Grail in deciphering these data remains predictive markers. Because median OS was significantly improved among patients with positive and negative PD-L1 status, we are still without appropriate predictive correlates of response. Fortunately, all patients on trial provided tumor tissue for analysis. We eagerly await further data from these analyses in a similar fashion to the remarkable recent data presented by Herbst and colleagues (Herbst RS. Nature. 2014;515:563-567) and Tumeh et al (Tumeh PC. Nature. 2014;515:568-5671). The future is bright with these trials, along with currently accruing combination trials in melanoma requiring multiple biopsies. Best of all, the remarkable work done in melanoma has now opened the door to consideration of PD-1 checkpoint inhibition as first-line therapy in multiple solid tumors.
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