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Robert C, et al. "Nivolumab in previously untreated melanoma without BRAF mutation". The New England Journal of Medicine. 2015. 372(4):320-330.
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Clinical Question

In patients with metastatic melanoma without a BRAF mutation, does nivolumab improve overall and progression-free survival compared to dacarbazine?

Bottom Line

Nivolumab substantially improved overall and progression-free survival for metastatic melanoma patients without a BRAF mutation.

Major Points

Metastatic melanoma carries a poor prognosis with conventional therapies including dacarbazine and interleukin-2. Two modalities of therapy have begun to radically change this prognosis: immunotherapy and BRAF inhibition. The BRIM-3 (2011) trial demonstrated the effectiveness of using BRAF inhibitors in metastatic melanoma patients with BRAF mutations. In 2010, a phase III RCT demonstrated that ipilimumab, a monoclonal antibody which augments the immune system by inhibiting CTLA-4, could also improve survival in metastatic melanoma.

The CheckMate-066 trial (2015) explored the clinical effectiveness of nivolumab, a monoclonal antibody that acts as an immune checkpoint inhibitor by blocking PD-1. This trial examined patients with metastatic melanoma without BRAF mutations and demonstrated that nivolumab had clinically significant survival benefits over chemotherapy, with increased tolerability and higher rates of complete response. Importantly, this benefit was conferred regardless of BRAF mutation status or PD-L1 expression, according to pooled analyses from four RCTs, supporting its place as a first-line therapy even for patients with BRAF mutations. [1]


NCCN Guidelines Melanoma (2015, adapted)[2]

  • Nivolumab and pembrolizumab are indicated for disease progression after treatment with ipilimumab.
  • There is consensus among NCCN that both drugs have higher response rates and less toxicity compared to ipilimumab and should be included as options for first-line treatment


  • Multicenter randomized, controlled trial
  • N=418
    • Nivolumab (n=210), 3 mg/kg IV every two weeks (and placebo every three weeks)
    • Dacarbazine (n=208), 1000 mg/m2 IV every three weeks (and placebo every two weeks)
  • Setting: 80 centers in Europe, Canada, Israel, Australia, and South America
  • Enrollment: January 2013 - February 2014
  • Median follow-up: 8.9 months in nivolumab group, 6.8 months in dacarbazine group
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival (OS)


Inclusion Criteria

  • Age ≥18 years
  • Untreated, metastatic or unresectable stage III or IV melanoma without a BRAF mutation
  • ECOG performance status of 0 or 1
  • Availability of tumor tissue for PD-L1 biomarker analysis

Exclusion Criteria

  • Active brain metastases
  • Uveal melanoma
  • Serious autoimmune disease history

Baseline Characteristics

No significant differences between groups.
  • Demographics: Age 65 years, 59% male
  • Geographic region: 69% Europe or Canada, 31% Israel, Australia, or South America
  • ECOG performance status: 0 (64.4%), 1 (34.4%), 2 (1%)
  • Disease extent: M1c (61%), M0, M1a, or M1b (39%)


Patients were randomized to:

    • Nivolumab, 3 mg/kg IV every two weeks (and placebo every three weeks)
    • Dacarbazine, 1000 mg/m2 IV every three weeks (and placebo every two weeks)

Randomization was stratified according to tumor stage and PD-L1 status. Treatment continued until disease progression or unacceptable level of toxicity.


Comparisons are nivolumab vs. dacarbazine.

Primary Outcomes

Overall survival at 12 months
72.9% vs 42.1% (HR 0.42; 95% CI 0.25 to 0.73; P<0.001)

Secondary Outcomes

Median progression-free survival
5.1 vs. 2.2 months (HR 0.43; 95% CI, 0.34 to 0.56; P<0.001)
Objective response rate
40.0% vs 13.9% (OR 4.06; P<0.001)

Subgroup analysis

Complete response rate
7.6% vs. 1.0%
Partial response rate
32.4% vs. 13.0%
HR for Mortality. Patients had significant survival benefit regardless of PD-L1 expression
PD-L1 positive: HR 0.30 (95% CI 0.15 to 0.60)
PD-L1 negative/indeterminant: HR 0.48 (95% CI 0.32 to 0.71)

Adverse Events

Any grade
74.3% vs. 75.6%
Grade 3-4
11.7% vs. 17.6%
Leading to discontinuation
6.8% vs. 11.7%
Deaths from drug-toxicity
0% vs. 0%
Nivolumab most commonly caused fatigue (19%), pruritis (17%), nausea (16.5%)


  • The relatively short follow-up precluded a thorough analysis of the long-term survival benefits of nivolumab as well as long-term adverse events.
  • While clearly demonstrating superiority over dacarbazine, this trial fails to compare the efficacy of nivolumab head-to-head against ipilimumab (with or without dacarbazine), which had already demonstrated increased efficacy over dacarbazine alone as a standard of care.
  • This trial chose to exclude BRAF positive patients. While a pooled analysis of 4 RCT’s has demonstrated similar efficacy of nivolumab irrespective of BRAF status, supporting its use in BRAF+ metastatic melanoma, ay excluding this subset of patients, this trial avoided an important comparison of nivolumab to BRAF inhibitors in BRAF positive patients.


Funded by Bristol-Myers Squibb, producers of nivolumab.

Further Reading