Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2011

Presenter: Wolchok
Presenter's Affiliation: Memorial Sloan Kettering Cancer Center, New York, NY


  • Metastatic melanoma is an aggressive and deadly disease with limited treatment options.
  • The incidence of metastatic melanoma, particularly in young adults, is rising world wide.
  • Typically, the 1-year survival after treatment is 25% and the 2-year survival is 10%.
  • DTIC was approved for use in 1975 when response rates were in the 15-20% range. DTIC continues to be the standard of care today.
  • The FDA approved high dose IL-2 for treatment of melanoma in 1998. Data showed a durable complete response (CR) in a limited number of patients (5-7%).
  • Ipilimumab (IPI) is a monoclonal antibody which blocks CTLA-4, the mechanism responsible for T-cell inactivation.
  • In 2010, the results of a trial demonstrating the overall survival (OS) advantage to IPI monotherapy in previously treated, unresectable, or metastatic melanoma patients was presented at the ASCO Annual Meeting.
  • IPI was approved for use by the FDA on March 25th, 2011 based on the observed survival benefit relative to peptide vaccine in previously-treated patients treated with 3 mg/kg of IPI.
  • The current study aims to assess IPI + DTIC as a first line regimen for metastatic melanoma.


  • This study was a double-blind, phase III, randomized trial
  • Eligibility criteria included metastatic melanoma, ECOG performance status of 0 or 1, and no prior therapy for advanced disease
  • Patients with brain metastasis or a history of autoimmune disease were excluded.
  • Patients were randomized 1:1 to:
    • IPI (10 mg/kg) + DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC q 3 weeks through week 22 (induction)
    • Placebo + DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC q 3 weeks through week 22 (induction)
  • Eligible patients received IPI or placebo every 12 weeks as maintenance therapy.
  • The primary endpoint of this study was OS. The initial endpoint was PFS, but was changed prior to unblinding in 2008.
  • A two-sided log-rank test was performed, stratified by baseline M stage and ECOG performance status


  • 502 patients from 22 countries were enrolled between August 2006 and January 2008. The primary analysis was conducted in March 2011.
  • Patient characteristics:
    • 56% had M1c disease
    • 40% had elevated LDH
    • 26% had had adjuvant therapy
  • A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2, and 3 year survival rates were seen in the IPI + DTIC arm:

IPI + DTIC (n=250)

DTIC alone (n=252)

1-year OS (%)



2-year OS (%)



3-year OS (%)



Median OS (months)



Median PFS (months)



Best overall response rate (%)



Median duration of response (months)



  • Toxicity:
    • 56% of patients in the IPI +DTIC arm, and 27% in the DTIC alone arm, had grade 3 adverse events, which included elevated ALT (22% vs 1%), diarrhea (4% vs 0%), and rash (1% vs 0%).
    • There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm due to gastrointestinal hemorrhage.
    • No high-grade endocrine events were seen in either group.

Authors' Conclusions

  • IPI (10mg/kg) + DTIC significantly improved OS vs. DTIC alone in first line treatment of metastatic melanoma (HR 0.72, p=0.0009).
  • Compared to prior studies, this cohort had higher rates of transaminitis but lower rates of diarrhea, colitis, and GI perforation.


  • IPI is the first drug to extend survival in patients with metastatic melanoma, and the results appear to be durable. Concurrent administration with DTIC appears to be feasible, although patients must be monitored closely for toxicity and adverse events. Further investigation of combination regimens is certainly warranted based on the results presented here.
  • This is the second randomized control trial showing significant improvement in survival in patients with metastatic melanoma after treatment with IPI.
  • Interestingly, the dose used in this study is higher than that used in previous trials, 10 mg/kg vs 3 mg/kg, but appeared to be reasonably well-tolerated overall.
  • Immune related adverse effects, such as inflammation of the skin, gastrointestinal system, liver, and endocrine system, must be monitored and managed during IPI therapy.
  • This landmark study may change the treatment paradigm for metastatic melanoma in the future.
  • Further study is required to identify the subset of patients most likely to benefit from IPI therapy. Additional study questions should address optimal dosing and duration of IPI therapy.