Higher Ipilimumab Dose Associated With Prolonged Survival in Melanoma

Joey Spada, Mercer University College of Pharmacy

Yervoy® (ipilimumab) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4) and has been found to increase antitumor immune responses.  Adjuvant ipilimumab therapy in melanoma patients has been associated with prolonged recurrence-free survival. [1]  The Food and Drug Administration (FDA) approved a dose of 3 mg/kg for the treatment of advanced melanoma in 2011.  A higher dose has been suggested to potentially increase efficacy based upon previous trials. [2]

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy [3]
Design Randomized, double blind, phase 3; N= 951
Objective To evaluate ipilimumab in patients who have undergone complete resection of stage III melanoma
Study Groups Ipilimumab (n= 475); placebo (n= 476)
Methods Eligible patients were 18 years of age or older with stage III cutaneous melanoma as classified by the American Joint Committee on Cancer (AJCC).  Complete lymphadenectomy was required within 12 weeks before randomization.  Patients were assigned to receive ipilimumab at a dose of 10mg/kg or placebo every 3 weeks for four doses (12 weeks) and then every 3 months thereafter.  Treatment was continued for 3 years or until either disease recurrence or an unacceptable level of toxic effects occurred.
Duration July 2008 – August 2011
Primary Outcome Measure Incidence of morbidity
Baseline Characteristics

 

  Ipilimumab Placebo
Male, n (%) 296 (62.3) 293 (61.6)
Female, n (%) 179 (37.7) 183 (38.4)
Median age, yrs (range) 51 (20 – 84) 52 (18 – 78)
Disease stage, n (%)
IIIA 98 (20.6) 88 (18.5)
IIIB 213 (44.8) 207 (43.5)
IIIC with 1-3 positive lymph nodes 69 (14.5) 83 (17.4)
IIIC with ≥ 4 positive lymph nodes 95 (20.0) 98 (20.6)
Type of lymph node involvement, n (%)
Microscopic 210 (44.2) 193 (40.5)
Macroscopic 265 (55.8) 283 (59.5)
Results   Ipilimumab deaths, n Placebo deaths, n

p-value

 

Disease stage
IIIA 24 22 N/A
IIIB 68 85 N/A
IIIC with 1-3 positive lymph nodes 34 45 N/A
IIIC with >4 positive lymph nodes 36 62 N/A
All patients 162 214 0.001
Type of positive lymph node
Microscopic 54 76 0.61
Macroscopic 108 138 0.80
Adverse Events Common Adverse Events: gastrointestinal (16.1%), hepatic (10.8%), endocrine (7.9%)
Serious Adverse Events: colitis (0.6%), myocarditis (0.2%), multi-organ failure associated with Guilliain-Barre syndrome (0.2%)
Percentage that Discontinued due to Adverse Events:  53.3% (ipilimumab); 4.6% (placebo)
Study Author Conclusions Ipilimumab at a dose of 10mg/kg resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival compared to placebo.  There were more immune-related adverse events with ipilimumab than with placebo.
           

Even with surgery and adjuvant therapy with ipilimumab at a dose of 3 mg/kg, only 45% of patients with stage III melanoma will be disease-free after 4 years.  In 2015, the FDA expanded the approval of ipilimumab to include adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection, at a dose of 10mg/kg.  Ipilimumab has numerous side effects which led to a worrisome drop-out rate in this study; this will need to be continuous monitoring.  Despite ipilimumab’s drawbacks, the results of this trial are encouraging due to the limited number of medications available the treatment of late stage melanoma. [3]

 

References

  1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant Ipilimumab versus Placebo After Complete Resection of High-risk Stage III Melanoma (EORTC 18071): A Randomised, Double-blind, Phase 3 Trial. Lancet Oncol 2015;16:522-30.
  1. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon Alpha Adjuvant Therapy in Patients with High-risk Melanoma: A Systematic Review and Meta-analysis. J Natl Cancer Inst 2010;102:493-501.
  1. Eggermont AM. Adjuvant ipilimumab in stage III melanoma: New landscape, new questions. Eur J Cancer. 2016;69:39-42.
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