Hoa Tang, Mercer University College of Pharmacy
It is estimated that in 2015, there will be more than 73,000 new cases from melanoma diagnoses and about 10,000 deaths caused by melanoma in the United States.1 Checkpoint inhibitors and the mitogen-activated protein kinase (MAPK) pathway inhibitors are suggested to use for patients with advanced melanoma.2 Ipilimumab, which is an anti cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) and nivolumab, which is an anti- programmed cell death 1 (PD-1) monoclonal antibody, are checkpoint inhibitors. A review of combination therapy for treatment of advanced melanoma notes that dual immune-ckeckpoint inhibitors may have potential for improve clinical outcomes due to the distinct mechanism of actions.3
A recently published study compared the combination of nivolumab and ipilimumab with ipilimumab monotherapy in patients with advanced melanoma. 4
|Title: Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma|
|Design||Randomized, double-blinded, placebo-controlled study; N= 142|
|Objective||To compare nivolumab in combination with ipilimumab with standard-of-care ipilimumab monotherapy as a first line treatment in patients with advanced melanoma|
|Study Groups||Combination group (n= 95) ipilimumab monotherapy group (n= 47); 2:1 ratio|
|Methods||Participants were randomized to received ipilimumab ( 3 mg per kilogram) combined with either nivolumab ( 1 mg per kilogram) or placebo once every three weeks for four doses, followed by nivolumab ( 3 mg per kilogram) or placebo every two weeks.|
|Duration||September 2013 through February 2014; a minimum follow-up of 11 months|
|Primary Outcome Measure||The rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors|
|Combination group- mean age 64 years, male 66%, stage IV disease 89%, M1c metastasis stage 43%, history of brain metastases 4%, BRAF V600 mutation 24%
Ipilimumab group- mean age 67 years, male 68%, stage IV disease 81%, M1c metastasis stage 45%, history of brain metastases 0%, BRAF V600 mutation 21%
|Results||Among the patients with BRAF wild-type tumors, the rate of investigator-assessed, confirmed objective response was 61% in the combination group and 11% in ipilimumab monotherapy group ( 95% confidence interval (CI): 3.91-54.49; p<0.001)
Among patients with BRAF V600 mutation positive tumors, the objective response was 52% in the combination group (95% CI: 31-73) and 10% in ipilimumab monotherapy group (95% CI: 0-45)
|Adverse Events||Common Adverse Events: Any treatment-related adverse event (91%vs. 93%), diarrhea (45% vs. 37%), rash (41% vs. 26%), fatigue (39% vs. 43%), pruritus (35% vs.28%), colitis (23% vs. 13%), nausea (22% vs. 24%), elevated aspartate aminotransferase/ alanine aminotransferase AST/ALT ( 21/22 % vs. 4/4 %), hypothyroidism (16% vs. 15%), decreased appetide (15% vs. 9%), headache (14% vs. 11%), vomiting (14% vs. 11%), increased lipase (13% vs. 4%), hypophysitis (12% vs. 7%), pneumonitis (11% vs. 4%), arthralgia (11% vs. 9%), chills (11% vs. 7%), vitiligo ( 11% vs. 9%), abdominal pain (11% vs. 9%), constipation (11% vs. 9%), myalgia (10% vs. 13%), dyspnea (10% vs. 11%), asthenia (9% vs. 11%), pruritic rash (3% vs. 11%)|
|Serious Adverse Events: Not reported|
|Percentage that discontinued due to Adverse Events: 47% in combination group and 17% in ipilimumab alone group|
|Study Author Conclusions||The combination of ipilimumab plus nivolumab resulted in durable responses and a substantially higher objective response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy among patients with BRAF wild-type advanced melanoma and those with BRAF-mutant advanced melanoma. The incidence of grade 3 or 4 adverse events was higher with combination therapy, but adverse events were generally manageable when established safety guidelines were used. The risk–benefit profile of combined PD-1 and CTLA-4 blockade, as compared with monotherapy, will be further clarified by data from ongoing phase 3 double-blind, randomized trials, such as the CheckMate 067 study.|
This trial shows that untreated, advanced melanoma patients with BRAF wild-type melanoma had significantly higher response rate to the ipilimumab-nivolumab combination therapy than the ipilimumab alone. As expected, treatment-related adverse events were also much higher with the combination therapy. Although risks versus benefits of dual checkpoint inhibitors combination are still under investigation, this ipilimumab-nivolumab combination may potentially be used for untreated patients with advanced melanoma.
- Cancer Facts & Figures 2015. American Cancer Society. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed April 22, 2015.
- Melanoma Treatment. National Cancer Institute. http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page4. Accessed April 22, 2015.
- Voskoboynik M, Arkenau HT. Combination therapies for the treatment of advanced melanoma: a review of current evidence. Biochem Res Int. 2014;2014:307059. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944792/. Accessed April 22, 2015.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med. 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1414428?query=featured_home. Accessed April 20, 2015.