Pembrolizumab versus Ipilimumab in Advanced Melanoma

Ashley Choi, Mercer University College of Pharmacy

Melanoma is considered as an aggressive, therapy-resistant malignancy of melanocytes per the melanoma study group of the Mayo Clinic Cancer Center.1  According to a review of early clinical studiesmelanoma is one of the most common kinds of cancer in Western countries and the fifth most common cancer in the United States.2  Also, the rate of melanoma incidence has been steadily increasing worldwide per the Mayo Clinic Cancer Center.1   Effective drug therapies for prevention and early detection are suggested to reduce mortality.2

According a review of early clinical studies, approximately 65% of all melanomas contain mutations, such as the B-Raf gene (BRAF)V600 mutation. Due to its high rate of mutation, melanoma is considered to have many unique neo-antigens that will facilitate an immune response against the cancer cell.  As part of the immunotherapies, they address the cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) blocking antibody, which allows T cells to proliferate and maintain activation by inhibiting the negative immune regulatory effect of CTLA-4.  The programmed death of the 1 (PD-1) blocking antibody, yields a more direct activation of cancer-specific T cells since ligands of PD-1 may be expressed by tumor cells directly.2

Per the package insert, Yervoy® (ipilimumab) is a humanized CTLA-4 monoclonal antibody (mAb) indicated for the unrespectable or metastatic melanoma treatment. The package insert suggests 3 mg/kg intravenously over 90 minutes every 3 weeks.3  Keytruda® (pembrolizumab) is a human programmed PD-1 antibody indicated by the unresectable of metastatic melanoma treatment per its package insert. The package insert recommends for the user to administer 2 mg/kg intravenously over 30 minutes every 3 weeks.4

Title: Pembrolizumab versus Ipilimumab in Advanced Melanoma5
Design International, randomized, controlled, open-label phase 3 study (N=834)
Objective To evaluate the superiority of either pembrolizumab every 2 week or every 3 week regimen over ipilimumab for progression-free survival in patients with advanced
Study Groups (1)  Subjects receiving pembrolizumab intravenously at a dose of 10 mg/kg of body weight for a 30-minute period every 2 weeks (n=279)
(2)  Subjects receiving pembrolizumab intravenously at a dose of 10 mg/kg of body weight for a 30-minute period every 3 weeks (n=277)
(3) Subjects receiving four cycles of ipilimumab intravenously at a dose of 3 mg/kg of body weight for a 90-minute period every 3 weeks (n=278)
Methods All participants were administered with assigned medication until disease progression, the onset of unacceptable side effects, an investigator’s decision to discontinue treatment, withdrawal of patient consent, 24 months of therapy (for pembrolizumab) or four cycles of therapy (for ipilimumab).  The responses were assessed at week 12 and every 6 weeks thereafter.  The progression-free and overall survival were estimated by using the Kaplan-Meier method.
Duration From September 18, 2013, to March 3, 2014
Primary Outcome Measure Progression-free survival and overall survival
Baseline Characteristics All subjects were: (1) 18 years of age or older, (2) histologically confirmed with unrespectable stage III or IV melanoma, (3) received no more than one previous systemic therapy for advanced disease, (4) with known BRAFV600 mutational status, (5) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or1, and (6) with provision of a tumor sample adequate for assessing PD-L1 expression.
Results Pembrolizumab Ipilimumab One-sided alpha level
2 weeks 3 weeks
6 month progression-free survival rates 47.3% 46.4% 26.5% 0.002
12 month (overall) survival rates 74.1% 68.4% 58.2% 0.00002
Adverse Events Common Adverse Events: pembrolizumab – fatigue (20.9% in the 2-week group and 19.1% in the 3-week group), diarrhea (16.9% and 14.4%, respectively), rash (14.7% and 13.4%, respectively), and pruritus (14.4% and 14.1%, respectively); ipilimumab – pruritus (25.4%), diarrhea (22.7%), fatigue (15.2%), and rash (14.5%)
Serious Adverse Events: pembrolizumab – diarrhea (2.5% and 1.1%, respectively); ipilimumab – diarrhea (3.1%) and fatigue (1.2%)
Percentage that Discontinued due to Adverse Events:
Study Author Conclusions In conclusion, this randomized study comparing two immune checkpoint inhibitors showed that pembrolizumab, as compared with ipilimumab, significantly prolonged progression-free and overall survival with fewer high-grade toxic events in patients with advanced melanoma.

The responses appeared in all of the three groups.  However, the use of pembrolizumab with the every 2 week or every 3 week regimen shows greater signs of improvement in progression-free survival and overall survival in comparison with ipilimumab in patients with advanced melanoma.  Furthermore, both regimens of pembrolizumab showed a 42% reduction in relative risk of progression or death and a 31–37% reduction in the relative risk of death.  This study suggests that the use of the anti-PD-1 antibody, such as the pembrolizumab regimen, would be appropriate for patients with the BRAFV600 mutation who had received previous BRAF inhibitor treatment.

References

  1. Markovic SN, Erickson LA, Rao RD, et al. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc. 2007;82(3):364-80.
  2. Mcarthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol. 2013;31(4):499-506.
  3. Yervoy® [package insert]. Princeton, NJ: Bristol-Myer Squibb Co.; Revised December 2013.
  4. Keytruda® [package insert]. County Cork, Ireland: Schering-Plough (Brinny) Co.; Revised June 2015.
  5. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32.
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