Integration of Ipilimumab in the First-line Setting Improves Survival for Patients with Metastatic Melanoma
For the second time, results of a phase III trial confirm the overall survival benefit conferred by ipilimumab in metastatic melanoma — this time in the frontline treatment setting in combination with dacarbazine.
These findings may soon change the treatment landscape for metastatic melanoma by establishing ipilimumab-based therapy as a first-line regimen of choice over dacarbazine, which is currently considered to be the standard of care.
Jedd D. Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center, presented the results of the MDX-024 study (Abstract LBA5).
Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T-cell activation, and thus functions to enhance T-cell activation and proliferation.
The agent was approved by the U.S. Food and Drug Administration (FDA) in late March 2011 for the treatment of advanced melanoma based on an overall survival benefit observed with ipilimumab monotherapy in patients with unresectable stage III/IV melanoma for whom previous treatment had failed.
According to Discussant Kim Margolin, MD, of the University of Washington and Fred Hutchinson Cancer Research Center, FDA approval of ipilimumab and the positive results of the MDX-024 study represent two "happy endings" in the tale of advanced melanoma.
"Historically, we have had little to offer patients, as the supposedly standard therapies have had limited activity and substantial toxicity," she explained.
The global, double-blind, placebo-controlled phase III MDX-024 trial recruited patients from 24 countries, ultimately enrolling 502 individuals with unresectable stage IIIc or IV metastatic melanoma who had received no prior therapy for advanced disease.
Although patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, there were no eligibility restrictions based on lactate dehydrogenase (LDH) concentration, BRAF mutation status, and human leukocyte antigen (HLA) type. Patients comprising the study population had a very poor prognosis, as 56% had M1c disease and 40% had elevated LDH.
Patients were randomly assigned to receive 850 mg/m2 of dacarbazine plus either 10 mg/kg of ipilimumab or placebo, all administered every 3 weeks for four cycles, followed by an additional four cycles of every-3-weekly dacarbazine alone. Patients without evidence of disease progression or dose-limiting toxicity after induction therapy went on to receive ipilimumab or placebo every 12 weeks as maintenance therapy in accord with their original treatment assignment.
Exposure to study therapy differed markedly between the two arms. Whereas 66% of patients assigned to placebo/dacarbazine received the first four doses of induction therapy, only 37.2% of patients assigned to ipilimumab/dacarbazine did so. Small proportions of patients in each arm went on to receive maintenance therapy (17.4% in the ipilimumab/dacarbazine arm and 21.1% in the placebo/dacarbazine arm), thus precluding the ability to draw conclusions regarding the effect of such treatment.
Despite the difference in exposure to induction therapy, ipilimumab/dacarbazine significantly prolonged overall survival — the primary study endpoint — by 2.1 months compared with dacarbazine alone (11.2 vs. 9.1 months, respectively; hazard ratio [HR]: 0.72; 95% CI [0.59, 0.87]; p < 0.0009; Fig. 1).
Other key endpoints mirrored this benefit. Ipilimumab/dacarbazine significantly prolonged progression-free survival compared with placebo/dacarbazine (2.8 vs. 2.6 months, respectively; HR: 0.76; 95% CI [0.63, 0.93]; p < 0.006), and responses appeared to be much more durable for ipilimumab/dacarbazine compared with those for placebo/dacarbazine (median of 19.3 vs. 8.1 months). No appreciable differences in the disease control rate (33.2% vs. 30.2%) and the best overall response rate (15.2% vs. 10.3%) were observed between the two respective arms.
The combination of ipilimumab and dacarbazine did result in a higher incidence of grade 3/4 adverse events compared with the control arm (56.3% vs. 27.5%). Ipilimumab-associated adverse events were consistent with previous studies and predominantly affected the liver, endocrine system, gastrointestinal tract, and skin.
The most notable differences in grade 3/4 adverse events between the ipilimumab/ dacarbazine and placebo/dacarbazine arms involved alanine aminotransferase increases (21.9% vs. 0.8%), aspartate aminotransferase increases (18.2% vs. 1.2%), and diarrhea (4.0% vs. 0%). No cases of gastrointestinal perforation or hypophysitis were observed in association with ipilimumab.
"In view of the increased hepatotoxicity of the ipilimumab plus dacarbazine combination, and the strong sense that there was no therapeutic advantage to the addition of the cytotoxic agent, it would not be advisable to include this agent in the standard clinical use of ipilimumab," Dr. Margolin said.
She suggested that the best way to proceed when applying ipilimumab in the clinical setting will involve identifying the optimal dose and duration of ipilimumab and determining whether special patient subsets respond better than others to the agent.
Dr. Wolchok noted that further development of ipilimumab is ongoing in both metastatic disease and the adjuvant setting, alone and in combination with alternative agents.