Fast track — ArticlesIpilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study
Introduction
Malignant melanoma is one of the most aggressive cancers.1 Adequate systemic treatments are needed because median overall survival for stage IV disease is only 6–9 months.2 Both dacarbazine and high-dose interleukin 2 are approved in the USA, and fotemustine is approved within the European Union. Dacarbazine, a cytotoxic chemotherapeutic agent, yields low objective response rates; moreover, responses are short-lived, complete responses are rare, and the effect on overall survival is unclear.1, 3 Interleukin 2 was approved on the basis of durable responses in 6% of patients, but predictive factors of response are not available, and toxic effects restrict use of this agent to carefully selected individuals and specialised treatment centres.4 Objective response rates have been enhanced by cytokines combined with chemotherapy, but this has not translated into an improvement in overall survival.5
A proposed immunotherapeutic approach for advanced melanoma entails targeting of cytotoxic T-lymphocyte antigen 4 (CTLA4),6, 7, 8, 9 which is expressed on the surface of activated CD4+ and CD8+ T cells, to induce inhibitory signals.10 Thus, CTLA4 blockade might increase the function of effector CD4+ and CD8+ T cells by removal of a key checkpoint mechanism.10 In murine models, antibody blockade of CTLA4 enhances immune responses resulting in tumour regression.11, 12
Ipilimumab is a human monoclonal antibody against CTLA4 currently in clinical development. Results of early studies in patients with advanced melanoma showed this agent's potential antitumour activity with various doses (0·1–20 mg/kg) and regimens (single or multiple doses, monotherapy, or in combination with dacarbazine, interleukin 2, or vaccines).13, 14, 15, 16, 17, 18, 19 In a phase 1/2 study, ipilimumab had antitumour activity in individuals with pretreated advanced melanoma, including patients who had failed previous treatment with interleukin 2 and biochemotherapy for metastatic disease.20 Findings of a phase 2 study in treatment-naive and previously treated individuals with advanced melanoma who received ipilimumab at 10 mg/kg, with or without prophylactic budesonide, showed 1-year survival of 55% or more.21
To date, no randomised clinical studies have assessed the dose-responsiveness of ipilimumab. Objective responses have been reported with ipilimumab at doses of 10 mg/kg or 3 mg/kg,13 and the possibility of clinical activity—ie, disease stabilisation—has been suggested with a dose of 0·3 mg/kg. In the current study, we aimed to assess the antitumour efficacy, pharmacokinetics, pharmacodynamics, overall survival, and safety of ipilimumab monotherapy at doses of 0·3 mg/kg, 3 mg/kg, and 10 mg/kg in patients with previously treated stage III (unresectable) or stage IV melanoma.22 We chose 0·3 mg/kg to characterise fully the variables in the low range of the therapeutic window and to allow differences from the 10 mg/kg dose to be detected for many variables.
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Patients
We undertook a multicentre, randomised, double-blind, parallel group study in 66 centres from 12 countries (study CA184-022). The first patient assessment was on April 6, 2006, and the last was on July 31, 2007. The study had four phases: screening, induction, maintenance, and follow-up. The database lock for the primary analysis took place on Nov 13, 2007.
We judged patients eligible for the study if they were aged at least 16 years old with a histological diagnosis of stage III (unresectable)
Results
284 patients were enrolled into the current study, and 217 were randomly allocated treatment between April 6, 2006 and Jan 24, 2007 (figure 1). The most frequent reason for screening failure was presence of a brain metastasis (32/67). Demographics and baseline characteristics were consistent across treatment groups (table 1). All 217 patients who underwent random allocation had received previous systemic therapy, 213 in the metastatic setting. 90% (196/217) had received interleukin 2,
Discussion
In the current study, ipilimumab monotherapy showed a dose-dependent effect on pharmacokinetic, biological, and clinical variables in patients with advanced melanoma. The primary endpoint (best overall response rate) was associated significantly with increasing dose of ipilimumab. This study was not designed to detect differences in survival between groups; however, favourable non-significant results were noted with the 10 mg/kg dose for both overall and progression-free survival, despite about
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