Elsevier

The Lancet Oncology

Volume 11, Issue 2, February 2010, Pages 155-164
The Lancet Oncology

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Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study

https://doi.org/10.1016/S1470-2045(09)70334-1Get rights and content

Summary

Background

Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma.

Methods

We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0·3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640.

Findings

The best overall response rate was 11·1% (95% CI 4·9–20·7) for 10 mg/kg, 4·2% (0·9–11·7) for 3 mg/kg, and 0% (0·0–4·9) for 0·3 mg/kg (p=0·0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0·3 mg/kg, respectively; the most common grade 3–4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0·3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0·3 mg/kg group).

Interpretation

Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.

Funding

Bristol-Myers Squibb.

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.

Section snippets

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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