Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial

Summary

Background

Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases.

Methods

In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m² intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692.

Findings

86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7–57·6), as did ten with brain metastases (50·0%, 27·2–72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase.

Interpretation

The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases.

Funding

Bristol-Myers Squibb.

Introduction

Although an improvement in survival for early stage melanoma has been reported with some treatments, patients with metastatic melanoma have poor outlooks. After diagnosis of stage IV melanoma, median survival is typically 6–9 months and only 10% of patients survive to 5 years.1, 2 Melanoma has a particular propensity to metastasise to the brain; up to half of patients with metastatic disease develop brain metastases, reducing their life expectancy to only 3–4 months.³ Furthermore, autopsy data have shown that up to 75% of patients who die from metastatic melanoma have brain metastases.³ Treatment options are surgery or stereotactic radiosurgery with or without adjuvant whole-brain radiation therapy for patients with single or localised metastases, or whole-brain radiation therapy for patients with several brain metastases.³ Because of their particularly poor prognosis, patients with brain metastases are generally excluded from clinical trials, meaning data for the efficacy of novel treatments in this population are scarce.

Chemotherapy has long been the mainstay of treatment for metastatic melanoma. Dacarbazine is the most widely used single chemotherapeutic agent despite reports of low response rates in phase 3 trials and no significant improvement in survival compared with supportive care.4, 5, 6 Fotemustine has also been investigated:⁷ in a retrospective study of treatment patterns of European patients with advanced melanoma,⁸ it was the second most common agent used as first-line systemic treatment in both France and Italy, despite modest clinical activity.

In 2011, ipilimumab—a fully humanised monoclonal antibody that inhibits the activity of cytotoxic T-lymphocyte-associated protein 4 to potentiate an antitumour immune response—received marketing authorisation from the US Food and Drug Administration and the European Commission. Ipilimumab is approved for clinical use in adult patients with metastatic melanoma in the USA or pretreated adult patients with metastatic melanoma in Europe. Approval was based on the results from a phase 3 trial,⁹ in which treatment with intravenous ipilimumab (3 mg/kg every 3 weeks for four doses) with or without gp100 vaccine significantly improved survival compared with a vaccine control.

Growing evidence suggests that ipilimumab (used at 10 mg/kg every 3 weeks for four doses) could be effective in patients with melanoma and brain metastases.10, 11 In a retrospective analysis of data from a phase 2 study of ipilimumab in patients with advanced melanoma,¹¹ two of 12 patients with stable brain metastases at baseline achieved a partial response, three had stable disease, and the median overall survival was 14 months (range 2·7–≥56·4). Furthermore, in a phase 2 trial of ipilimumab¹⁰ in 72 patients with advanced melanoma, of whom 51 patients had asymptomatic brain metastases, median overall survival was 7 months, with 31% of patients surviving 1 year.

Early preclinical and clinical evidence suggests that the chemotherapy-induced release of tumour antigens might amplify the antitumour activity of ipilimumab. In a randomised phase 3 study of 502 patients with previously untreated metastatic melanoma,¹² treatment with ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m²) significantly improved overall survival compared with dacarbazine alone. 47% of patients treated with ipilimumab plus dacarbazine survived to 1 year versus 36% of those given dacarbazine alone (hazard ratio [HR] for death 0·72; p<0·001).¹² Notably, the side-effect profile with ipilimumab plus dacarbazine was different from that reported in previous ipilimumab studies, most probably because of unanticipated interactions between the two drugs. Therefore, the efficacy and toxicity profile of ipilimumab could vary depending on the context in which it is given.12, 13

We investigated the safety and efficacy of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. We chose to use fotemustine as the combination chemotherapy agent because it yielded a higher overall response rate and longer times to occurrence of brain metastases than did dacarbazine in a randomised phase 3 trial.14, 15 Additionally, unlike dacarbazine, fotemustine can cross the blood–brain barrier, and thus potentially has activity against brain metastases.