DOI: 10.1097/01.OTU.0000398562.48570.81
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Issn Print: 1742-8009
Publication Date: 2010/03/01
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Excerpt
The anti-angiogenesis agent bevacizumab is approved for use in patients with non-squamous non-small cell lung cancer (NSCLC), but is not safe for use in patients with squamous cell histology. By contrast, the tumor vascular disrupting agent vadimezan (previously called ASA404) appears safe and active in both squamous and non-squamous cell histologies, according to an analysis presented at the first American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer.
‘Bevacizumab approval is restricted to non-squamous non-small cell lung cancer, and there are other contraindications for its use in patients who are at risk of thrombotic or bleeding complications’, said Dr Mark McKeage, associate professor of clinical pharmacology at the University of Auckland, New Zealand, who presented the new analysis.
‘Similar problems have been found in Phase III trials with other vascular targeting therapies, such as sorafenib, where there has been increased mortality in patients with squamous histology. ASA404 had a similar activity and safety profile in patients with squamous and non-squamous NSCLC in our analysis of two pooled phase II studies.
The primary data from the Phase II studies showed activity and safety of the drug in combination with carboplatin-paclitaxel chemotherapy and have been published previously. In a randomised controlled trial, 73 patients with previously untreated advanced NSCLC were treated with standard chemotherapy plus vadimezan (at a dose of 1,200 mg) or chemotherapy alone.
The median response rate was 31% versus 22% in the two arms, respectively, and median overall survival was 14.0 versus 8.8 months. The second Phase II trial was an open-label single-arm study designed to test the safety of a higher dose of vadimezan. Thirty patients were treated with a standard chemotherapy plus vadimezan. The median overall survival was 14.4 months.
To get a better sense of whether the new agent is active and safe in both squamous and non-squamous histology, Dr McKeage and colleagues combined the data from the two published studies and reanalysed them by histological subtype, with particular attention paid to blood and lymphatic adverse events.
The overall rate of Grade 3 or higher adverse events was 68% in patients with squamous histology treated with chemotherapy plus vadimezan, 73% in squamous patients receiving chemotherapy alone, 61% in non-squamous patients treated with the chemotherapy plus vadimezan, and 64% in non-squamous patients treated with chemotherapy alone.
None of the patients in the trial experienced a serious adverse event of bleeding, pulmonary haemorrhage, or haemoptysis. Grade 3 or higher blood and lymphatic adverse events occurred in 18% of the squamous patients treated with chemotherapy plus vadimezan, 0% of the squamous patients treated with chemotherapy alone, 22% of the non-squamous patients treated with chemotherapy plus vadimezan, and 20% of the non-squamous patients treated with chemotherapy alone.
Five patients had Grade 3 or higher cardiac events (two squamous patients receiving combination therapy, two non-squamous patients receiving combination therapy, and one squamous patient receiving chemotherapy alone); none of the cardiac events occurred in patients treated with the higher dose of ASA404 plus chemotherapy.
‘The key point here is that the rate of Grade 3 and 4 adverse events was similar when chemotherapy was given with ASA404 and when given alone, and they were also similar in squamous and non-squamous patients’, Dr McKeage said. ‘These data support the ongoing Phase III investigation of ASA404 with standard first-and second-line chemo in advanced NSCLC without any restriction on histology.
