Elsevier

The Lancet Oncology

Volume 16, Issue 4, April 2015, Pages 447-456
The Lancet Oncology

Articles
Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial

https://doi.org/10.1016/S1470-2045(15)70056-2Get rights and content

Summary

Background

Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.

Methods

This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102.

Findings

From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7–36·1) versus 27·1 weeks (23·1–31·9) for placebo (hazard ratio 0·98, 95% CI 0·83–1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]).

Interpretation

In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma.

Funding

Merck & Co, Inc.

Introduction

Malignant pleural mesothelioma is a rare malignancy that, in most cases, is related to previous exposure to asbestos. Malignant pleural mesothelioma generally spreads locally within the pleural cavity, and the most common first symptom is dyspnoea due to a pleural effusion. Available therapies generally have little effect on prognosis. Surgery in combination with radiation and chemotherapy can be used for healthy patients with early stage disease, but most patients have unresectable disease and are treated mainly with palliative chemotherapy. The standard first-line treatment for patients with advanced malignant pleural mesothelioma consists of a combination of pemetrexed and cisplatin, which, compared with treatment with cisplatin alone, increases median overall survival from 9·3 to 12·1 months (log-rank p-value 0·020).1 For subsequent therapy lines, no standard salvage therapy exists. Vinorelbine and gemcitabine are often used in this setting on the basis of results from first-line trials or small phase 2 trials, but the proportion of patients achieving a response are negligible, and no data suggest that treatment with these drugs increases survival.2

Vorinostat (suberoylanilide hydroxamic acid) is an oral drug that binds to the catalytic site of histone deacetylase subtypes 1, 2, 3, and 6, thereby inhibiting their activity.3 In addition to directly regulating transcription through changes in chromatin structure, histone deacetylase inhibitors modulate the acetylation of transcription factors and other non-histone proteins. This modulation leads to a range of biological effects that have been shown to be relevant in malignant pleural mesothelioma in preclinical studies.4 Histone deacetylase inhibitors sensitise malignant pleural mesothelioma cells to apoptosis by downregulation of BCL-XL and XIAP.5, 6, 7 Histone deacetylase inhibitors reduce the expression of VEGF and HIF1,8 and the effects of angiogenesis inhibition in malignant pleural mesothelioma have been studied extensively in the laboratory,9, 10 and in clinical trials.11 Histone deacetylase inhibitors also exert various immunomodulatory effects.12

Vorinostat showed preliminary signs of clinical activity in patients with malignant pleural mesothelioma given this treatment in the original phase 1 trial of the oral formulation.13 From the 73 patients given treatment, 13 had malignant pleural mesothelioma, all but one of whom had previously received chemotherapy.14 Six of these patients continued in the study for more than 4 months. Two patients had radiographic partial responses, including one patient who had received five previous regimens, although their responses were not confirmed in subsequent imaging. These results, along with the desperate need to develop effective therapies for this group of patients, prompted interest in proceeding with this large randomised trial to establish whether treatment with vorinostat improves survival for patients with mesothelioma.

Section snippets

Study design and patients

In this phase 3, double-blind, randomised, placebo-controlled trial, we enrolled patients aged 18 years or older from 90 international centres (appendix) with pathologically confirmed malignant pleural mesothelioma of any histological subtype, a Karnofsky performance score of at least 70, and progression of disease after one or two previous chemotherapy regimens. The expected median survival for this patient population was 6 months. Previous treatment should have included pemetrexed plus

Results

From July 12, 2005, to Feb 14, 2011, enrolment was completed with 661 patients from 90 international centres in 24 countries randomly assigned and included in the intention-to-treat analysis (figure 1). 329 patients received vorinostat and 332 received placebo. Baseline characteristics of the patients were balanced across the two treatment groups (table 1). Median follow-up time was 195 (IQR 94–335) days for patients in the vorinostat group and 173 (90–325) days for the placebo group.

Treatment

Discussion

In this randomised study, to our knowledge the largest ever done in malignant pleural mesothelioma, the use of single-drug vorinostat did not improve overall survival compared with placebo in patients who had previously received chemotherapy (panel). Progression-free survival was significantly improved but not in a clinically meaningful manner. Limited efficacy data were available from the phase 1 trial before the initiation of this phase 3 trial, and as such, the trial had strict stopping

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      Compared with active treatments, serious Tr-AEs were higher with the anti-CTLA4 plus anti-PD1 versus single-agent anti-PD1 immunotherapy (26.2 versus 14.3%) [9], and with the addition of ramucirumab to chemotherapy (43.8 versus 29.6%) [8], but lower with single-agent anti-PD1 than chemotherapy (19.4 versus 25.7%) [7], and with the addition of NGR-hTNF to chemotherapy (8.8 versus 10.4%) [18]. The reported Tr-deaths were higher than placebo or BSC/ASC with the anti-CTLA4 (1.3 versus 0%) [16] and the histone deacetylase (HDAC) inhibitor (0.9 versus 0.3%) [17]. Compared with active treatments, Tr-deaths were higher with anti-CTLA4 plus anti-PD1 versus single-agent anti-PD1 immunotherapy (4.9 versus 0%) [9].

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