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

Our plain-English summary of 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, by L.M. Krug, H.L. Kindler, H. Calvert, et al (The Lancet. Oncology, 2015).

The study

• Authors: L.M. Krug, H.L. Kindler, H. Calvert, C. Manegold, A.S. Tsao, D. Fennell, R. Öhman, R. Plummer, W.E. Eberhardt, K. Fukuoka, R.M. Gaafar, J.J. Lafitte, G. Hillerdal, Q. Chu, W.A. Buikhuisen, G.M. Lubiniecki, X. Sun, M. Smith, P. Baas
• Journal: The Lancet. Oncology
• Published: 2015;16(4):447-56
• Type of article: Randomized trial
• Cited by: 166 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

Copyright © 2015 Elsevier Ltd. All rights reserved.

In plain English

This phase 3, double-blind, randomised, placebo-controlled trial tested the drug vorinostat in people with advanced malignant pleural mesothelioma whose disease had progressed after one or two previous chemotherapy regimens. It did not study asbestos exposure. From July 2005 to February 2011, 661 patients at 90 centres in 24 countries were assigned to vorinostat (329) or placebo (332). Vorinostat was taken by mouth, 300 mg twice daily on set days of each 21-day cycle. Median overall survival was 30.7 weeks with vorinostat and 27.1 weeks with placebo (hazard ratio 0.98, 95% CI 0.83 to 1.17; p=0.86). Progression-free survival was longer with vorinostat (hazard ratio 0.75, 95% CI 0.63 to 0.88), a difference the authors judged not clinically meaningful. Grade 3 or worse fatigue or malaise affected 51 (16%) patients on vorinostat and 25 (8%) on placebo. The authors concluded that vorinostat given as second-line or third-line therapy did not improve overall survival and cannot be recommended for these patients. They raised the possibility that the best dose and schedule had not been chosen.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase 3, double-blind, randomised (1:1), placebo-controlled drug trial
• Who was studied: 661 patients aged 18 or older with advanced malignant pleural mesothelioma that had progressed after one or two previous chemotherapy regimens. They were enrolled at 90 international centres in 24 countries between July 12, 2005 and Feb 14, 2011. 329 were assigned to vorinostat and 332 to placebo.
• Exposure: Treatment, not asbestos exposure, was studied. Patients took oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 of each 21-day cycle. This schedule came from a protocol amendment. Before it, 11 patients received 300 mg twice daily for 14 consecutive days of a 21-day cycle.
• Main results:
  • Median overall survival was 30.7 weeks (95% CI 26.7 to 36.1) in the vorinostat group and 27.1 weeks in the placebo group.
  • For overall survival, the placebo group's 95% CI was 23.1 to 31.9 weeks. The hazard ratio for vorinostat versus placebo was 0.98 (95% CI 0.83 to 1.17; p=0.86).
  • At the third interim analysis (277 deaths), median overall survival was 31.7 weeks in the vorinostat group and 25.0 weeks in the placebo group (HR 0.86, 95% CI 0.67 to 1.10; p=0.15).
  • After the third interim analysis, median survival was 29.0 weeks in the vorinostat group and 30.3 weeks in the placebo group (HR 1.32, 95% CI 0.98 to 1.77; p=0.063).
  • Progression-free survival was longer in the vorinostat group than in the placebo group (HR 0.75, 95% CI 0.63 to 0.88; p less than 0.001).
  • The authors described the improvement in progression-free survival as not clinically meaningful.
  • Grade 3 or worse fatigue or malaise occurred in 51 (16%) patients in the vorinostat group and 25 (8%) in the placebo group. Grade 3 or worse dyspnoea occurred in 35 (11%) and 45 (14%) respectively.
  • Patients who stopped study medication because of a drug-related adverse event: 20 (6%) of 329 in the vorinostat group and two (less than 1%) of 332 in the placebo group.
  • In the vorinostat group, the investigator judged three deaths (less than 1%) at least possibly related to vorinostat. Their causes were renal impairment, pneumonia and acute renal failure.
  • From baseline to week 12, mean forced vital capacity changed by -6.0% in the vorinostat group and -5.6% in the placebo group.
• The authors' conclusion: The authors concluded that vorinostat given as second-line or third-line therapy did not improve overall survival. They said it cannot be recommended for patients with advanced malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors questioned whether the optimum dose and schedule of vorinostat had been chosen.
  • The authors said the 1:1 placebo design hampered enrolment over the 5-year accrual period.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Overall Survival, Disease Progression, Performance Status, Histology, Median Overall Survival, Hazard Ratio.

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