Vorinostat Fails to Improve Advanced Malignant Mesothelioma Overall Survival

Useful trial design lessons learned from the negative vorinostat findings for advanced malignant pleural mesothelioma

medwireNews: The histone deacetylase inhibitor vorinostat does not significantly improve survival outcomes for patients with advanced malignant pleural mesothelioma, VANTAGE-014 trial results indicate.

The 329 patients given vorinostat 300 mg twice daily on nine days of a 21-day cycle did not have significantly longer overall survival than the 332 patients given placebo, at a median of 30.7 and 27.1 weeks, respectively.

Thus, second- or third-line vorinostat as a single agent “cannot be recommended” for this patient group, say Lee Krug, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors in The Lancet Oncology.

Nevertheless, the team emphasises that “several valuable lessons were learned” on trial design during VANTAGE-014, noting that patient accrual was hampered by use of a placebo group for half the trial participants which was found to be unappealing to patients and their physicians. But these control group findings can now be used as a “benchmark” for future studies, the researchers say, with pulmonary function data and a large tumour pathology bank available for molecular analysis among other achievements of the study.

Marina Garassino, from Istituto Nazionale di Tumori in Milan, Italy, and Silvia Marsoni, from Istituto di Candiolo in Turin, Italy, – the authors of an accompanying comment – commend the researchers for the large well-designed trial despite the failure of the three planned interim analyses to detect vorinostat’s lack of efficacy.

However, they suggest that the limited preclinical and phase I trial data available for histone deacetylase inhibitors did not justify the launch of a phase III trial.

Acknowledging that difficulties in patient selection for trials of targeted drugs are a known cause of rising drug development attrition, they conclude: “[W]e need robust and functionally validated preclinical evidence supporting hypothesis-driven trials, new study designs, and endpoints that really capture patient benefits.

“All this can be obtained from the beginning, tightening the collaboration between the stakeholders in drug development: patients, academia, and the pharmaceutical industry.”

References

Krug LM, Kindler HL, Calvert H, et al. 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. Lancet Oncol 2015; Advance online publication 19 March. dx.doi.org/10.1016/S1470-2045(15)70056-2

Garassino MC, Marsoni S. A lesson from vorinostat in pleural mesothelioma. Lancet Oncol 2015; Advance online publication 19 March. dx.doi.org/10.1016/S1470-2045(15)70084-7

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