No Survival Benefit of Vorinostat in Progressive Advanced Malignant Pleural Mesothelioma
In the phase III VANTAGE-014 study reported in The Lancet Oncology, Krug et al found that treatment with the histone deacetylase inhibitor vorinostat (Zolinza) did not improve overall survival vs placebo in patients with malignant pleural mesothelioma who had progressed on previous chemotherapy.
Study Details
In this double-blind trial, 661 patients from 90 sites in 24 countries with measurable disease and progression after one or two previous systemic regimens were randomly assigned between July 2005 and February 2011 to receive vorinostat (n = 329) or placebo (n = 332). Vorinostat was given at 300 mg twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of 21-day cycles. The primary efficacy endpoint was overall survival in the intention-to-treat population.
The vorinostat and placebo groups were generally balanced for age (median 64 and 65 years, range = 38–92 and 29–86 years), sex (86% and 81% female), ethnicity (88% and 86% white, 1% black in both), epithelioid histology (83% and 81%), stage III or IV disease (90% and 91%), receipt of one prior chemotherapy regimen (77% in both), prior pemetrexed (Alimta) use (97% in both), forced vital capacity (median 2.4 L and 2.2 L), and mesothelioma dyspnea score (median 41 and 38).
Overall Survival
Median follow-up was 195 days in the vorinostat group and 173 days in the placebo group. Median overall survival was 30.7 weeks (95% confidence interval [CI] = 26.7–36.1 weeks) in the vorinostat group vs 27.1 weeks (95% CI = 23.1–31.9 weeks) in the placebo group (hazard ratio [HR] = 0.98, P = .86). No differences in outcome were observed according to sex, race, geographic region, histologic subtype, disease stage, age, Karnofsky performance score, previous surgical resection, or number of previous systemic regimens. Median progression-free survival was 6.3 vs 6.1 weeks (HR = 0.75, P < .001).
The authors noted that at the time of the third interim survival analysis, at approximately 50% of total events, median overall survival was 31.7 vs 25.0 weeks (HR = 0.86, P = .15). Subsequently, however, median overall survival was 29.0 vs 30.3 weeks (HR = 1.32, P = .063). A significant interaction was observed between survival effect and enrollment before or after the third interim analysis (P = .02). This change in survival trend was not explained by changes in age, weight, Karnofsky performance score, sex, race, histologic subtype, disease stage, number of previous regimens, previous use of pemetrexed, forced vital capacity, mesothelioma dyspnea score, plasma vascular endothelial growth factor level, toxicity, or drug formulation.
Adverse Events
The most common grade ≥ 3 adverse events in vorinostat patients were fatigue or malaise (16% vs 8% in the placebo group), dyspnea (11% vs 14%), and nausea (7% vs < 1%). Dose reduction was required in 11% vs 2% of patients, and treatment-related adverse events resulted in treatment discontinuation in 6% vs < 1%.
The investigators concluded: “In this randomized 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.”
Lee M. Krug, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet Oncology article.
The study was funded by Merck & Co. For full disclosures of the study authors, visit www.thelancet.com.
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