September 29, 2011 (Stockholm, Sweden) — The largest randomized phase 3 study ever conducted in patients with advanced malignant pleural mesothelioma has failed; no survival benefit was seen with vorinostat (Zolinza, Merck & Co).
"Despite the negative data, we want to pledge our best efforts to continue to find new therapies for this dreadful disease," said principal investigator Lee Krug, MD, from the Memorial Sloan-Kettering Cancer Center in New York City. He was addressing a presidential session here at the 2011 European Multidisciplinary Cancer Congress. The study was chosen as a best abstract.
Vorinostat, a histone deacetylase inhibitor, is marketed for use in the treatment of cutaneous T-cell lymphoma. Dr. Krug explained that the manufacturer agreed to fund the large study of mesothelioma after a small phase 1 study suggested a benefit from this drug. In that small trial, 5 of 13 patients experienced stable disease lasting 4 to 13 months.
The phase 3 study was conducted in 660 patients with malignant pleural mesothelioma who had progressed after 1 or 2 systemic therapies, including pemetrexed (Alimta) and cisplatin.
All patients received best supportive care, and were randomized to receive placebo or vorinostat 300 mg orally twice daily for 3 days, each week of a 21-day cycle.
There was no significant difference in median overall survival between the vorinostat and placebo groups (30.7 vs 27.1 weeks; hazard ratio [HR], 0.98; P = .858). Median progression-free survival was slightly better with vorinostat (6.3 vs 6.1 weeks); this reached statistical significance but is not considered to be clinically significant, Dr. Krug noted.
Further analysis found no significant differences between the 2 groups in overall response rate, forced vital capacity, dyspnea, or in the proportion of patients reporting serious adverse events.
"This is the biggest study so far," said Rolf Stahel, MD, from the University Hospital in Zurich, Switzerland, "but the overall results are negative, and they are also negative in each subgroup."
Dr. Stahel said that another approach to the treatment of mesothelioma — adding bevacizumab (Avastin) to chemotherapy — has also recently failed.
"What is on the horizon" he asked. Noting that his group recently reported finding a mutation in the BAP1 gene in mesothelioma, he explained that "we may have to break down into subgroups of mutations, even in very rare diseases such as mesothelioma."
Mesothelioma, a rare but fatal cancer resulting from exposure to asbestos, is diagnosed in about 2000 to 3000 individuals each year in the United States. The number of cases is expected to peak from 2015 to 2020, according to Dr. Krug. The use of asbestos has decreased since the 1970s, and the latency period between exposure and mesothelioma is 20 to 50 years.
The trial was funded by Merck & Co, the manufacturer of vorinostat.
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 1LBA. Presented September 24, 2011.
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Cite this: Largest Trial So Far in Mesothelioma Disappoints - Medscape - Sep 29, 2011.