A phase 2b clinical trial testing the efficacy of the anticancer drug tremelimumab for the treatment of relapsed malignant mesothelioma found that the drug may be ineffective in treating the disease.
Malignant mesothelioma is a rare and aggressive cancer of the pleural (found in the lung) or peritoneal (found in the abdomen)or pericardial (found in the heart) membranes, which is caused by exposure to asbestos. Pleural mesothelioma is caused by inhalation of the asbestos fibers, whereas peritoneal mesothelioma is caused by inhaled or swallowed asbestos fibers. Pericardial mesothelioma, an extremely rare cancer, is caused by asbestos fibers lodged in the heart cavity. There is no cure for the disease and overall prognosis is poor. The incidence of mesothelioma in Canada at approximately two per 100,000 individuals every year is amongst the highest in the world.1 The high incidence rate is primarily a result of asbestos mining in Quebec and British Columbia. Although the last asbestos mines in the country were shut in 2011, its use and export are not banned.
Current Treatments for Malignant Mesothelioma
Among the first line of drugs used to treat advanced pleural malignant mesothelioma and peritoneal mesothelioma are cisplatin and pemetrexed combined. Additionally, the inclusion of bevacizumab to cisplatin-pemetrexed combined has been shown to improve survival in newly diagnosed cases of pleural malignant mesothelioma. There is no second-line treatment available for relapsed or refractory mesothelioma and the prognosis is generally poor for such patients.
A study funded by the pharmaceutical giant AstraZeneca tested the efficacy of tremelimumab as a second-line, stand-alone treatment for relapsed or refractory mesothelioma.2 The study was carried out at 105 centers in 19 countries, and its results were published in The Lancet Oncology recently. The patients included were aged 18 years or older and had confirmed surgically untreatable pleural or peritoneal malignant mesothelioma that had progressed despite one or two previous systemic treatments.
Methods
The patients were first grouped based on their risk for disease recurrence and progression, site of tumor (pleural versus peritoneal), and line of therapy (second line versus the third line). Patients from each group were then randomly assigned to either the tremelimumab group or the placebo (control) group. A total of 380 patients received tremelimumab intravenously (10 milligrams/kilogram of body weight) every 4 weeks a total of 7 times followed by dosing every 12 weeks until treatment was discontinued owing to an adverse event, disease progression despite treatment, patient non-compliance, initiation of other treatment, or other reasons. The 189 patients in the placebo group received a matching placebo and followed an identical regimen. Patients were periodically assessed using lab tests and tumor imaging with CT scans.
The primary outcome that was monitored was overall patient survival, that is the time from the start of the study until the death of the patient. Also monitored were a number of secondary outcomes, which included 18-month overall survival, response to treatment, progression-free survival, and safety and tolerability of tremelimumab.
No Effect on Overall Survival
The results show that tremelimumab treatment did not affect overall survival.On the last date when data were collected, 80% of the patients in the tremelimumab group had died, whereas 81% of the patients died in the control group. The median survival times in the tremelimumab treatment and placebo groups were 7.7 months and 7.3 months, respectively. Additionally, there was no difference between the tremelimumab and placebo groups with regard to any of the secondary outcomes monitored. Notably, a higher proportion of patients in the tremelimumab group had treatment-emergent adverse events (undesirable events that were either not present before treatment or worsened in frequency or intensity after its commencement) compared to the placebo group. The most common adverse events were dyspnea, diarrhea, and colitis.
Challenges in Bringing New Drugs to Market
The failure of this drug in phase 2b trial illustrates the tremendous challenges involved in bringing new drugs to the market. It is estimated that of all the drug candidates that enter phase I clinical trials, only 9.6% are likely to be eventually approved for use by a regulatory agency.3 This number is a mere 5.1% for anticancer drug candidates. As for tremelimumab, trials checking the anticancer efficacy of this drug in combination with other drugs, most notably anti-PD-L1 antibodies, are currently underway.4
Written by Usha B. Nair, Ph.D.
References
- Mesothelioma in Canada. By Matt Manuey. https://www.asbestos.com/mesothelioma/canada/. Updated: June 8, 2017. Accessed: July 30, 2017.
- Maio M, Scherpereel A, Calabrò L, Aerts J, Cedres Perez S, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Taboada M, Puglisi M, Stockman PK, Kindler HL. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017 Jul 17. pii: S1470-2045(17)30446-1. doi: 10.1016/S1470-2045(17)30446-1. [Epub ahead of print] PubMed PMID: 28729154.
- Clinical Development Success Rates 2006-2015. Biotechnology Innovation Organization. https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf. 2016. Accessed: July 31, 2017.
- gov. https://clinicaltrials.gov/ct2/results?cond=&term=tremelimumab&cntry1=&state1=&recrs=. Accessed July 31, 2017.
