Clinical Trial Results for Tremelimumab in Mesothelioma Treatment

Overview of Malignant Mesothelioma

A recent phase 2b clinical trial assessed the efficacy of the anticancer drug tremelimumab for treating relapsed malignant mesothelioma. The findings suggest that the drug may not be effective against this aggressive cancer. Malignant mesothelioma is a rare cancer affecting the pleural, peritoneal, or pericardial membranes, primarily caused by asbestos exposure. Pleural mesothelioma arises from inhaling asbestos fibers, while peritoneal mesothelioma can result from inhaling or swallowing these fibers. Pericardial mesothelioma, an exceedingly rare form, occurs when asbestos fibers become lodged in the heart cavity. Unfortunately, there is no cure for mesothelioma, and the overall prognosis remains poor. In Canada, the incidence of mesothelioma is around two cases per 100,000 individuals annually, one of the highest rates globally, largely due to historical asbestos mining activities in Quebec and British Columbia. Despite the closure of the last asbestos mines in 2011, its use and export have not been banned.

Current Treatments for Malignant Mesothelioma

Standard treatment for advanced pleural and peritoneal mesothelioma typically involves a combination of cisplatin and pemetrexed. The addition of bevacizumab to this regimen has been shown to enhance survival rates in newly diagnosed pleural mesothelioma patients. However, there are no effective second-line treatments available for those with relapsed or refractory mesothelioma, leading to a generally poor prognosis for these patients.

Study Design and Methods

The clinical trial, funded by AstraZeneca, investigated tremelimumab as a second-line treatment for relapsed or refractory mesothelioma. Conducted at 105 centers across 19 countries, the study’s findings were published in The Lancet Oncology. Eligible patients, aged 18 and older with confirmed surgically untreatable pleural or peritoneal malignant mesothelioma, had experienced disease progression despite one or two prior systemic treatments.

Participants were stratified based on their recurrence risk, tumor site, and line of therapy before being randomly assigned to receive either tremelimumab or a placebo. A total of 380 patients received intravenous tremelimumab at a dosage of 10 milligrams per kilogram of body weight every four weeks for a total of seven administrations, followed by dosing every 12 weeks until treatment was halted due to adverse events, disease progression, non-compliance, or other reasons. The placebo group consisted of 189 patients who followed the same regimen with matching placebo treatments. Periodic assessments included lab tests and tumor imaging via CT scans.

The primary outcome measured was overall survival, defined as the time from the study’s commencement until the patient’s death. Secondary outcomes included 18-month overall survival, treatment response, progression-free survival, as well as the safety and tolerability of tremelimumab.

Study Findings and Outcomes

The study results indicated that tremelimumab did not improve overall survival. At the last data collection point, 80% of patients in the tremelimumab group had died, compared to 81% in the control group. The median survival times were 7.7 months for the tremelimumab group and 7.3 months for the placebo group. Additionally, no significant differences were observed between the two groups regarding secondary outcomes. Notably, a greater proportion of patients receiving tremelimumab experienced treatment-emergent adverse events, including dyspnea, diarrhea, and colitis.

Challenges in Drug Development

The results of this phase 2b trial highlight the significant challenges associated with bringing new drugs to market. Research indicates that only about 9.6% of drug candidates entering phase I trials are likely to receive regulatory approval, with this figure dropping to 5.1% for anticancer drugs. Ongoing trials are investigating the efficacy of tremelimumab in conjunction with other therapies, particularly anti-PD-L1 antibodies.

Author Information

Written by Usha B. Nair, Ph.D.

References

1. Mesothelioma in Canada. By Matt Manuey. https://www.asbestos.com/mesothelioma/canada/. Updated: June 8, 2017. Accessed: July 30, 2017.
2. Maio M, et al. 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. doi: 10.1016/S1470-2045(17)30446-1.
3. 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.
4. https://clinicaltrials.gov/ct2/results?cond=&term=tremelimumab&cntry1=&state1=&recrs=. Accessed July 31, 2017.