First-line durvalumab plus chemotherapy prolongs OS in malignant pleural mesothelioma
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The addition of durvalumab to chemotherapy appeared to confer a significant OS benefit as initial treatment for unresectable malignant pleural mesothelioma, according to study results presented during the ASCO20 Virtual Scientific Program.
“Pemetrexed plus cisplatin is the only FDA-approved systemic treatment for malignant pleural mesothelioma,” Patrick M. Forde, MD, thoracic oncologist at Johns Hopkins University, said during a presentation. “In the Australian DREAM trial, researchers showed the [immunoglobulin G1] anti-PD-L1 antibody durvalumab [Imfinzi, AstraZeneca] had an [objective response rate] of 48% and 6-month PFS of 57%. We are now reporting our results of the U.S.-based PrE0505 trial.”
The single-arm phase 2 study by Forde and colleagues included 55 patients (median age, 68 years; range, 35-83; 81.8% men) with previously untreated, unresectable malignant pleural mesothelioma who received treatment at 15 U.S. sites between 2017 and 2018. Histologic subtypes included epithelioid (75%), biphasic (11%), sarcomatoid (13%) and desmoplastic (2%).
Patients received 1,120 mg durvalumab combined with 500 mg/m² pemetrexed and 75 mg/m² cisplatin every 3 weeks for six cycles, followed by 1,120 mg durvalumab every 3 weeks for up to 1 year among those with stable disease.
OS served as the primary endpoint. Researchers monitored dose-limiting toxicities among the first 15 patients. Toxicity, objective response by modified RECIST, PFS and correlative analyses served as secondary endpoints. Exploratory objectives included baseline tumor PD-L1 expression and intratumoral CD8 T-cell density, whole genome sequencing tumor-normal pairs and immunologic analyses.
Median follow-up was 20.6 months, by which time 29 deaths had occurred. Median duration of durvalumab treatment was 12 months.
More than half (56.4%) of patients achieved partial response, 40% had stable disease and one patient had primary progressive disease.
Results showed median OS of 20.4 months (95% CI, 13-28.5), compared with 12.4 months among a historical control cohort treated with the pemetrexed/cisplatin regimen. Researchers reported OS rate of 87.2% (95% CI, 75.1-93.7) at 6 months, 70.4% (95% CI, 56.3-80.7) at 1 year and 44.2% (95% CI, 30.2-57.3) at 2 years.
Median PFS was 6.7 months. PFS rates were 69.1% at 6 months, 16.4% at 1 year and 10.9% at 2 years.
More than half (56.4%) of patients achieved partial response, 40% had stable disease and one patient had primary progressive disease.
In an exploratory analysis, researchers found tumors harbored an average tumor mutational burden of 22 somatic sequence alterations and varying levels of aneuploidy.
“When we correlated these results with OS, we did not observe a significant association between PD-L1 tumor expression and either OS or PFS. Equally, we did not observe an association between CD8 intratumoral infiltration and either PFS or OS,” Forde said.
The combination was well-tolerated with no unexpected toxicities.
“The phase 3 PrE0506/DREAM3R trial is planned to begin this year in the United States and Australia and will evaluate durvalumab plus chemotherapy vs. chemotherapy alone,” Forde said.
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Forde PM, et al. Abstract 9003. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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