A single-arm, phase 2 study of the programmed cell death ligand 1 (PD-L1) inhibitor, durvalumab, in combination with pemetrexed plus cisplatin/carboplatin in systemic therapy-naive patients with malignant pleural mesothelioma not eligible for curative surgery demonstrated promising results, according to findings published in the Journal of Thoracic Oncology.1
In a previously conducted phase 3 study of chemo-naive patients with pleural mesothelioma who were not candidates for curative surgery, the median time to progression was 3.9 months for those treated with cisplatin alone and 5.7 to 7 months for patients receiving a combination of cisplatin plus pemetrexed.2 While immune checkpoint inhibitor therapy is emerging as a potentially beneficial treatment in this setting, there remains a need for effective systemic regimens for this population of patients.
In this multicenter, open-label, single-arm study conducted in Australia (Australia New Zealand Clinical Trials Registry: ACTRN12616001170415), adult patients with malignant pleural mesothelioma were treated with 6 cycles of cisplatin/carboplatin, pemetrexed, and durvalumab, with continuation of durvalumab for another 12 cycles following completion of chemotherapy. Tumor response to treatment and progression were evaluated using mRECIST criteria for malignant pleural mesothelioma as well as iRECIST criteria specific for patients receiving immunotherapy-based therapy.
The primary study endpoint was progression-free survival (PFS) at 6 months by mRECIST, with secondary study end points including objective response rate (ORR) by mRECIST and iRECIST, PFS by mRECIST and iRECIST, overall survival, and safety.
Of the 54 patients included in the primary analysis, 65%, 78%, and 50% completed 6 cycles of platinum-based chemotherapy, 6 cycles of pemetrexed, and at least 12 cycles of durvalumab, respectively.
At 6 months, 57% of patients were alive without evidence of disease progression.
At a median follow-up of 28.2 months, median PFS was 6.9 months and 7.0 months by mRECIST and iRECIST, respectively.
Confirmed ORRs were 48% by both mRECIST and iRECIST, although no complete responses were achieved.
Of note, pseudoprogression was observed in 2 patients, although for purposes of evaluation these patients were included in the group who experienced progressive disease at 6 months since progression was the first recorded response.
Regarding this finding, the study authors noted that “the potential for pseudoprogression should be considered in future clinical trials, with an allowance for treatment to continue beyond early progression if the patient is showing symptom improvement.”
Median OS was 18.4 months, with 65% and 37% of patients alive at 1 and 2 years, respectively.
Of the 5 patients who died while on study, none of the deaths were considered to be related to the study drugs. The most common grade 3/4 adverse events (AEs) were neutropenia, nausea, and anemia which were reported in 13%, 11%, and 7% of patients, respectively, and grade 3/4 immune-related AEs were reported in 15% of patients.
In their concluding remarks, the study authors noted that “the DREAM trial met its criteria for activity and safety, showing that the combination of durvalumab and chemotherapy for mesothelioma is worthy of further research in a proposed [randomized] phase 3 trial, with outcomes from chemo-immunotherapy that accord with emerging evidence of the efficacy of this strategy in other thoracic cancers.”
- Nowak AK, Lesterhuis WJ, Kok P-S, et al. Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in. Lancet Oncol. 2020;21:1213-1223. doi:10.1016/S1470-2045(20)30462-9
- Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636 –2644.