Frontline Durvalumab/Chemotherapy Shows Promising Activity in Mesothelioma

In the first reported trial of an immune checkpoint inhibitor with chemotherapy in patients with treatment naïve malignant pleural mesothelioma, durvalumab (Imfinzi) in combination with cisplatin and pemetrexed (Alimta) demonstrated clinical activity and tolerability, according to a study published in The Lancet Oncology.¹

“There is already emerging evidence of the effectiveness of the treatment in other thoracic cancers, but before these results, we didn’t know it could also be successful in mesothelioma,” Anna Nowak, MD, PhD, the director at The University of Western Australia National Centre for Asbestos Related Diseases and lead author of the study, said in a statement.²

In the multicenter, single-arm, open-label, phase 2 DREAM trial (ACTRN12616001170415) 54 patients were evaluated out of the 55 enrolled between December 28, 2016 and September 27, 2017. After a median follow-up of 28.2 months (interquartile range, 26.5-30.2). There were 31 of the 54 patients alive and progression-free at 6 months (57% by modified Response Evaluation Criteria in Solid Tumors for immunotherapy [iRECIST]; 95% CI, 44%-70%). There was a median progression-free survival (PFS) of 7 months (range, 5.7-9.0) and a 12-month PFS of 22% (95% CI, 14%-37%).

The PFS rate by modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) was 54% at 6 months (95% CI, 42%-69%). The median PFS was 6.9 months (range, 5.5-9.0 months). The overall survival rate was 85% and 65% at 6 and 12 months, respectively. The median was 18.4 months (range, 13.1-24.8 months).

The objective tumor response by mRECIST showed there was partial response in 26 (48%) patients, stable disease in 21 (39%) patients, and progressive disease in 7 (13%) patients. The median duration of response was 5.6 months (range, 4.8-9.9 months).

Grade 3/4 adverse events that were most common in the trial were neutropenia in 7 patients (13%), nausea in 6 patients (11%), and anemia in 4 patients (7%). Overall, there were 60 serious adverse events in 29 patients on the study. Investigators believed 5 of these events may have been related to durvalumab; 2 had renal impairment, 1 had adrenal insufficiency, 1 had an infusion reaction, and 1 had visual blurring. Although 5 patients died while on the study treatment, these deaths were not attributed to the combination.

“There is a strong unmet need to improve available therapies in mesothelioma and the results of this trial suggest chemoimmunotherapy could become a valuable treatment in this disease,” Nowak said in a press release.

This trial was conducted in 9 hospitals throughout Australia. Patients need to be 18 years of age or older and have histologically confirmed malignant pleural mesothelioma. Eligible patients could not be suitable for surgery for their cancer. They also needed an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and measurable disease by mRECIST for mesothelioma which had not been treated with systemic therapy. Any histologic subtype was eligible for this study.

For the first 6 patients, there was 2 cycles of treatment as a safety run-in, and there were no dose-limiting toxicities. After that, all patients received cisplatin at 75 mg/m², pemetrexed at 500 mg/m^2, and durvalumab at 1125 mg intravenously. Treatments were given on day 1 every 3 weeks for up to 6 cycles. The was an area under the curve of 5 for changing from cisplatin to carboplatin allowed on the trial, and 13 patients switched after at least 1 dose of cisplatin. Patients could continue on durvalumab for up to 12 months.

Patients on this trial had a median age of 68 (range, 61-73) and most were male (83%). There were 60% of participants with an ECOG performance status of 0, and the rest had a performance status of 1. Five patients had previous non-radical surgery. Mainly, patients had epithelioid histology (83%), and the other 17% had either biphasic, desmoplastic, or sarcomatoid histology.

The primary end point of the study was 6-month progression-free survival per mRECIST in the intention-to-treat population. The safety analysis was conducted in all patients who received one or more dose of any study drug. Secondary end points included objective tumor response rate, frequency and severity of adverse events, progression-free survival, time from first response to progression or death, and overall survival.

“In conclusion, 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 chemoimmunotherapy that accord with emerging evidence of the efficacy of this strategy in other thoracic cancers,” the investigators wrote in their discussion.

_References:

_{1. Nowak AK, Lesterhuis J, 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(9):1213-1223. doi:10.1016/S1470-2045(20)30462-9}

_{2. Combined cancer therapies most effective to treat mesothelioma. News release. The University of Western Australia. September 2, 2020. Accessed September 3, 2020. https://bit.ly/3gYGgs5}