Advanced mesothelioma: frontline chemoimmunotherapy shows promise in DREAM trial

Lung cancer

By Mardi Chapman

16 Sep 2020

A combination of durvalumab and standard first-line chemotherapy has shown promise for the management of untreated patients with advanced mesothelioma unsuitable for surgery.

The phase 2 single-arm Australian study, published in The Lancet Oncology, is the first clinical trial reporting on the combination of a checkpoint inhibitor and standard chemotherapy in malignant pleural mesothelioma.

The DREAM study comprised 54 patients from nine Australian hospitals treated intravenously with cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg on the same day and repeated every 21 days for a maximum of six cycles.

Durvalumab was then continued as a single agent for another 12 cycles after completion of chemotherapy.

Six patients underwent a two-cycle safety run-in which found no dose-limiting toxicities.

The primary endpoint, progression-free survival at 6 months by mRECIST, was achieved by 31 patients (57%) which compares favourably to the expected 45% with standard chemotherapy.

“At a median follow-up of 28·2 months (IQR 26·5–30·2), median progression-free survival was 6·9 months (95% CI 5·5–9·0; figure 1A) by mRECIST and 7·0 months (5·7–9·0; table 2; appendix p 1) by iRECIST,” the study authors said.

There was no apparent association between tumour expression of PD-L1 and progression-free survival (6·3 months with PD-L1-negative tumours v 6·6 months for patients PD-L1-positive tumours).

The study found the confirmed objective tumour response was 48% according to both mRECIST and iRECIST.

The median overall survival was 18·4 months, with a 12-month overall survival of 65%) and a 24-month overall survival of 37%. Median time on study was 8.1 months with most patients discontinuing treatment due to disease progression (60%).

There were two unexpected cases of pseudoprogression.

Safety outcomes

Five patients (9%) had serious adverse events that were considered possibly related to durvalumab. They included renal impairment (4%), adrenal insufficiency (2%), infusion reaction (2%), and visual blurring (2%).

Twelve patients (22%) experienced immune-related adverse events, including hypothyroidism (9%), increased amylase or lipase (4%), pneumonitis (4%), adrenal insufficiency (2%), hyperthyroidism (2%) and renal impairment (2%).

The most common grade 3–4 adverse events were neutropenia (13%), nausea (11%) and anaemia (7%).

The study concluded that the trial met its criteria for activity and safety, supporting the need for further research.

Lead author Professor Anna Nowak, from the University of Western Australia, told the limbic a phase 3 study had been developed in collaboration with the US group PrECOG, had ethics approval, and was expected to commence within a few months.

However it was possible that some people might not wait for the findings.

“Checkpoint inhibitors have been demonstrated to have modest response rates in the second line, so we would expect that some people are self-funding checkpoint blockade at the moment,” she said.

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