DREAM3R Phase 3 Trial: Durvalumab Plus Chemo Shows Signals but Falls Short of Proof

What Happened in DREAM3R

The DREAM3R trial tested whether adding durvalumab (Imfinzi), a PD-L1 checkpoint inhibitor, to standard platinum/pemetrexed chemotherapy would improve survival for people with unresectable pleural mesothelioma.

The trial was well-designed. It built on two successful Phase 2 studies that showed the combination exceeded activity benchmarks. But DREAM3R opened for enrollment in February 2021, directly into the pandemic, and never recovered.

Of the 480 patients needed for statistical power, only 174 were enrolled. The trial was stopped early.

Trial Results

Outcome	Durvalumab + Chemo (n=114)	Chemo Alone (n=60)
Median overall survival	21 months	18 months
Median progression-free survival	8 months	7 months
Objective response rate	58%	35%

The hazard ratio for overall survival was 0.92, with a wide confidence interval (0.63 to 1.36). The progression-free survival hazard ratio was 0.70, suggesting a 30% reduction in risk of progression. Neither reached statistical significance.

Why the Trial Fell Short

Three factors converged against DREAM3R.

The pandemic. COVID-19 slowed clinical trial enrollment globally. People with mesothelioma, who are often older with compromised lung function, were particularly difficult to recruit during a respiratory pandemic.

The shifting standard of care. In October 2020, the FDA approved nivolumab plus ipilimumab (CheckMate 743) as the first immunotherapy combination for mesothelioma. Once that became available, many clinicians prescribed it off-trial rather than randomizing patients to a chemo-only control arm.

Protocol changes. In response, DREAM3R amended its design to add a nivolumab/ipilimumab arm. But the change came too late to rescue enrollment.

Dr. Anna Nowak of the University of Western Australia, who presented the results at ESMO 2025, said it plainly: “Due to the early stopping of DREAM3R, it is unlikely that the study question will ever be answered.”

What the 58% Response Rate Means

The response rate stands out. At 58%, it was notably higher than the 35% in the chemo-only arm and higher than what either CheckMate 743 (40%) or KEYNOTE-483 (52%) achieved.

This doesn’t prove durvalumab plus chemo is superior. But it signals that the combination has real activity, and Dr. Nowak suggested the high response rate could be explored in neoadjuvant (pre-surgery) settings, where tumor shrinkage before an operation could improve outcomes.

How This Fits With Current Treatment Options

People newly diagnosed with pleural mesothelioma now have two FDA-approved first-line immunotherapy options.

Trial	Drugs	Median OS	HR	FDA Approved
CheckMate 743	Nivolumab + ipilimumab	18.1 months	0.73	October 2020
KEYNOTE-483	Pembrolizumab + chemo	17.3 months	0.79	September 2024
DREAM3R	Durvalumab + chemo	21 months	0.92 (NS)	No

KEYNOTE-483 effectively answered the question DREAM3R was asking. Both tested whether adding a checkpoint inhibitor to chemotherapy improves survival. KEYNOTE-483, with 440 patients, had the statistical power to confirm the benefit. DREAM3R, with 174, did not.

Trial Details

• Full name: DREAM3R (DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma)
• Registration: NCT04334759
• Sponsors: University of Sydney, PrECOG, ECOG-ACRIN Cancer Research Group
• Funding: AstraZeneca
• Principal Investigator: Dr. Peey Sei Kok (University of Sydney)
• Results presented: ESMO 2025 (Berlin)