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In the phase 3 DREAM3R trial (NCT04334759, ACTRN12620001199909), first-line durvalumab (Imfinzi) plus chemotherapy demonstrated consistent overall survival (OS), progression-free survival (PFS), and objective response rates (ORR)benefits in advanced pleural mesothelioma as in previous phase 2 trials. However, slow accrual and standard-of-care practice changes created inconclusive results and leave unanswered questions.¹

Data were presented at the 2025 European Society for Medical Oncology (ESMO) Congress. Durvalumab and chemotherapy yielded a median OS of 21 months (95% CI, 18–27) vs 18 months for chemotherapy alone (95% CI, 14–30) for a HR of 0.92 (95% CI, 0.63–1.36; stratified log-rank P =.9). Median PFS were 8 months (95% CI, 8–10) with the combination vs 7 months (95% CI, 6–8) with chemotherapy alone (HR, 0.70; 95% CI, 0.5–0.98; P =.20). ORRs were 58% and 35%, respectively (P =.005).

The safety profiles of chemotherapy with or without durvalumab were consistent with the known profiles of the agents. Fatigue, nausea, and anemia were the most common adverse events (AEs) in both arms.

What Was the Rationale and Design of the DREAM3R Trial?

Durvalumab was assessed in the phase 2 DREAM (ACTRN12616001170415) and PrE0505 (NCT02899195). In these studies, durvalumab showed promising activity in combination with pemetrexed and either cisplatin or carboplatin chemotherapy.

The phase 3 DREAM3R study randomized patients 2:1 to receive durvalumab 1500 mg every 3 weeks plus chemotherapy every 3 weeks for 4 to 6 cycles, followed by durvalumab maintenance 1500 mg every 4 weeks until progressive disease or unacceptable toxicity, or chemotherapy every 3 weeks for 4 to 6 cycles. Accrual started in February 2021.

However, the results of the CheckMate 743 study (NCT02899299) published in 2021 showed that nivolumab (Opdivo) and ipilimumab (Yervoy) significantly improved OS vs chemotherapy.² As the standard of care in pleural mesothelioma had changed, the study design changed to incorporate a nivolumab/ipilimumab arm, and randomization changed to 1:1 durvalumab/chemotherapy or physician’s choice of nivolumab/ipilimumab or chemotherapy.¹ At this ESMO Congress, only data from the durvalumab and chemotherapy cohorts were presented.

A total of 114 patients received chemotherapy and durvalumab and 60 patients received chemotherapy alone. The study’s primary end point was OS. Secondary end points included PFS, ORR, and AEs.

What Are the Next Steps?

During her presentation, Anna Nowak, MD, deputy vice chancellor at the University of Western Australia, noted that, while DREAM3R was a well-designed study, due to the early stopping of DREAM3R, it is unlikely that the study question will ever be answered.

“The key limitation is that slow accrual led to early stopping, and this slow accrual was no doubt, an artifact, partly of the global pandemic, but also then of a change of clinical practice as a result of the of the CheckMate 743 study and subsequent regulatory approval and standard clinical care use,” Nowak explained. “These design modifications add complexity to the interpretation of this clinical trial, and of course, chemotherapy alone would no longer be considered standard of care.”

Nowak did note that the high objective tumor response and control observed with chemotherapy and durvalumab raised the potential for future testing in the neoadjuvant setting. Additionally, correlative biomarkers that were collected from DREAM3R are also under ongoing analysis.

Further, Nowak emphasized the importance of timely activation of randomized phase 3 trials after positive phase 2 trials “is critically important to seize the window of opportunity for accrual and provide reliable answers.” Nowak added that, “the reasons for the delay in starting this trial were multifactorial.”

DISCLOSURES: Nowak declared participation on AstraZeneca Data Safety Monitoring Board, board membership on Cancer Council Western Australia, position on Cancer Australia Advisory Council, and president-elect of the International Mesothelioma Interest Group.

REFERENCES:

1. Nowak A. Primary results of DREAM3R: DuRvalumab (MEDI4736) with chemotherapy as first line treatment in advanced pleural Mesothelioma – A phase 3 Randomised trial. Presented at: 2025 ESMO Congress; October 17–20, 2025; Berlin, Germany. Abstract LBA104.

2. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021 Jan 30;397(10272):375-386. doi: 10.1016/S0140-6736(20)32714-8. Epub 2021 Jan 21.

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Hong Kong investor CK Infrastructure, whose overture for Thames Water was spurned earlier this year, has called on the UK to renationalise the troubled utility, warning that an unsatisfactory bidding process has led to a plan that imperils the company.

Potential bidders for Thames Water, which is struggling under nearly £20bn of debt, were “excluded” from making an offer, according to a complaint by CKI to the sector regulator, Ofwat, earlier this month and seen by the Financial Times.

KKR, the private equity firm that Thames Water selected as its preferred bidder to take it over, walked away in June. That has left Britain’s largest water company in the hands of its creditors, which include the hedge fund Elliott Management and the US private capital firm Apollo Global Management.

CKI accused the creditors — who have said they would publicly list Thames Water and write down its debt by 25 per cent in exchange for leniency on fines and targets — of short-termism, in an explosive intervention to Ofwat.

The Hong Kong-based firm slams the creditors’ plan as a “high-risk proposition that gives rise to unnecessary risk of further failures”.

“Only a single consortium is allowed to take part [in the rescue process], including distressed debt hedge funds who lack tangible operating experience in the water sector and who so far appear to be aiming for an early exit and payout in March 2030, with Thames Water’s future then passed to someone else,” CKI said in the Ofwat letter, signed by Andrew Hunter, deputy managing director of CK Infrastructure’s UK business.

CKI, which owns Northumbrian Water, added that it “would willingly put our plan to the test against that of others”, if the government temporarily renationalises Thames Water.

The Sunday Times reported that CKI had written to Ofwat.

The regulator is currently mulling the creditors’ proposal, which would see them take over the business formally in exchange for £3.15bn equity, a writedown of the debt and a stock market listing as soon as 2030.

Hunter warned that the creditors are not injecting sufficient cash and that the additional debt is being loaned at “high” interest rates, suggesting that an even larger proportion of customers’ cash will go towards servicing the borrowings.

If the creditor plan does not go ahead, Thames Water — which provides water and sewerage services to 16mn households in London and the south east — could become the first water company in England to be temporarily renationalised under the government’s special administration regime.

The intervention by CKI throws down the gauntlet to the government, which has insisted that it favours a “market-led” solution while refusing to comment on the creditors’ proposals.

The special administration regime, or SAR, is designed to ensure that essential utilities keep running if a company fails. A special administrator — a private company — would be brought into stabilise and restructure the business ahead of a sale to new owners or renationalisation.

CKI alleged in the letter that bidding was far from market-led, given that KKR was given exclusivity and that the process has not reopened since the private equity firm walked away.

CKI’s letter goes on to claim that the creditors’ request for leniency on fines and pollution targets creates a “moral hazard” and that CKI would seek no such special treatment.

CKI and Ofwat declined to comment.

The Department for the Environment, Food and Rural Affairs said: “The company remains financially stable, but we have stepped up our preparations and stand ready for all eventualities, including applying for a Special Administration Regime if that were to become necessary.”

The creditors’ consortium said on Sunday that it had “put forward a comprehensive plan which restores the company’s financial resilience and delivers a stretching operational turnaround led by an experienced world-class board.”

It countered that CKI had not put in a “viable” proposal for Thames Water, and that its plan to invest in infrastructure would have “slowed the turnaround and significantly delayed a return to compliance” and “alienated the UK’s debt markets for water companies”.

Thames Water referred queries to the creditor consortium.