AZ’s Dato-DXd misses survival endpoint in lung cancer trial
Susan Galbraith, executive vice-president, Oncology R&D, AstraZeneca
The overall survival (OS) data has come in from the TROPION-Lung01 study of AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan (Dato-DXd) in lung cancer – and the result likely isn’t what they were hoping for.
The TROP2-directed antibody-drug conjugate (ADC) has already been filed for approval by the FDA as a treatment for advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) in adults who have undergone prior systemic therapy based on progression-free survival data from the study, with a decision due in December.
In the latest update, AZ and Daiichi Sankyo said the OS data “numerically favoured” Dato-DXd, but did not reach statistical significance in the final analysis. However, they said that the totality of the results from the study supports marketing applications for the drug, which are also under review in Europe and other world markets.
AZ’s head of oncology R&D, Susan Galbraith, pointed out that Dato-DXd is the only investigational therapy to show a “clinically meaningful” survival improvement in these patients compared to docetaxel, currently a go-to option in patients who have failed prior targeted drugs or immunotherapies.
PFS is often used as a primary endpoint in cancer studies as it delivers an earlier readout and means drugs can be made available to patients more quickly, but it doesn’t always follow that extending the time to disease progression tracks with longer survival – and the TROPION-Lung01 data is another example of that.
Whether OS data should be a pre-requisite for new cancer drugs staying on the market in the long-term is a matter for debate, with some arguing that staving off disease progression is a key concern for patients, and it can be hard to demonstrate OS in a realistic timeframe with recent advances in the efficacy of cancer treatment. Others, meanwhile, say that relying on PFS means patients may think a treatment is more effective than it actually is.
The FDA and other regulators have increasingly been prepared to give accelerated approval to new cancer drugs based on PFS data, thanks in part to the rapid development of new therapies for cancer in recent years. However, there have been signs that the US agency may be shifting its thinking and placing greater emphasis on showing an OS benefit in a subsequent confirmatory trial – something that was achieved in less than half of drugs granted accelerated approval by the FDA between 2013 and 2017 in a recent analysis.
According to Daiichi Sankyo’s head of R&D, Ken Takeshita, the OS trend in TROPION-Lung01 should be considered in the context of the PFS data and a more than doubling in the overall response rate and duration of response compared to docetaxel.
“[This] data will support our ongoing discussions with regulatory authorities globally to potentially bring datopotamab deruxtecan to patients as quickly as possible and mark another step forwards in creating new standards of care for patients with cancer,” he said.
Dato-DXd is in other studies looking at its potential as a first-line therapy in NSCLC, which if positive could provide an opportunity to demonstrate a benefit for the drug on both PFS and OS, as well as moving it into earlier use.
The ADC is also under a parallel review for unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer who have received prior systemic therapy for unresectable or metastatic disease, based on the results of the TROPION-Breast01 study.
AZ licensed rights to Dato-DXd in July 2020 for $1 billion upfront, plus up to $5 billion in regulatory and sales milestones. It was the second major licensing deal between the two companies, coming after a $6.9 billion deal for HER2-directed ADC Enhertu (trastuzumab deruxtecan) in the previous year.
