Analysts predict sales of Dato-DXd could hit $5.9 billion in 2030, but the antibody-drug conjugate faced a series of setbacks in 2024.
As it awaits a breast cancer ruling set for the end of this month, AstraZeneca and Daiichi Sankyo’s next big antibody-drug conjugate prospect is entering a critical period. The partners are on track to win approval for datopotamab deruxtecan (Dato-DXd) in two cancers and post pivotal data that could establish the TROP2-directed ADC as a new standard of care. Yet a 2024 marked more by setbacks than successes has raised doubts about whether the asset can fulfill its promise.
Dato-DXd is the latest ADC from the teams that developed Enhertu, AstraZeneca and Daiichi Sankyo’s blockbuster HER2 cancer drug. Like Gilead Sciences’ Trodelvy, Dato-DXd is designed to deliver a cytotoxic payload to cells that express TROP2, a receptor overexpressed in some breast, gastric, lung and ovarian cancers.
The size of the opportunities in breast and, in particular, lung cancer led Evaluate analysts to name the ADC as the second biggest potential drug launch of 2025 and predict sales could hit $5.9 billion in 2030. The coming year will go some way toward showing whether Dato-DXd can live up to that forecast, or whether the setbacks experienced in 2024 were early signs of a bleaker future for the drug.
Dato-DXd’s Tough Year
The series of setbacks began in May 2024, when AstraZeneca and Daiichi Sankyo reported Dato-DXd’s failure to improve overall survival (OS) in a Phase III lung cancer trial. September brought a double dose of bad news, with the full lung cancer data disappointing analysts and the ADC failing to improve OS in breast cancer. AstraZeneca and Daiichi Sankyo closed out the year by withdrawing filings for approval in lung cancer on both sides of the Atlantic, although the partners resubmitted for a subgroup of patients in the U.S.
Dale Shuster, head of global precision medicine at Daiichi Sankyo, discussed the withdrawal of the FDA filing at the company’s Science and Technology Day in December. Shuster said the Phase III lung cancer trial “was not reviewed favorably with the FDA.” The project needs “a predictive biomarker to segregate the subpopulation for those that benefit the most from Dato-DXd,” Shuster said. Regulatory feedback also informed the decision to pull the European filing.
The withdrawals deprived AstraZeneca and Daiichi Sankyo of the chance to win approval in a broad population of patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have tried other systemic therapies. Instead, the partners are seeking FDA approval in patients with EGFR-mutated NSCLC, a subpopulation in which they saw longer OS in a pooled analysis of patients across two trials.
AstraZeneca and Daiichi Sankyo are yet to share a decision date for the resubmitted filing, but Jefferies analysts said in a December note to investors that mid-2025 seems likely. By then, the FDA may have approved Dato-DXd in breast cancer. The deadline for that decision is Jan 29. Jefferies analysts wrote that they expect the FDA to approve Dato-DXd in breast cancer, but added that the indication “is a relatively small opportunity.”
The partners need to “secure approvals in lung cancer in order to meet the market’s multi-billion-dollar expectations for this asset,” the analysts said.
If Dato-DXd does secure a first approval in lung cancer, the competition may include Daiichi Sankyo and Merck’s HER3-directed ADC patritumab deruxtecan (HER3-DXd). Dato-DXd and HER3-DXd have both shown efficacy in EGFR-mutated NSCLC, raising the possibility that Daiichi Sankyo will have competing products. Mark Rutstein, head of global oncology clinical development at Daiichi Sankyo, discussed how that could play out at the Science and Technology Day, noting that the ADCs have different safety profiles and may be used in sequence. Daiichi Sankyo is working to understand the sequencing.
“We have datasets in flight to try to understand DXd resistance in general, so if it’s target mediated, if it’s payload mediated. We are very focused on understanding . . . if sequencing would be feasible and then how we might go about that,” Rutstein said.
The Most Important Event
In a year with two approval decisions looming, the Jefferies analysts see topline results from the AVANZAR trial as “the most important piece of news for Dato . . . and by extension the most important event for Daiichi.”
AVANZAR is testing Dato-DXd in combination with AstraZeneca’s checkpoint inhibitor Imfinzi in first-line NSCLC. It is part of a broader, multi-study push to position the ADC as the new standard of care in NSCLC. Analysts expect to see topline AVANZAR data in the second half of 2025. Jefferies analysts wrote in their December note to investors that they are optimistic the two FDA decisions and AVANZAR data will “turn out well.”
AstraZeneca and Daiichi Sankyo could face competition in this area from Gilead’s rival ADC Trodelvy. The biotech stopped development in second-line or later NSCLC but is continuing first-line development in collaboration with Merck, which is testing its checkpoint inhibitor Keytruda in combination with Trodelvy in first-line NSCLC in a Phase III trial.
As well as opening up the first-line NSCLC market, AVANZAR is a chance to validate a TROP2 QCS NMR biomarker that could unlock other opportunities. According to Shuster, a retrospective analysis of Phase III data showed patients positive for the biomarker were more likely to respond to Dato-DXd. The biomarker data have boosted confidence at the companies even as other events have sown doubts among observers, as Susan Galbraith, executive vice president of oncology research and development at AstraZeneca, said on an earnings call in November.
“I think the overall profile that we have with Dato-DXd and the potential to maximize the benefit using the biomarker in broader patient populations is something that we’re now probably increasingly confident about given the latest data that have emerged,” Galbraith said.
Daiichi Sankyo’s roadmap includes a pivotal trial that will compare Dato-DXd to docetaxel in second-line lung cancer patients identified using the biomarker.
