Astrazeneca and Daiichi’s big reveal disappoints

High level results on datopotamab raise safety and efficacy concerns, putting billion-dollar sales forecasts at risk.

The stakes could not have been much higher for Daiichi Sankyo and Astrazeneca ahead of the Tropion-Lung01 readout. The trial represents the first pivotal test of datopotamab deruxtecan, an antibody-drug conjugate that has attracted multibillion-dollar sales forecasts in the wake of the partners’ $6bn licensing deal.

Today’s cautiously worded press release, which omitted any actual numbers but included the admission of patient deaths, knocked confidence in the project’s potential. True, the trial is not over, with one co-primary met and data on the other, overall survival, still immature. But datopotamab needs to impress on these measures for any hope of meeting huge commercial expectations.

Should toxicity prove to be worse than feared, strong efficacy becomes even more important. The safety fear here is interstitial lung disease, a known problem for Daiichi Sankyo’s ADCs. The Her2-directed Enhertu carries a boxed warning about ILD, and this side-effect has also been seen in earlier datopotamab studies, albeit without causing deaths.

At Asco this year a 3% grade 3 ILD rate was revealed in the first-line Tropion-Lung02 trial, with no grade 4 or 5 events, the latter equating to death. Tropion-Lung01, the trial toplined today, was conducted in a later second-line non-small cell lung cancer setting, with datopotamab pitted against docetaxel.

“Some Grade 5 events were observed” in Tropion-Lung01, the partners said today; Astrazeneca had not replied to Evaluate Vantage’s request for more detail at time of press. The company has previously maintained that ILD is a bigger problem in more heavily pre-treated patients, a statement that seems to be supported by this disclosure and the Asco data.

Patients in Tropion-Lung01 had already failed first-line targeted agents and, in some cases, chemo as well. At this stage of NSCLC further treatment options are limited, a factor that always shifts the benefit-risk equation for interventions under consideration. But until datopotamab’s exact toxicity profile emerges, it is hard to know the extent to which this finding might impact its future.

Astrazeneca’s shares fell as much as 7% in London on the news, which came after markets had closed in Japan.

Safety concerns were compounded by the partners' muted description of efficacy. At an interim analysis datopotamab demonstrated a statistically significant improvement in progression-free survival versus docetaxel, they said, but the absence of the words “clinically meaningful” was taken to mean an underwhelming absolute benefit had been seen.

Docetaxel is thought to generate around a four-month PFS benefit in a second-line setting, and analysts had estimated that datopotamab needed to beat this by at least two months for a statistical hit on that primary endpoint. A much more pronounced benefit was expected, however, with some reckoning the ADC could double docetaxel’s benefit.

Overall survival data were not mature at this analysis though an early trend was observed in favour of datopotamab, the partners said. Much now relies on that measure moving into statistical, and clinical, significance. 

Europe’s biggest cancer meeting, Esmo, which takes place in October, is thought a likely venue for a more detailed presentation of this data. While the exact benefit and risks here remain crucial to know, this is a worrying first reveal. 

With six further phase 3 trials across lung and breast cancer ongoing, Astra and Daiichi have a lot riding on datopotamab. Tropion-Breast01 should also read out later this year, and this result just got a lot more important.

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