AstraZeneca, Daiichi reveal Dato-DXd's overall survival failure before FDA decision

AstraZeneca and Daiichi Sankyo's TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd), has not shown significant improvement in overall survival (OS) in patients with non-small cell lung cancer (NSCLC) when compared to the chemotherapy agent docetaxel. This outcome joins a series of similar results from other pharmaceutical companies that have attempted to surpass the efficacy of docetaxel in treating this condition.

Docetaxel has been a standard treatment for second-line metastatic NSCLC for over two decades. Over the years, several companies, including Bristol Myers Squibb with Opdivo, Roche with Tecentriq, and Merck & Co. with Keytruda, have tried to demonstrate superior OS outcomes but have not succeeded. Gilead Sciences also made an attempt with its TROP2-directed ADC, Trodelvy, but the results were similarly disappointing.

Dato-DXd, which operates through the same mechanism as Trodelvy, initially offered some hope due to improvements in progression-free survival (PFS) and response rates, goals that Gilead had missed. AstraZeneca was optimistic that Dato-DXd's stable linker and proven warhead might make it the superior treatment option. However, the median OS was 12.9 months for patients treated with Dato-DXd, compared to 11.8 months for those treated with docetaxel. While AstraZeneca described this as a "clinically meaningful trend toward improving OS," the difference was not statistically significant.

In a prespecified subgroup of patients with nonsquamous NSCLC, the results were slightly better. The median OS in this group was 14.6 months for Dato-DXd and 12.3 months for docetaxel, but again, the difference did not achieve statistical significance. Although the hazard ratio favored Dato-DXd in both the overall population and the nonsquamous subgroup, the upper confidence intervals exceeded one, indicating that docetaxel could still outperform Dato-DXd in some cases.

Despite the setback in OS data, AstraZeneca and Daiichi have provided the survival data to regulatory bodies that are evaluating Dato-DXd for approval. The FDA accepted a filing for the drug in February for the treatment of patients with previously treated nonsquamous NSCLC. Although a positive OS result would have bolstered their case, AstraZeneca and Daiichi can still present other favorable data to support the approval of Dato-DXd.

Besides the PFS improvements, which served as a co-primary endpoint alongside OS, the companies can highlight the tolerability and safety profile of Dato-DXd. Fewer patients in the ADC treatment arm experienced severe adverse events or discontinued treatment compared to those on docetaxel. Although stomatitis and nausea were more common with Dato-DXd, the incidence of diarrhea and hematologic disorders was higher among patients treated with docetaxel.

In summary, while Dato-DXd did not outperform docetaxel in overall survival for NSCLC patients, the drug has shown other potential advantages, particularly in terms of progression-free survival and safety. These aspects will play a key role as AstraZeneca and Daiichi pursue regulatory approval.

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