AstraZeneca and Daiichi Sankyo’s TROP2-directed antibody-drug conjugate (ADC) has failed to improve overall survival (OS) in non-small cell lung cancer (NSCLC), extending the list of molecules that have fallen short in head-to-head fights with docetaxel.
It is more than 20 years since investigators established the chemotherapy agent docetaxel as the go-to treatment option for second-line metastatic NSCLC. In that time, studies of drugs involving Bristol Myers Squibb’s Opdivo, Roche’s Tecentriq and Merck & Co.’s Keytruda have all failed to better the OS achieved by docetaxel.
Gilead Sciences tried to topple the chemotherapy using its TROP2-directed ADC Trodelvy, only to join the list of OS failures. AstraZeneca and Daiichi’s ADC datopotamab deruxtecan (Dato-DXd) has the same mechanism as Trodelvy. But improvements in progression-free survival (PFS) and response rates, endpoints that Gilead missed, and AstraZeneca’s belief that Dato-DXd’s stable linker and proven warhead make it best in class offered encouragement that this time might be different.
It wasn’t. Median OS was 12.9 months in the Dato-DXd cohort and 11.8 months in the docetaxel group. AstraZeneca called the result a “clinically meaningful trend toward improving OS,” but the difference fell short of statistical significance.
The gap between the two cohorts was wider in the prespecified nonsquamous subgroup, where the OS figures for Dato-DXd and docetaxel were 14.6 months and 12.3 months, respectively, but the difference again missed the threshold for statistical significance. The hazard ratio favored Dato-DXd in the overall population and the subgroup. Yet, in both cases, the upper ends of the confidence intervals topped one, the threshold at which docetaxel would outperform Dato-DXd.
AstraZeneca and Daiichi have shared the OS data with regulators that are reviewing filings for approval of Dato-DXd. The FDA accepted a filing for approval in previously treated nonsquamous NSCLC in February. Adding an OS hit to the data set would have strengthened AstraZeneca and Daiichi’s hand, but the pair can cite other evidence that Dato-DXd offers advantages over docetaxel.
In addition to the hit on PFS, a co-primary endpoint with OS, the partners can point to tolerability and safety data to make the case for Dato-DXd. Fewer patients in the ADC arm had grade 3 or worse adverse events and discontinued treatment. Stomatitis and nausea were more frequent with Dato-DXd, but the incidence of diarrhea and hematologic disorders was higher on docetaxel.