Designed using Daiichi Sankyo's proprietary DXd ADC technology, Dato-DXd is one of five lead ADCs in the oncology pipeline of Daiichi Sankyo and one of the most advanced programs in AstraZeneca's ADC scientific platform. In NSCLC, the TROPION-Lung07, TROPION-Lung08, and AVANZAR Phase III trials are evaluating Dato-DXd in combination with immune checkpoint inhibitors as potential first-line treatment options for patients with advanced or metastatic disease, a strategy shaped by the results initial trials.

ASCO 2025 brought new results of TROPION-Lung01 study of received Dato-DXd + KEYTRUDA ± platinum chemotherapy as first-line therapy for advanced NSCLC. Previously, the TROPION-Lung01 study showed that the ADC can extend Progression-free Survival (PFS) in patients with pretreated disease; the new study examined its capability to be effective in the first-line setting as well. In the doublet group, 71.4% of patients had PD-L1 expression <50%, 11.9% had expression of ≥50%, and 16.7% were not evaluated for PD-L1 expression; in the triplet group, those rates were 74.1%, 18.5%, and 7.4%, respectively. 

Treatment-related adverse events (TRAEs) of Grade 3 or higher occurred in 40.5% of those receiving the doublet therapy and in 55.6% of those receiving triplet therapy. Serious TRAEs occurred in 11.9% and 22.2% of the groups; in the doublet group, 13 patients had a TRAE that led to discontinuation of the ADC, a similar rate to that seen in the triplet.

KOL insights

“Because TROPION-Lung02 was not randomized, it is difficult to make definitive conclusions. However, it raises concerns about the role of the triplet, given relatively similar efficacy and higher rates of toxicity.” – Expert Opinion

Conclusion

The ADC Dato-DXd + KEYTRUDA both with and without platinum chemotherapy was reasonably well tolerated and produced durable antitumor activity in the first-line setting in patients with advanced NSCLC, according to Phase I results from the TROPION-Lung02 trial. In November 2024, Daiichi Sankyo and AstraZeneca announced they have submitted a new BLA for accelerated approval in the US for Dato-DXd for the treatment of adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior systemic therapies, including an EGFR-directed therapy. The new BLA is based on results from the TROPION-Lung05 Phase II trial and supported by data from the TROPION-Lung01 Phase III and TROPION-PanTumor01 Phase I trials. Also, the previously submitted BLA based on the TROPION-Lung01 Phase III trial for patients with nonsquamous NSCLC was voluntarily withdrawn. 

These regulatory updates reflect a strategic pivot by Daiichi Sankyo and AstraZeneca toward more targeted patient populations and lines of therapy, emphasizing the potential of Dato-DXd in biomarker-selected and treatment-experienced settings. Continued evaluation across multiple trials will determine its future role in the evolving NSCLC treatment landscape.