Dato-DXd Increases Intracranial Responses/PFS in NSCLC With Brain Mets

The median CNS PFS with Dato-DXd was 5.0 months vs 3.0 months with docetaxel in patients with NSCLC who have brain metastases.

Results from a post-hoc analysis of the phase 3 TROPION-Lung01 trial (NCT04656652) shared at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer demonstrated that datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) yielded numerical increases to intracranial activity in patients with advanced or metastatic non–small cell lung cancer (NSCLC) who have brain metastases.1

At the August 30, 2024, data cutoff, findings from the study demonstrated that patients who received Dato-DXd (n = 38) experienced a median central nervous system (CNS) progression-free survival (PFS) of 5.0 months (95% CI, 3.5-not estimable [NE]) compared with 3.0 months (95% CI, 1.3-6.6) among those who received docetaxel (n = 30; unstratified HR, 0.48; 95% CI, 0.23-0.98). The 3-month CNS PFS rates were 77% and 48%, respectively, and the 6-month CNS PFS rates were 41% and 29%, respectively.

“In this post-hoc analysis of TROPION-Lung01, intracranial response and PFS showed numerical improvement vs docetaxel,” Elvire Pons-Tostivint, MD, PhD, of the Department of Medical Oncology at the University Hospital of Nantes in France, wrote in the presentation. “Dato-DXd demonstrated intracranial activity in patients with advanced or metastatic NSCLC and brain metastases, consistent with previous studies of DXd antibody-drug conjugates in multiple solid tumors.”

In June 2025, Dato-DXd was granted accelerated approval by the FDA for the treatment of adult patients with locally advanced EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy.2 The regulatory decision was supported by prior data from TROPION-Lung01 and the phase 2 TROPION-Lung05 trial (NCT04484142).

What Were the Key Design and Baseline Patient Characteristics of TROPION-Lung01?

TROPION-Lung01 was an open-label study that enrolled patients with stage IIIB, IIIC, or IV NSCLC.1 Eligible patients also needed to have an ECOG performance status of 0 or 1 and have not received prior docetaxel. Those with clinically inactive, asymptomatic brain metastases were eligible for enrollment.

Patients without actionable genomic alterations needed to have received 1 to 2 prior lines of therapy, including platinum-based chemotherapy and an anti–PD-(L)1 monoclonal antibody. Those with actionable genomic alterations, consisting of EGFR, ALK, NTRK, BRAF, ROS1, MET exon 14 skipping, and/or RET alterations, needed to have received 1 to 2 prior approved targeted therapies, platinum-based chemotherapy, and at least 1 anti–PD-(L)1 monoclonal antibody.

Patients were randomly assigned 1:1 to receive Dato-DXd at 6 mg/kg every 3 weeks or docetaxel at 75 mg/m2 every 3 weeks. Stratification occurred based on disease histology, actionable genomic alterations, the inclusion of an anti–PD-(L)1 monoclonal antibody in the most recent prior therapy, and region.

The dual primary end points were PFS by blinded independent review committee (BICR) per RECIST 1.1 criteria and overall survival (OS). CNS overall response rate (ORR), disease control rate (DCR), and PFS by CNS BICR per CNS RECIST criteria, as well as percentage change from baseline in the sum of diameters in measurable brain metastases, were also assessed in the post-hoc analysis.

At baseline, patients in the Dato-DXd and docetaxel arms were a median age of 65.5 years (range, 35-81) and 57.5 years (range, 34-77), respectively. Most patients in both arms had an ECOG performance status of 1 (71% vs 63%), nonsquamous histology (82% vs 83%), and did not have actionable genomic alterations (68% vs 60%). The median times from diagnosis to random assignment were 14.4 months (range, 3.0-87.0) and 20.6 months (range, 3.4-73.1), respectively.

What Were the Additional CNS Efficacy Data from the TROPION-Lung01 Study?

Additional findings from the post hoc analysis revealed that patients with untreated brain metastases or disease progression after radiotherapy with CNS measurable disease who received Dato-DXd (n = 16) achieved a CNS confirmed ORR of 38% (95% CI, 15%-65%) and a CNS confirmed DCR of 88% (95% CI, 62%-98%). The CNS confirmed complete response (CR), partial response (PR), and stable disease rates were 6%, 31%, and 50%, respectively.

In the docetaxel arm (n = 11), the CNS confirmed ORR was 0% (95% CI, 0%-29%), and the CNS confirmed DCR was 36% (95% CI, 11%-69%). No patients achieved a CNS CR or PR, and 36% experienced CNS stable disease.

There was a benefit in terms of CNS PFS in favor of the Dato-DXd arm among patients with nonsquamous histology (n = 56; HR, 0.37; 95% CI, 0.16-0.83), EGFR-unmutated disease (n = 46; HR, 0.51; 95% CI, 0.21-1.27), and EGFR-mutated disease (n = 22; HR, 0.33; 95% CI, 0.09-1.20). Patients with squamous histology (n = 12) did not experience a CNS PFS benefit with Dato-DXd (HR, 1.81; 95% CI, 0.30-11.02).

“Limitations [of this post-hoc analysis] include small numbers in some subgroups, high censoring due to missing CNS imaging, and on-treatment scans only [being] required for patients with baseline brain metastases,” Pons-Tostivint and her coauthors wrote in conclusion.

References

1. Pons-Tostivint E, Okamoto I, Ahn MJ, et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients with advanced/metastatic NSCLC in TROPION-Lung01. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA10.01.
2. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed September 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer