Frontline Dato-DXd Looks Promising in NSCLC

Cancer Cell © Wellcome Collection

As a first-line treatment, the combination of datopotamab deruxtecan (Datroway; Dato-DXd) and durvalumab (Imfinzi) with or without carboplatin showed encouraging activity in patients with advanced or metastatic non–small cell lung cancer (NSCLC) with no actionable genomic alterations. These data from the TROPION-Lung04 (NCT04612751) study were presented at the European Society for Medical Oncology (ESMO) Targeted Anticancer Therapies Congress 2025 in March.

In the phase 1b, multicenter, open-label, dose escalation/confirmation and expansion TROPION-Lung04 study, patients with advanced or metastatic NSCLC were assigned to 4 cohorts. The ESMO presentation discussed results from cohorts 2 and 4 only. The study had 2 parts: sequential dose escalation and dose expansion.

In cohort 2, patients received 6 mg/kg of Dato-DXd and 1120 mg of durvalumab every 3 weeks as first-line treatment. There was 1 patient in the sequential dose escalation part and 14 patients in the dose expansion part. In cohort 4, patients received the same regimen with the addition of 4 cycles of carboplatin (area under the curve 5) every 3 weeks. In this cohort, there were 6 patients in the sequential dose escalation part and 31 patients in the dose expansion part.

Responses were observed in both squamous and nonsquamous NSCLC and across all evaluated PD-L1 levels. At the October 24, 2024, data cutoff, the confirmed objective response rate (ORR) across all patients in cohort 2, regardless of squamous or nonsquamous histology, was 53.3% (95% CI, 26.6%-78.7%). In cohort 4, this rate was 56.8% (95% CI, 39.5%-72.9%) across all patients. The ORR was then stratified by histology, with rates of 50.0% in squamous and 54.5% in nonsquamous disease in cohort 2 and 47.4% and 66.7%, respectively, in cohort 4. Across both cohorts, only 1 patient of the 4 with squamous histology in cohort 2 achieved complete response (25.0%).

The overall disease control rate (DCR) was 86.7% (95% CI, 59.5%-98.3%) in cohort 2 and 89.2% (95% CI, 74.6%-97.0%) in cohort 4. When stratified by squamous vs nonsquamous histology, the DCRs were 75.0% vs 90.9%, respectively, in cohort 2 and 89.5% vs 88.9%, in cohort 4. The median duration of response (DOR) in cohort 2 was 15.0 months (95% CI, 4.5%-28.8%) and 8.8 months in cohort 4 (95% CI, 5.8%-not evaluable). According to investigators, responses were observed across all PD-L1 expression levels.

In cohort 2, the median progression-free survival (PFS) was 7.3 months (95% CI, 2.029.5). In cohort 4, it was 8.7 months (95% CI, 5.6-10.1). Eligible patients were 18 years or older and had previously treated or treatment-naive advanced or metastatic NSCLC, an ECOG performance status of 0 or 1, and no actionable genomic alterations. PD-L1 status was not a factor in determining eligibility. The study’s primary end points were safety and tolerability; key secondary end points were DCR, DOR, ORR, and PFS assessed by investigator per RECIST v1.1.

Regarding baseline characteristics and demographics, approximately 80% of participants were men in both cohorts 2 and 4. Sixty percent of patients were White in cohort 2 and 56.8% in cohort 4; 40% and 43.2%, respectively, were Asian. The median age in cohort 2 was 63 years and 66 years in cohort 4. This was the first line of therapy for all patients across cohorts 2 and 4. In cohort 2 there were 73.3% with nonsquamous histology and 48.6% of patients in cohort 4; 20.0% and 13.5%, respectively, had a history of brain metastases.

Regarding PD-L1 expression, 33.3% of patients in cohort 2 and 43.2% in cohort 4 had a PD-L1 expression of less than 1%. In cohort 2, 26.7% of patients had a PD-L1 expression between 1% and 49%; in cohort 4, it was 32.4%. Meanwhile, PD-L1 expression of 50% or higher was observed in 40.4% of individuals in cohort 2 and 24.3% in cohort 4.

Zero patients in cohort 2 and 6 patients in cohort 4 had a tumor staging of IIIA to IIIC. In addition, 100.0% of patients in cohort 2 and 83.8% in cohort 4 had tumor staging of IVA to IVB.

Regarding safety, all patients across both cohorts experienced treatment-emergent adverse events (TEAEs). In cohort 2, 60% of patients experienced grade 3 or higher TEAEs, and 46.7% of these were treatment related. In cohort 4, 70.3% of patients experienced TEAEs, and 62.2% were treatment related. Serious AEs were observed in 46.7% of patients in cohort 2 and 51.4% in cohort 4; 40.0% and 27.0%, respectively, were treatment related.

TEAEs leading to treatment discontinuation were observed in 26.7% of patients in cohort 2 and 24.3% in cohort 4. Zero patients in cohort 2 and 2 (5.4%) in cohort 4 had TEAEs leading to death.

Stomatitis was observed in 53.3% of patients in cohort 2; 13.3% experienced grade 3 or higher. In cohort 4, stomatitis was observed in 67.6% of patients; in 8.1%, it was grade 3 or higher. Ocular surface events were observed in 26.7% of patients in cohort 2; no cases were grade 3 or higher. In cohort 4, 37.8% of patients experienced ocular surface events; 2.7% were grade 3 or higher. In cohort 2, 20.0% of patients experienced adjudicated drug-related interstitial lung disease (ILD)/pneumonitis; 6.7% were grade 3 or higher. In cohort 4, 16.2% of patients experienced adjudicated drug-related ILD/ pneumonitis; 2.7% were grade 3 or higher.

Dato-DXd is an antibody-drug conjugate that combines a humanized anti-TROP2 IgG1 monoclonal antibody with a topoisomerase I inhibitor payload connected by a plasma-stable, cleavable linker.

According to investigators, 3 trials are evaluating Dato-DXd combined with immune checkpoint inhibitor combinations, with or without chemotherapy, in the first line for patients with advanced or metastatic NSCLC without actionable genomic alterations: phase 3 AVANZAR (NCT05687266), phase 3 TROPION-Lung07 (NCT05555732), and phase 3 TROPION-Lung08 (NCT05215340).

REFERENCE:

Cuppens K, Papadopoulos K, Nishio M, et al. First-line (1L) datopotamab deruxtecan (Dato-DXd) + durvalumab ± carboplatin in advanced or metastatic non-small cell lung cancer (a/mNSCLC): results from TROPION-Lung04 (cohorts 2 and 4). Ann Oncol. 2025;10(suppl 2):1-7. doi:10.1016/esmoop/ esmoop104162