ASCO 2025: TROPION-Lung02 Evaluates Frontline Dato-DXd Plus Pembrolizumab, With or Without Chemotherapy in Advanced NSCLC

Datopotamab deruxtecan (dato-DXd) plus pembrolizumab with or without platinum chemotherapy shows promise as a frontline therapy for patients with advanced non–small cell lung cancer (NSCLC), according to findings from the TROPION-Lung02 trial.

Benjamin Levy, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, in Baltimore, Maryland, presented the results at the 2025 American Society of Clinical Oncology Annual Meeting.

Dato-DXd, a trophoblast cell surface antigen 2 (TROP2)–directed antibody-drug conjugate (ADC), was tested for safety and tolerability in patients with advanced NSCLC across six cohorts. The secondary end point was efficacy.

The study enrolled 96 patients who either received Dato-DXd plus pembrolizumab alone (doublet, n=42) or with pembrolizumab plus cisplatin or carboplatin (triplet, n=54) as first-line therapy.

The median ages were similar in the doublet and triplet groups (65 and 64 years, respectively). In the doublet group, patients received treatment for a median of 9.7 months. In the triplet group, median duration of treatment was 5.8 months. Treatment is ongoing for 29% and 15% of patients, respectively.

Patients who received both regimens experienced adverse events (AEs). The most common were stomatitis (doublet, 57%; triplet, 33%) and nausea (doublet, 42%; triplet, 48%), primarily grades 1 and 2. Moreover, treatment-related serious AEs occurred in five patients in the doublet group and 12 patients in the triplet group. No deaths related to Dato-DXd were observed.

Furthermore, both regimens showed comparable objective response rates (ORRs) overall and across histologies (nonsquamous vs squamous). Overall ORR was 55% in the doublet group and 56% in the triplet group.

Patients in the doublet group showed a longer duration of response (DOR) and progression-free survival (PFS). Compared with the triplet group, patients treated with Dato-DXd plus pembrolizumab alone had better median DOR (13.7% vs 20.1%, respectively). Moreover, median PFS was 11.2 months with the doublet therapy versus 6.8 months with the triplet therapy.

“In this largest data set to date evaluating an ADC combined with an anti-PD-1/L1 agent in the 1L [first-line] setting, the combination of Dato-DXd plus pembro [pembrolizumab] treatment both with and without Pt-CT [platinum chemotherapy] elicited durable antitumor activity in pts [patients] with aNSCLC [advanced NSCLC],” the researchers said.

These findings support continued investigation of ADC-immunotherapy combinations as a frontline strategy for treating patients with advanced NSCLC, the researchers concluded.