First-line combination of an antibody–drug conjugate plus immunotherapy shows promise in non-small cell lung cancer

As presented at the ESMO Targeted Anticancer Therapies (TAT) Congress 2025 (Paris, 3–5 March), the combination of the TROP-2-directed antibody–drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) with durvalumab or with durvalumab plus carboplatin led to confirmed objective response rates of 53.3% and 56.8%, respectively, in the TROPION-Lung04 phase Ib trial (Abstract 8O). The results are from an updated analysis of two cohorts of treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations who received Dato-DXd plus durvalumab either without carboplatin (cohort 2; n=15) or with carboplatin (cohort 4; n=37).

Disease control rates were more than 85% in both cohorts and responses were observed in squamous and non-squamous histologies, and across PD-L1 expression levels. Median progression-free survival (PFS) was 7.3 months (95% confidence interval [CI] 2.0–29.5 months) in cohort 2 and 8.7 months (95% CI 5.6–10.1 months) in cohort 4.

In the primary endpoint analysis, safety profiles were consistent with those expected from the individual agents. Grade ≥3 treatment-emergent adverse events occurred in 60.0% of patients in cohort 2 and 70.3% in cohort 4, most commonly anaemia and neutropenia in cohort 4 (both 24%). There was one case in each cohort of grade ≥3 adjudicated treatment-related interstitial lung disease/pneumonitis.

While immune checkpoint inhibitors have improved outcomes for untreated patients with NSCLC without actionable genomic alterations, most patients eventually experience disease progression (Ther Adv Med Oncol. 2020:12:1758835920937902). Building on the efficacy seen with Dato-DXd alone compared with chemotherapy in pre-treated patients in the TROPION-Lung01 phase III study (J Clin Oncol. 2025;43:260–272), a subgroup analysis of the TROPION-Lung02 phase I trial showed signs of antitumour activity with Dato-DXd in combination with pembrolizumab in treatment-naïve patients (J Clin Oncol. 2024;42(16_suppl):8617). The benefits of an ADC alone and as combination therapy have also been demonstrated in the first-line setting in the DESTINY-Breast07 phase Ib/II trial presented at ESMO TAT 2025.

Whether early-phase efficacy and safety with ADC–immunotherapy combinations will translate into positive phase III findings in the first-line NSCLC setting is now being tested in several trials including TROPION-Lung07 (NCT05555732), TROPION-Lung08 (NCT05215340), AVANZAR (NCT05687266) and EVOKE-03 (NCT05609968).