[Comment] Redefining first

Redefining first-line standards with new partners Affiliations & Notes aDivision of Medical Oncology, National Cancer Centre Singapore, Singapore bDepartment of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif 94805, France cDepartment of Medicine, Paris–Saclay University, Paris, France Article Info Publication History: Published May 29, 2026 DOI: 10.1016/S0140-6736(26)01038-X External LinkAlso available on ScienceDirect External Link Copyright: © 2026 Published by Elsevier Ltd. Download started OkAlthough antibody-drug conjugates (ADCs) have been touted as potential drugs or agents in the treatment of non-small-cell lung cancer (NSCLC), two randomised phase 3 trials evaluating the TROP2 ADCs datopotamab deruxtecan1 and sacituzumab govitecan2 did not show a significant survival benefit when compared with second-line docetaxel. Despite these initial disappointments, the ability of ADCs to modulate the tumour microenvironment has piqued interest in combining these agents with immune checkpoint inhibitors (ICIs).3 Early data from phase 2 studies conducted in the first-line setting suggested a potential increase in toxicities with this combination, and efficacy signals appeared moderate when contextualised against pivotal phase 3 chemoimmunotherapy trials.4–6 Nevertheless, the promise of biological synergism has already led to the enrolment of at least 8000 patients in ten ongoing phase 3 first-line trials for advanced wild-type NSCLC evaluating ADC-ICI with or without chemotherapy. References 1. Ahn, M-J ∙ Tanaka, K ∙ Paz-Ares, L ∙ et al., and the TROPION-Lung01 Trial Investigators Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study J Clin Oncol. 2025; 43:260-272 2. Paz-Ares, LG ∙ Juan-Vidal, O ∙ Mountzios, GS ∙ et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III EVOKE-01 study J Clin Oncol. 2024; 42:2860-2872 3. Zippelius, A ∙ Tolaney, SM ∙ Tarantino, P ∙ et al. Unveiling the molecular and immunological drivers of antibody-drug conjugates in cancer treatment Nat Rev Cancer. 2025; 25:925-944 4. Levy, B ∙ Paz-Ares, L ∙ Lin, C-C ∙ et al. Datopotamab deruxtecan plus pembrolizumab with or without platinum-based chemotherapy for advanced or metastatic NSCLC: the phase Ib TROPION-Lung02 trial J Thorac Oncol. 2026; published online March 21. https://doi.org/10.1016/j.jtho.2026.103688 5. Reck, M ∙ Patel, JD ∙ Gray, JE ∙ et al. First-line sacituzumab govitecan plus pembrolizumab in metastatic NSCLC: PD-L1 TPS less than 50% and more than or equal to 50% cohorts of the EVOKE-02 study J Thorac Oncol. 2026; 21:103509 6. Gray, JE ∙ Neal, JW ∙ Patel, JD ∙ et al. First-line sacituzumab govitecan plus pembrolizumab and carboplatin in metastatic non-small cell lung cancer: nonsquamous and squamous cohorts of the EVOKE-02 study Clin Cancer Res. 2026; published online April 10. https://doi.org/10.1158/1078-0432.CCR-25-4485 7. Xiong, A ∙ Yao, W ∙ Zheng, W ∙ et al. Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer (OptiTROP-Lung05): interim analysis of a randomised, open-label, phase 3 trial Lancet. 2026; published online May 29. https://doi.org/10.1016/S0140-6736(26)00968-2 8. Mok, TSK ∙ Wu, Y-L ∙ Kudaba, I ∙ et al., and the KEYNOTE-042 Investigators Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial Lancet. 2019; 393:1819-1830 9. Garassino, MC ∙ Gadgeel, S ∙ Speranza, G ∙ et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study J Clin Oncol. 2023; 41:1992-1998 10. Novello, S ∙ Kowalski, DM ∙ Luft, A ∙ et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study J Clin Oncol. 2023; 41:1999-2006 11. Reck, M ∙ Rodríguez-Abreu, D ∙ Robinson, AG ∙ et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥50 J Clin Oncol. 2021; 39:2339-2349 12. Houda, I ∙ Ulas, EB ∙ Hashemi, SMS ∙ et al. 1445P, a randomized phase III trial on Pembrolizumab Alone versUs pembrolizumab-chemotherapy in first LInE NSCLC (PAULIEN), results of the interim analysis Ann Oncol. 2023; 34:S821-S822 13. Izmirlieva, M FDA shows unease about marketing approval applications based on single-country trials. Pharmaceutical Technology. March 11, 2022 https://www.pharmaceutical-technology.com/pricing-and-market-access/fda-unease-marketing-approval/ Date accessed: May 20, 2026 14. Xiong, A ∙ Wang, L ∙ Chen, J ∙ et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small-cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China Lancet. 2025; 405:839-849