H&O How much enthusiasm is there for antibody-drug conjugates (ADCs) in lung cancer?
BL There is a tremendous amount of enthusiasm for this class of compounds in lung cancer. We have already witnessed the success of trastuzumab deruxtecan (T-DXd; Enhertu, Daiichi-Sankyo/AstraZeneca) in both human epidermal growth factor receptor 2 (HER2)-mutated and HER2-overexpressed lung cancer. This agent has led the way, and we are trying to repeat its success with other compounds. The success of T-DXd is predicated on having a firm biomarker, and the success of future ADCs depends on finding more relevant biomarkers. The foundation of success for other drugs in lung cancer has been biomarker enrichment, and ADCs are no exception.
H&O Which ADC targets are the most promising in lung cancer?
BL We already know that the HER2 space has been a success for ADCs in lung cancer, on the basis of T-DXd. If you look at the landscape right now for emerging ADCs, c-MET–directed ADCs and TROP2-directed ADCs hold the most promise. The US Food and Drug Administration (FDA) approved telisotuzumab vedotin (Emrelis, AbbVie) in May 2025 for patients with advanced non–small cell lung cancer (NSCLC) that harbors c-MET overexpression. Even more recent is the June 2025 approval of datopotamab deruxtecan (Dato-DXd; Datroway, Daiichi Sankyo/AstraZeneca) as the first TROP2-directed therapy for patients with previously treated advanced epidermal growth factor receptor (EGFR)-mutated NSCLC. Additional c-MET–directed and TROP2-directed therapies are being tested.
H&O What are the most important studies looking at ADCs in lung cancer?
BL The studies that solidified the use of T-DXd in HER2-mutated lung cancer are DESTINY-Lung01 and DESTINY-Lung02.1,2 In addition, the phase 2 DESTINY-PanTumor02 study showed durable clinical benefit with T-DXd among pretreated patients who had a variety of HER2-expressing tumors.3 The greatest benefit was observed in the immunohistochemistry (IHC) 3+ population.
The phase 2 TROPION-Lung05 and TROPION-Lung01 studies solidified the use of Dato-DXd in the EGFR-positive space and led to its approval.4 We also have the phase 2 LUMINOSITY trial, which led to the approval of telisotuzumab vedotin in patients with previously treated c-MET protein–overexpressing, EGFR wild-type advanced NSCLC.5
Just as important as the studies showing efficacy for these agents are the ones showing that ADCs are not efficacious in certain settings in lung cancer. In the TROPION-Lung01 study,6 Dato-DXd was not superior to docetaxel as second-line therapy in an all-comer population, and the EVOKE-01 study showed the same thing for sacituzumab govitecan (Trodelvy, Gilead),7 underscoring the need for enrichment and biomarker strategies.
H&O What is the pipeline looking for regarding next-generation ADCs and lung cancer?
BL We have an incredible pipeline, and I have several points I would like to make about it. First, many of the ADCs that have been approved for use in previously treated patients are moving to the front line. For example, we hope to see positive data regarding the use of T-DXd and Dato-DXd in the front line for HER2-mutated lung cancer. In addition, at the 2025 American Society of Clinical Oncology Annual Meeting, I presented some early data on first-line Dato-DXd in lung cancer from the phase 1 TROPION-Lung02 study.8 In this phase 1b/2 trial, 96 patients with previously untreated advanced NSCLC received Dato-DXd plus pembrolizumab (Keytruda, Merck) either with or without platinum chemotherapy. Results in both groups were good, with a median objective response rate of 54%, median duration of response of 20.1 months, and median progression-free survival of 11.2 months. Importantly, we evaluated a novel biomarker, TROP2 normalized membrane ratio, that may better tell us which patients will respond to TROP2-directed therapies.
We are awaiting results from 2 confirmatory phase 3 studies of Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy as first-line treatment for advanced NSCLC: TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340). In addition, several EVOKE studies, including EVOKE-02, are looking at first-line sacituzumab govitecan in patients with advanced or metastatic NSCLC (NCT05186974).
We are also looking at newer types of ADCs. These include bispecific ADCs, in which the agent binds to 2 targets on a cell, and biparatopic ADCs, in which the agent binds to 2 separate epitopes on the same antigen of a cell surface protein. We should see many of these sophisticated new ADCs emerge over the next 5 to 10 years. Other potential approaches to ADC development are the use of dual payloads, or novel payloads or linkers to make an agent more potent or stable. Researchers are even investigating the use of immune-stimulating ADCs, which bind to a cell surface antigen to engage immune effector cells.
H&O Which bispecific ADCs are in development?
BL One bispecific ADC that has gained a lot of interest is BL-B01D1, or iza-bren, which received FDA Breakthrough Therapy designation in August. Iza-bren is an inhibitor of both EGFR and HER3, and early results are very encouraging for patients with EGFR-mutant lung cancer. In a phase 2 study that was presented at the 2025 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, a combination of iza-bren and osimertinib (Tagrisso, AstraZeneca) as first-line therapy demonstrated a 100% objective response rate after a median follow-up of 12.8 months in 154 patients with EGFR-mutated locally advanced or metastatic NSCLC.9
H&O What are the main toxicity challenges with ADCs, and how do they differ from those of conventional treatments?
BL The toxicities are contingent on the specific ADC. With Dato-DXd, we need to be especially mindful of stomatitis. Inflammation and ulcers around the mouth can make it very difficult for patients to eat and swallow. An additional 2 toxicities of special concern that occur with Dato-DXd, T-DXd, and sacituzumab govitecan are interstitial lung disease and ocular toxicity, the latter of which can lead to eye pain and dryness.
In addition to these adverse events of special interest, we see the same toxicities that we see with traditional chemotherapy, such as cytopenia, alopecia, and gastrointestinal toxicity. The adverse events tend to be less severe than what we see with traditional chemotherapy, but they still occur.
H&O How do you select patients who are most likely to benefit from ADC therapy?
BL Biomarker selection is extremely important with ADC therapy. We know that Dato-DXd and sacituzumab govitecan, the TROP2-targeting ADCs, do not work any better than the traditional standard of care when they are given to patients on an all-comer basis. Each of the ADCs that are currently approved for use in lung cancer has its niche, which is predicated on biomarker enrichment. T-DXd is only for patients with HER2-mutated or HER2-overexpressed lung cancer, Dato-DXd is only for those with EGFR-mutated lung cancer, and telisotuzumab vedotin is only for patients with c-MET–overexpressing lung cancer.
H&O How do ADCs fit into the sequencing of treatments alongside immunotherapy and targeted agents?
BL Sequencing is complicated and depends on the ADC. T-DXd is currently approved as a second-line treatment after chemotherapy for patients whose tumors harbor HER2 mutations, although we expect to have data on the first-line use of this agent. Another complicating variable is the tyrosine kinase inhibitor zongertinib (Hernexeos, Boehringer Ingelheim), which received FDA approval in August for use in patients with HER2-mutated lung cancer. Should we use T-DXd followed by zongertinib, or zongertinib followed by T-DXd? We are still trying to iron out the sequencing strategies. Telisotuzumab vedotin is currently used as a second- or third-line therapy in MET-overexpressed NSCLC, and Dato-DXd is approved for use only after EGFR tyrosine kinase inhibition and chemotherapy, so we cannot use either of these agents as frontline therapy. We need to be mindful of where these drugs fit into the treatment continuum.
In addition to the sequencing strategy for various types of drugs, we need to consider the possibility of sequencing ADCs with other ADCs. That is a consideration that we expect to encounter more often in the future, when more ADCs are available.
H&O What are the biggest breakthroughs needed to advance ADC therapy in lung cancer?
BL I would say that 2 breakthroughs are needed to advance ADC therapy in lung cancer. First is biomarker enrichment; we want to know how to better identify those patients who are more likely to receive benefit from these drugs. Biomarker identification has been elusive for many ADCs, and I think that is where we need to see a lot of work. Second is the need to mitigate toxicity better. Although these drugs may appear on the surface to be magic bullets, we know that they produce collateral damage—both the same adverse events that we see with traditional cytotoxic chemotherapy and adverse events of special interest. We need to learn more about how to monitor patients better and mitigate some of these toxicities.
Disclosures
Dr Levy has served as a consultant and on the advisory boards for Merck, Daiichi Sankyo, AstraZeneca, and Johnson & Johnson.
References
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2. Jänne PA, Goto Y, Kubo T, et al. Final analysis results and patient-reported outcomes from DESTINY-Lung02-a dose-blinded, randomized, phase 2 study of trastuzumab deruxtecan in patients with HER2-mutant metastatic NSCLC [published online July 30, 2025]. J Thorac Oncol. doi:10.1016/j.jtho.2025.07.129.
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8. Levy BP, Paz-Ares LG, Lin CC, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC) [ASCO abstract 8501]. J Clin Oncol. 2025;43(16)(suppl).
9. Zhou F, Wang Q, Wang H, et al. Phase II study of iza-bren (BL-B01D1) in combination with osimertinib in patients with EGFR-mutated locally advanced or metastatic non–small cell lung cancer. Presented at: IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 2114.