Antibody-Drug Conjugates in Lung Cancer: The Tip of the Iceberg

Antibody-drug conjugates (ADCs) have become increasingly relevant in cancer care over the past decade, with 2 FDA approvals in 2025 shedding light on their growing role in lung cancer.^1-3

ADCs consist of three components: an antibody that binds to tumor cell surface antigens; a chemical linker; and a cytotoxic payload. Fundamentally, ADCs are “targeted” delivery of chemotherapy to cells expressing the tumor-associated antigen, but some payloads can diffuse into adjacent antigen-negative tumor cells, addressing the challenge of intratumoral heterogeneous antigen expression through this bystander effect.¹Unfortunately, such “off-target” as well as “on-target, off-tumor” actions create novel, at times severe, ADC toxicities.⁴

Three ADCs are currently FDA-approved for different subpopulations of non–small cell lung cancer (NSCLC).

Fam-trastuzumab deruxtecan -nxki (T-DXd; Enhertu) targets HER2, carrying a topoisomerase I inhibitor payload.⁵ T-DXd received FDA accelerated approval in 2022 for use in patients with previously treated, advanced HER2-mutant NSCLC.⁶ The recommended dose for this indication is 5.4 mg/kg intravenously (IV) every 21 days.⁵ In the phase 2 DESTINY-Lung02 trial (NCT04644237), 102 patients with HER2-mutated advanced NSCLC received T-DXd at this dose and achieved an overall response rate (ORR) of 50% (95% CI, 39.9%-60.1%).⁷ Further analysis also suggests a 50% (95% CI, 23%-77%) intracranial response in patients with baseline brain metastases treated at the 5/4 mg/kg dose (n = 14).⁸ The most common grade 3 treatment-related adverse effects (TRAEs) were hematologic or gastrointestinal, although these rarely led to treatment discontinuation.⁷ Drug-related interstitial lung disease (ILD) occurred in 14.9% of patients, although grade 3 or higher events were rare (2%). Importantly, pneumonitis and ILD represented the most frequent causes of drug discontinuation at 5.9% and 5% of patients, respectively.

In the phase 2 DESTINY-Lung01 trial (NCT03505710), T-DXd given at 5.4 mg/kg produced an ORR of 34.1% (95% CI, 20.1%-50.6%) in patients with previously treated NSCLC with HER2 high expression (3+) by immunohistochemical (IHC) staining (n = 41).⁹ Although this represented less robust activity compared with NSCLC harboring HER2 mutations, these data contributed to the 2024 FDA pan-approval of T-Dxd for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.^5,10 The 5.4-mg/kg dose was also recommended in this approval.⁵

The National Comprehensive Cancer Network (NCCN) Guidelines list T-DXd as a preferred subsequent therapy option in both HER2-mutant and HER2-overexpressing (IHC 3+) NSCLC.¹¹ T-DXd is actively being studied as frontline treatment for advanced NSCLC with a HER2 mutation or HER2 overexpression; the phase 3 DESTINY-Lung04 trial (NCT05048797) is evaluating the ADC as monotherapy, and the phase 3 DESTINY-Lung06 study (NCT06899126) is evaluating T-DXd in combination with pembrolizumab (Keytruda) and chemotherapy.^12,13 Evaluation of T-DXd in the neoadjuvant space for both HER2 alterations has also begun in the phase 2 HERCULES trial (NCT07428044).¹⁴

Telisotuzumab vedotin-tllv (Emrelis) targets the c-Met protein and carries a microtubule inhibitor payload.¹⁵ It received accelerated FDA approval in 2025 for adult patients with locally advanced or metastatic nonsquamous NSCLC harboring high c-Met protein overexpression (≥50% of tumor cells with IHC 3+) who have received a prior systemic therapy.³ Dosing is 1.9 mg/kg IV every 2 weeks.¹⁵ In the multi-cohort phase 2 LUMINOSITY trial (NCT03539536), evaluable patients with nonsquamous, EGFR wild-type, high c-Met expressing NSCLC (n = 84) experienced an ORR of 35% (95% CI, 24%-46%). Among patients (n = 88) with intermediate c-Met protein expression (≥25% to <50% of tumor cells with IHC 3+), the ORR 22.9% (95% CI, 14.4%-33.4%).¹⁶

In a safety analysis, peripheral sensory neuropathy was a prevalent AE (30.2% of patients). Furthermore, neuropathy led to treatment discontinuation in nearly 10% of patients (peripheral sensory, 7.0%; peripheral sensorimotor, 2.3%). Pulmonary toxicity was less frequent, but still notable. Pneumonitis occurred in 10.5% of patients (grade ≥3, 2.9%), and this led to drug discontinuation in 7.6% of patients.

NCCN guidelines currently list telisotuzumab vedotin as a recommended subsequent therapy option for patients with EGFR wild-type, nonsquamous NSCLC with high c-MET expression.¹¹ The confirmatory phase 3 TeliMET NSCLC-01 trial (NCT04928846) is enrolling patients with intermediate, as well as high, c-MET expression, indicating that a lower c-MET expression threshold remains of interest for future approvals.¹⁷ A dose-optimization phase 2 study (NCT06568939) is also ongoing, comparing 1.6 mg/kg vs 1.9 mg/kg.¹⁸

Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) combines a TROP2-targeted antibody with a topoisomerase I inhibitor payload, and this ADC received accelerated FDA approval in 2025 for the treatment of adult patients with locally advanced or metastatic, EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy.^2,19 Dosing is 6 mg/kg IV every 21 days.¹⁹ The phase 3 TROPION-Lung01 (NCT04656652) and phase 2 TROPION-Lung05 (NCT04484142) trials evaluated the activity of Dato-DXd in patients with relapsed/refractory NSCLC, and, surprisingly, high TROP2 expression did not meaningfully enrich for responders.^20,21Conversely, a pooled analysis of patients with EGFR-mutated NSCLC (n = 117) showed a promising ORR at 43% (95% CI, 34%-52%.²¹ In this pooled analysis, oral mucositis or stomatitis occurred in 69% of patients (grade ≥3, 9%). Ocular surface AEs were observed in 32% of patients, but rarely were grade 3 or higher (3%); none led to drug discontinuation. Drug-related ILD or pneumonitis, although uncommon (any-grade, 4%; grade ≥3, <1%), was still the toxicity most frequently leading to drug discontinuation.

Per NCCN Guidelines, Dato-DXd is a preferred subsequent therapy for patients with EGFR-mutant adenocarcinoma.¹¹ Ongoing trials are investigating Dato-DXd in combination with osimertinib (Tagrisso) as frontline treatment in the phase 3 TROPION-Lung14 trial (NCT06350097), as well as the addition of Dato-DXd in combination with ongoing osimertinib post-progression in the phase 3 TROPION-Lung15 trial (NCT06417814).^22,23 Importantly, there are also frontline trials evaluating Dato-DXd, in combination with immune checkpoint inhibitors in patients with EGFR wild-type NSCLC, including the phase 3 TROPION-Lung08 trial (NCT05215340) evaluating Dato-DXd plus pembrolizumab, and the phase 3 TROPION-Lung10 trial (NCT06357533) investigating Dato-DXd plus rilvegostomig.^24,25

TROP2-directed ADCs are also being explored in small cell lung cancer (SCLC), with a persistent need to identify a reliable biomarker, since TROP2 expression levels have not been strongly associated with responses to these agents.²⁶ There is also ongoing development of novel ADCs in SCLC, concurrently with the expansion of ADCs in the NSCLC space.^1,26 This ADC revolution depends on the integration of old and new target antigens, cytotoxic payloads, and ongoing refinement of linker technology.^1,27

For example, patritumab deruxtecan (HER3-DXd) has shown activity in TKI-resistant, EGFR-mutated NSCLC and is moving into phase 3 studies in this space, including the HERTHENA-Lung02 trial (NCT05338970).^28,29

Another HER3-targeting ADC with a topoisomerase I inhibitor payload, BNT326 (YL202), is in an ongoing phase 1/2 study (NCT07070232) evaluating its safety and activity in patients with NSCLC with or without targetable mutations.³⁰ A bispecific ADC, izalontamab brengitecan targets both EGFR and HER3, with a topoisomerase 1 inhibitor payload, with intriguing response rates observed thus far in heavily pretreated patients with EGFR-mutated NSCLC.^31,32

B7-H3–targeting agents are being increasingly explored in SCLC.²⁶ Ifinatamab deruxtecan (I-DXd) has a topoisomerase I inhibitor payload and demonstrated an ORR of 48% with a central nervous system ORR of 46.2% in previously treated patients with extensive stage SCLC (ES-SCLC), making it the focus of the phase 3 Ideate-Lung02 trial (NCT06203210) in this population.^26,33 Combination trials using I-DXd as frontline treatment for ES-SCLC, as well as the exploration of other B7-H3–targeted ADCs, are ongoing in early phase studies.²⁶

SEZ6-targeting ADCs are also gaining traction. ²⁶ ABBV-706, with a topoisomerase I inhibitor payload, is being more extensively studied as monotherapy for previously treated patients with ES-SCLC in a phase 3 trial (NCT07365241), as well as in combination with atezolizumab (Tecentriq) in the frontline setting in the phase 2 SEZanne trial (NCT07155174).^34,35

ADCs represent a growing field in lung cancer for which the 2025 approvals are just the tip of the iceberg.

Well is an assistant professor of hematology, medical oncology, and palliative care in the University of Wisconsin (UW) Department of Medicine at UW Carbone Cancer Center in Madison.

References

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2. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed April 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
3. FDA grants accelerated approval to telisotuzumab vedotin-tllv for non-small cell lung cancer with high c-Met protein overexpression. FDA. May 14, 2025. Accessed April 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-non-small-cell-lung-cancer-high-c-met-protein-overexpression
4. Nguyen TD, Bordeau BM, Balthasar JP. Mechanisms of ADC toxicity and strategies to increase ADC tolerability. Cancers. 2023;15(3). doi:10.3390/cancers15030713
5. Enhertu. Prescribing information. FDA. Updated December 2025. Accessed April 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761139s038s042lbl.pdf
6. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed April 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung-cancer
7. 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. J Thorac Oncol. 2025;20(12):1814-1828. doi:10.1016/j.jtho.2025.07.129
8. Jänne PA, Planchard D, Goto K, et al. Trastuzumab deruxtecan for ERBB2-mutant metastatic non-small cell lung cancer with or without brain metastases: a secondary analysis of randomized clinical trials. JAMA Netw Open. 2025;8(11):e2543107. doi:10.1001/jamanetworkopen.2025.43107
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10. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed April 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
11. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 5.2026. NCCN. March 13, 2026. Accessed May 1, 2026. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
12. A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for unresectable, locally advanced/​metastatic non-small cell lung cancer with HER2 mutations. ClinicalTrials.gov. Updated April 3, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT05048797
13. Study of trastuzumab deruxtecan, pembrolizumab, and platinum-based chemotherapy in first-line HER2 overexpressing non-small cell lung cancer (DESTINY-Lung06). ClinicalTrials.gov. Updated January 8, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06899126
14. A study of trastuzumab deruxtecan in people with non-small cell lung cancer. ClinicalTrials.gov. Updated February 23, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07428044
15. Emrelis. Prescribing information. FDA. Updated May 2025. Accessed April 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761384s000lbl.pdf
16. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein-overexpressing advanced nonsquamous EGFR-wildtype non-small cell lung cancer in the phase II LUMINOSITY trial. J Clin Oncol. 2024;42(25):3000-3011. doi:10.1200/JCO.24.00720
17. A study to assess disease activity and adverse vents of intravenous (IV) telisotuzumab vedotin compared to IV docetaxel in adult participants with previously treated non-squamous non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated April 14, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT04928846
18. A study to assess adverse events and how intravenously (IV) infused telisotuzumab vedotin (ABBV-399) moves through the body as a monotherapy in adult participants with previously treated non-squamous non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated February 23, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06568939
19. Datroway. Prescribing information. FDA. Updated January 2025. Accessed April 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761394s000lbl.pdf
20. Ahn MJ, Tanaka K, Paz-Ares L, et al. 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(3):260-272. doi:10.1200/JCO-24-01544
21. Ahn MJ, Lisberg A, Goto Y, et al. A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC. J Thorac Oncol. 2025;20(11):1669-1682. doi:10.1016/j.jtho.2025.06.002
22. Phase III, open-label study of first-line osimertinib with or without datopotamab deruxtecan for EGFRm locally advanced or metastatic non-small cell lung cancer (TROPION-Lung14) ClinicalTrials.gov. Updated November 17, 2025. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06350097
23. A study to investigate the efficacy and safety of Dato-DXd with or without osimertinib compared with platinum based doublet chemotherapy in participants with EGFR-mutated locally advanced or metastatic non-small cell lungcCancer (TROPION-Lung15). ClinicalTrials.gov. Updated March 2, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06417814
24. Study of Dato-DXd plus pembrolizumab vs pembrolizumab alone in the first-line treatment of subjects with advanced or metastatic NSCLC without actionable genomic alterations (TROPION-Lung08). ClinicalTrials.gov. Updated January 7, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT05215340
25. Phase III, open-label, study of first-line Dato-DXd in combination with rilvegostomig for advanced non-squamous NSCLC with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations (TROPION-Lung10). ClinicalTrials.gov. Updated March 16, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06357533
26. Monaca F, Gomez-Randulfe I, Torres-Jiménez J, et al. Antibody-drug conjugates in small-cell lung cancer: DLL3, B7-H3, TROP2 and beyond. J Thorac Oncol. Published online April 13, 2026. doi:10.1016/j.jtho.2026.103726
27. Yang L, Ma J, Liu B, et al. Recent advances in peptide linkers of antibody-drug conjugates. J Med Chem. 2025;68(17):18099-18113. doi:10.1021/acs.jmedchem.5c01500
28. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/JCO.23.01476
29. HERTHENA-Lung02: a study of patritumab deruxtecan versus platinum-based chemotherapy in metastatic or locally advanced EGFRm NSCLC after failure of EGFR TKI therapy. ClinicalTrials.gov. Updated January 31, 2025. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT05338970
30. A clinical study to test if an investigational treatment called BNT326 is safe and potentially beneficial when used alone or in combination with other investigational treatments such as BNT327, for people with advanced malignant tumors. ClinicalTrials.gov. Updated March 12, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07070232
31. Ma Y, Huang Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study. Lancet Oncol. 2024;25(7):901-911. doi:10.1016/S1470-2045(24)00159-1
32. Hong SD, Wang YS, Zhao HY, et al. Izalontamab brengitecan (Iza-bren; BL-B01D1), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, for patients with EGFR-mutated NSCLC: pooled analysis of phase I and phase II trials. Ann Oncol. Published online January 27, 2026. doi:10.1016/j.annonc.2026.01.009
33. A study of ifinatamab deruxtecan versus treatment of physician's choice in subjects with relapsed small cell lung cancer (IDeate-Lung02). ClinicalTrials.gov. Updated March 2, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT06203210
34. A study to evaluate adverse events and change in disease activity of intravenous ABBV-706 versus standard of care in adult participants with relapsed/​refractory small cell lung cancer. ClinicalTrials.gov. Updated January 26, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07365241
35. A study to evaluate the optimal dose, adverse events and change in disease activity of intravenous ABBV-706 in combination with atezolizumab versus standard of care as first-line treatment in adult participants with previously untreated extensive stage small cell lung cancer (SEZanne). ClinicalTrials.gov. Updated April 14, 2026. Accessed April 25, 2026. https://clinicaltrials.gov/study/NCT07155174