Evolving Roles of Antibody-Drug Conjugates in the Treatment of NSCLC

The treatment of non–small cell lung cancer (NSCLC) has changed dramatically in recent years with the rise of biomarker-driven targeted therapies and immune checkpoint inhibitors (ICIs). Among the most significant innovations are antibody-drug conjugates (ADCs), which combine the precision of monoclonal antibodies with the potency of cytotoxic payloads. These agents have introduced new therapeutic options for patients with both biomarker-selected and biomarker-agnostic disease.

At the 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, Giannis Mountzios, MD, MSc, PhD, medical oncologist and director at the 4th Oncology Department and Clinical Trials Unit at the Henry Dunant Hospital Center in Athens, Greece, provided an in-depth overview of the evolving role of ADCs in NSCLC. During his presentation, Mountzios described ADCs’ structural foundations, the critical role of payload design, clinical evidence supporting approved agents, and the challenges that continue to shape their development.1

Anatomy of an ADC

A rendering of antibody–drug conjugate molecules. Image Credit: © Nasnunt - stock.adobe.com

ADCs are built from 3 key components: the antibody, the linker, and the payload, Mountzios explained. The antibody, often an IgG1 monoclonal antibody, is designed for high target specificity. Its Fc gamma domain not only helps guide the ADC to the cancer cell but also engages immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement activation, thereby conferring intrinsic anticancer properties independent of the payload.1

“Second, you have the linker, which may be either cleavable—meaning that the payload can be released outside of the cancer cells, within the tumor microenvironment and extracellular structures—or noncleavable, meaning that the payload can be released only intracellularly,” Mountzios said during the WCLC session. “Of course, this has important implications on the pharmacodynamic and pharmacokinetic properties of the ADC.”1

Finally, the payload provides the cytotoxic activity, Mountzios explained. These highly potent small molecules usually disrupt DNA structure or tubulin polymerization, inducing apoptosis.1

Beyond this classic structure, ADC technology has rapidly diversified. New classes include bispecific and biparatopic ADCs.1

“Bispecific and biparatopic ADCs are able to target 2 different antigenic epitopes, either on the same cell or in different cells. We have prodrug antibody conjugates that carry a peptide mask protecting the payload from being released outside the tumor microenvironment and allowing release through enzyme-dependent or pH-dependent mechanisms within the tumor milieu,” Mountzios explained. “We also have immune-stimulating ADCs and protein-degrader ADCs, which act through ubiquitination and proteasome degradation of the target protein of interest, and finally, dual-drug ADCs, which can carry 2 different kinds of payloads on the same ADC.”1

The Role of the Payload

Among the 3 ADC components, the payload often dictates therapeutic potency and toxicity, Mountzios noted. Payloads generally fall into 3 categories: antimicrotubule agents such as auristatins and maytansinoids, DNA-cleaving agents such as calicheamicins, and topoisomerase inhibitors such as camptothecins. The biochemical structure of the payload determines not only the mechanism of action but also the size and pharmacokinetic properties of the ADC.1

Mountzios compared payload design to aerospace engineering, where the size and orbit of a spacecraft are defined by the weight of its cargo. Similarly, the size and molecular behavior of ADCs are determined by the nature of their payload. One clinical example comes from 2 anti-TROP2 ADCs: sacituzumab govitecan (Trodelvy; Gilead Sciences), which uses the irinotecan metabolite SN-38, and datopotamab deruxtecan (Dato-DXd, Datroway; Daiichi Sankyo), which employs a deruxtecan payload approximately 10-fold more potent. Small differences in drug-to-antibody ratio further distinguish these agents, contributing to meaningful variations in efficacy and safety in clinical use, according to Mountzios.1

Mechanism of Action

The mechanism of ADC activity begins with antibody binding to a target epitope on the cancer cell surface. The ADC is then internalized, after which lysosomal degradation releases the cytotoxic payload. Once liberated, the payload interferes with DNA or tubulin, leading to cancer cell death. In addition to this direct effect, certain payloads exert a bystander effect by diffusing into neighboring tumor cells, an advantage in heterogeneously expressing cancers, but also a potential source of off-tumor toxicity.1

It is also important to note that the antibody component itself may contribute anticancer activity, independent of the payload, Mountzios explained. Through ADCC, complement-dependent cytotoxicity, and antibody-dependent phagocytosis, the antibody portion provides additional therapeutic benefit and can synergize with payload activity.1

Biomarker-Selected and Biomarker-Agnostic ADCs

ADCs can be divided into biomarker-selected and biomarker-agnostic categories. Biomarker-selected ADCs require the presence or overexpression of a specific biomarker to achieve clinical efficacy. Examples include telisotuzumab vedotin (Emrelis; AbbVie), approved for MET immunohistochemical overexpression, and trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo), approved for both HER2 mutations and HER2 protein expression. In contrast, biomarker-agnostic ADCs demonstrate efficacy across a broader population, with outcomes that appear less dependent on biomarker levels. TROP2-targeting ADCs and HER3-targeting ADCs, such as patritumab deruxtecan (HER3-DXd; Daiichi Sankyo and Merck), fall into this category. This distinction is clinically significant, as it influences both patient selection and the breadth of therapeutic applicability, according to Mountzios.1

Clinical Evidence and Regulatory Approvals

Several ADCs are now approved for the treatment of NSCLC. T-DXd received FDA accelerated approval on August 11, 2022, for HER2-mutant NSCLC after prior systemic therapy, supported by the DESTINY-Lung02 (NCT04644237) trial, which demonstrated objective response rates (ORRs) exceeding 50% and median overall survival (OS) close to 18 months.1-3 Telisotuzumab vedotin was granted accelerated approval on May 14, 2025, for patients with high c-Met protein overexpression (≥ 50% of tumor cells with strong [3+] staining) after prior systemic therapy, following encouraging results from the LUMINOSITY trial (NCT03539536).1,4,5 In the same year on June 23, Dato-DXd gained accelerated approval for pretreated EGFR-mutant (EGFRm) NSCLC based on pooled analyses from TROPION-Lung05 (NCT04484142) and TROPION-Lung01 (NCT04656652), which reported an ORR of 43% and median OS of 15.6 months.1,6

Not all late-stage trials have succeeded. The HERTHENA-Lung02 study (NCT05338970) of patritumab deruxtecan was discontinued after failing to demonstrate OS benefit.1,7 These mixed results emphasize both the promise and the hurdles in bringing ADCs successfully from early-phase studies into clinical practice, Mountzios explained.1

Sacituzumab Tirumotecan: A Case Study in EGFRm NSCLC

Sacituzumab tirumotecan represents one of the latest additions to the ADC landscape. In the phase 2 OptiTROP-Lung03 trial (NCT05631262),8 patients with pretreated EGFRm NSCLC were randomized to receive either sacituzumab tirumotecan or docetaxel.1 Results were favorable for the ADC, with a median progression-free survival of 6.9 months compared with 2.8 months for docetaxel. ORRs were significantly higher with sacituzumab tirumotecan, and OS benefits remained evident even after accounting for crossover, which occurred in more than one-third of patients.1

These data led to approval of sacituzumab tirumotecan in China in March 2025 for pretreated EGFR-positive NSCLC. The study highlights how novel ADCs can extend options for patients with specific molecular subsets of lung cancer who have exhausted other targeted therapies, Mountzios explained.1

Remaining Challenges

Despite the advances, ADCs face several ongoing challenges, according to Mountzios. Target selectivity and specificity remain critical, as imperfect targeting can result in off-tumor effects. On-target, off-tumor toxicity is particularly concerning when the antigen of interest is also expressed at low levels in normal tissues. Additionally, resistance mechanisms—including downregulation of antigen expression, altered trafficking, or drug efflux—can limit durability of response.1

Combination strategies represent another frontier. ADCs are being evaluated with ICIs, chemotherapy, and tyrosine kinase inhibitors; however, balancing enhanced efficacy with the risk of overlapping toxicities such as pneumonitis remains a pressing issue, according to Mountzios.1

“We have key challenges remaining, and the main of them are how to improve the selection of our target, how to improve and identify robust biomarkers, how to reduce the notorious on-target off-tumor toxicity, and of course, to identify the best setting and sequence for the implementation of those combinations with chemotherapy or ICIs and targeted agents,” Mountzios said.1

Conclusion

ADCs represent one of the most dynamic and rapidly advancing classes of therapies in NSCLC, bridging the precision of targeted antibodies with the potency of cytotoxic payloads. The approvals of T-DXd, telisotuzumab vedotin, Dato-DXd, and sacituzumab tirumotecan illustrate how ADCs are reshaping treatment paradigms for biomarker-selected and biomarker-agnostic populations alike. However, setbacks seen in late-phase trials and the persistent challenges of toxicity, resistance, and biomarker development emphasize that refinement is still needed. With ongoing clinical trials and technological innovation, ADCs are poised to become not only essential tools in the treatment of NSCLC but also key drivers in the broader evolution of precision oncology.

REFERENCES

1. Mountzios G. Bracing for Impact: A New Wave of ADCs in NSCLC. World Conference on Lung Cancer; Barcelona, Spain; September 6-9, 2025.
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. Updated August 16, 2022. Accessed September 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
3. Trastuzumab Deruxtecan in Participants With HER2-mutated Metastatic Non-small Cell Lung Cancer (NSCLC) (DESTINY-LUNG02). Clinicaltrials.gov. Updated October 24, 2024. Accessed September 7, 2025. https://www.clinicaltrials.gov/study/NCT04644237
4. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression. FDA. Updated May 14, 2025. Accessed September 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
5. Study of Telisotuzumab Vedotin (ABBV-399) in Participants With Previously Treated c-Met+ Non-Small Cell Lung Cancer. Clinicaltrials.gov. Updated August 26, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT03539536
6. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. Updated June 23, 2025. Accessed September 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
7. 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 September 7, 2025. https://clinicaltrials.gov/study/NCT05338970
8. SKB264 Monotherapy in Selected Subjects with Advanced Solid Tumors. Clinicaltrials.gov. Updated February 28, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT05631262