Barcelona, Spain – A significant shift is underway in the treatment of non-small cell lung cancer (NSCLC), driven by innovative antibody-drug conjugates (ADCs). These agents, combining the precision of antibodies with the potency of cytotoxic drugs, are providing fresh therapeutic avenues for patients, as detailed at the 2025 World Conference on Lung Cancer.

Understanding the Architecture of Antibody-Drug Conjugates

giannis Mountzios, MD, MSc, PhD, a leading medical oncologist from the Henry Dunant Hospital Center in Athens, Greece, outlined the basic structure of ADCs. These complex molecules comprise three essential components: the antibody, the linker, and the payload. The antibody, typically an IgG1 monoclonal antibody, is engineered for exceptional target specificity, guiding the ADC directly to cancer cells and also activating immune responses.

The linker component is critical, determining whether the payload is released inside cancer cells only (non-cleavable) or both inside and outside the cell (cleavable).This distinction significantly impacts how the drug behaves in the body. the payload, a potent cytotoxic molecule, disrupts cellular processes – DNA structure or tubulin polymerization – leading to cancer cell death. Newer ADC designs include bispecific and biparatopic agents, expanding targeting capabilities, as well as immune-stimulating and protein-degrader ADCs.

The Critical Role of the Payload

The payload’s characteristics generally define an ADC’s therapeutic strength and potential toxicity. These payloads fall into three main groups: antimicrotubule agents, DNA-cleaving agents, and topoisomerase inhibitors. mountzios likened payload design to spacecraft engineering, where the payload’s size and weight influence the overall ADC structure and behavior. As an example, sacituzumab govitecan and datopotamab deruxtecan, both targeting TROP2, demonstrate differing potencies due to variations in their payloads and drug-to-antibody ratios.

How Antibody-Drug Conjugates Work

The process begins with the antibody binding to a specific target on the cancer cell’s surface.The ADC is then absorbed into the cell, where the payload is released via lysosomal degradation. This released payload then interferes with vital cellular functions, ultimately causing cell death. Importantly, the antibody itself can contribute to anti-cancer activity through immune mechanisms, enhancing the overall therapeutic effect. Some payloads can also diffuse into neighboring cells, offering a ‘bystander effect’ useful for cancers with uneven biomarker expression, but also carrying a risk of off-target toxicity.

Biomarker-Driven vs. Broad-spectrum ADCs

ADCs are categorized as either biomarker-selected or biomarker-agnostic. Biomarker-selected ADCs, such as telisotuzumab vedotin for MET overexpression and trastuzumab deruxtecan for HER2 mutations, require the presence of a specific biomarker for effectiveness.Conversely, biomarker-agnostic ADCs, like those targeting Trop2 or Her3, demonstrate efficacy across a wider patient population, irrespective of biomarker levels. This distinction is crucial for tailoring treatment strategies.

Recent Approvals and Clinical Trial Data

Recent years have witnessed several key approvals. Trastuzumab deruxtecan received accelerated FDA approval in August 2022 for HER2-mutant NSCLC, demonstrating over 50% objective response rates and a median overall survival approaching 18 months. Telisotuzumab vedotin gained accelerated approval in May 2025 for patients with high c-Met protein overexpression, while datopotamab deruxtecan followed in June 2025 for pre-treated EGFR-mutant NSCLC. Sacituzumab tirumotecan was also approved in China in March 2025 for EGFR-positive NSCLC following promising Phase 2 trial results.

Though, progress isn’t always linear. The HERTHENA-Lung02 study of patritumab deruxtecan was halted after failing to show a significant overall survival benefit, highlighting the challenges in ADC development.

Sacituzumab Tirumotecan: A New Option for EGFR-Mutated NSCLC

Results from the phase 2 OptiTROP-Lung03 trial demonstrated that sacituzumab tirumotecan significantly improved progression-free survival in patients with pretreated EGFR-mutated NSCLC compared to docetaxel, with a median progression-free survival of 6.9 months versus 2.8 months. These encouraging results have broadened the treatment landscape for this patient subset.

Challenges and Future Directions

Despite significant progress, challenges remain. Ensuring target selectivity to minimize off-tumor effects is crucial, as is addressing potential resistance mechanisms.Combination therapies – ADCs with immunotherapies or chemotherapy – are being actively investigated, but require careful management to avoid overlapping toxicities.

“We have key challenges remaining,” Mountzios stated. “improving target selection, identifying robust biomarkers, reducing off-tumor toxicity, and determining optimal combination strategies are paramount.”

Did You Know? ADCs represent a convergence of biological and chemical engineering, requiring precise control over antibody specificity, linker stability, and payload potency.

Pro Tip: Biomarker testing is crucial for identifying patients most likely to benefit from biomarker-selected ADCs.

What role do you foresee for ADCs in personalized cancer treatment? How can we best manage the potential toxicities associated with these powerful therapies?

Share your thoughts and experiences with cancer treatment in the comments below!