Antibody-Drug Conjugates in Lung Cancer
- Fay
- 12 minutes ago
- 6 min read
Introduction
Antibody-drug conjugates (ADCs) are emerging as the fastest-growing class of novel drugs in oncology. While the concept itself is not new, they are gradually reshaping the landscape of cancer treatment. For lung cancer, the therapeutic landscape has undergone a dramatic transformation over the past decade—evolving from chemotherapy alone to the addition of targeted therapies and immunotherapies. Now, ADCs are also becoming a significant new option for lung cancer patients.
The unique feature of ADCs lies in their function as “guided chemotherapy drugs.” Conventional chemotherapy drugs attack cells throughout the body, causing numerous side effects. In contrast, ADCs use antibodies to “locate” specific markers on the surface of cancer cells, delivering the drug precisely to the target before releasing potent cytotoxic agents. This approach retains the powerful killing ability of chemotherapy while incorporating the precision of targeted therapy, significantly enhancing both drug safety and efficacy.
To date, over ten ADC drugs have received approval from the U.S. FDA, with the majority approved in recent years, demonstrating the accelerating pace of development in this field. In the context of lung cancer, researchers are actively exploring ADC applications. They are not only evaluating their efficacy across different types of lung cancer patients but also experimenting with combination therapies and design improvements to address issues like drug resistance and side effects. It is fair to say that ADCs are paving a new path for lung cancer treatment.
Established ADC Targets in Lung Cancer
In lung cancer treatment, scientists have identified several molecular “targets” particularly suited for developing ADCs. These targets act like small “markers” on the surface of cancer cells, enabling drugs to precisely locate and attack tumors.
HER2
HER2 is a protein best known in breast and gastric cancer, but a smaller group of lung cancer patients also carry HER2 mutations or overexpression. These patients often respond poorly to standard treatments, making HER2 a valuable target.
The HER2-directed ADC trastuzumab deruxtecan (T-DXd) links a HER2 antibody with a chemotherapy payload. In clinical trials, T-DXd produced meaningful tumor shrinkage and extended survival in patients with HER2-mutated non–small cell lung cancer (NSCLC). In 2022, the U.S. FDA approved T-DXd as the first ADC for HER2-mutated lung cancer, establishing a new standard of care. The main safety concern is interstitial lung disease (ILD), a type of lung inflammation that requires careful monitoring.
HER3
HER3 is another member of the HER protein family. Unlike HER2, it is not strongly cancer-promoting on its own, but it collaborates with other proteins to drive drug resistance—especially in patients who initially benefit from EGFR inhibitors. Because HER3 is widely expressed in NSCLC, it is an attractive ADC target.
The HER3-directed ADC patritumab deruxtecan (HER3-DXd) has shown promising results. In trials of patients with EGFR-mutated NSCLC who had progressed after targeted therapy, HER3-DXd achieved encouraging tumor responses. Importantly, benefits were observed even in patients with complex resistance mechanisms. The most common side effects included low blood counts and fatigue, while ILD occurred in a small proportion of patients but was generally manageable. HER3-DXd is now being compared with chemotherapy in a large phase III trial.
TROP-2
TROP-2 is a cell-surface protein expressed in more than half of lung cancer cases and is often linked to poor survival. Two TROP-2–targeted ADCs are advancing rapidly:
Datopotamab deruxtecan (Dato-DXd): In early studies, Dato-DXd showed durable tumor shrinkage in patients with advanced NSCLC, including those with prior targeted therapy. Trials are now exploring Dato-DXd both alone and in combination with immunotherapy as a first-line treatment. Side effects such as nausea and mouth sores are common, while ILD remains an important risk under close observation.
Sacituzumab govitecan (SG): Already approved in breast and bladder cancers, SG is being tested in NSCLC. Early trials showed modest response rates, but some patients achieved durable benefit. Common side effects include gastrointestinal symptoms and low blood counts. Ongoing phase III trials will clarify its role compared with chemotherapy.
Together, TROP-2–directed ADCs may expand treatment choices for a broad population of lung cancer patients.
MET
MET is a growth-promoting receptor that can become abnormally active in lung cancer through gene amplification, mutations, or protein overexpression. Patients with MET-driven disease often face rapid progression, making it a compelling ADC target.
The MET-directed ADC telisotuzumab vedotin (Teliso-V) links a MET antibody with a microtubule inhibitor. Early studies showed encouraging response rates, especially in patients with MET-overexpressing, EGFR wild-type NSCLC, with some cohorts achieving over 30% tumor shrinkage. However, lung inflammation (pneumonitis) emerged as an unexpected side effect in some studies, highlighting the need for careful patient selection and monitoring. Phase III trials are ongoing to confirm its benefit compared with chemotherapy.
Toxicity and Safety Concerns of ADCs in Lung Cancer
ADCs were originally designed to kill cancer cells more precisely and safely, reducing the harm to the body caused by traditional chemotherapy. While new ADC drugs have indeed improved safety to some extent, side effects remain a significant challenge that must be seriously addressed in clinical practice.
The side effects of ADCs primarily stem from two sources: one involves the drug targeting tumor cells but also affecting normal tissues (referred to as “off-target effects in non-tumor tissues”); the other arises when the drug prematurely releases its toxic components in the body, causing unnecessary damage. Common side effects include liver damage, neurological symptoms, and ocular issues. Some drugs can even trigger severe pulmonary diseases like interstitial lung disease (ILD), a side effect that has resulted in fatalities in certain clinical trials.
Take trastuzumab deruxtecan (T-DXd) as an example: in studies for breast and lung cancer, approximately 15% of patients developed ILD to varying degrees, with a small proportion experiencing severe or even fatal cases. To mitigate risks, the latest clinical trials explicitly exclude patients with preexisting lung conditions or prior lung resection from enrollment criteria. Physicians must exercise heightened vigilance when administering these drugs, promptly discontinuing treatment upon symptom onset and initiating early corticosteroid therapy.
Another challenging issue is that even ADCs of the same type may exhibit markedly different side effect profiles. For instance, two drugs with identical payloads might cause one to be more prone to nerve damage while the other primarily triggers skin or eye issues. Such variations remain unpredictable, highlighting our incomplete understanding of ADC side effect mechanisms.
For patients, the most crucial point is this: while ADCs represent new hope in cancer treatment, they are not “zero-side-effect” miracle drugs. During treatment, physicians must conduct regular monitoring, and patients should promptly report any discomfort. In the future, advancements like “breath analysis” to detect lung injury risks early may further enhance ADC safety. For now, however, careful patient selection and constant vigilance remain key to the clinical use of ADCs.
Future Challenges and Considerations
As ADCs continue to enter clinical practice, researchers are realizing that their long-term effectiveness will depend on overcoming several key challenges. One major issue is drug resistance. Just like with chemotherapy or targeted therapy, cancer cells can eventually find ways to evade ADCs. For example, studies in the lab have shown that after prolonged exposure to certain ADCs, cancer cells may reduce the amount of target proteins on their surface, pump drugs out more effectively, or alter the way they internalize and process the drug. In lung cancer, specific genetic and protein changes have already been linked to resistance to ADCs carrying common chemotherapy payloads.
Another important question is how best to select patients for ADC treatment. Unlike traditional targeted therapies that require a specific gene mutation, ADCs can sometimes work even when the target protein is present at low levels. This raises debate about whether patients should be pre-screened based on antigen expression, and what the right “cutoff” should be. Developing reliable biomarkers that can predict who will benefit most from ADCs is an urgent priority.
Looking ahead, combination therapies are likely to play an important role. Trials are already testing ADCs together with immunotherapies, drugs that change the tumor environment, or treatments that boost target protein expression on cancer cells. The goal is to make ADCs work better, last longer, and overcome resistance.
On the innovation side, scientists are working on next-generation ADC designs. These include site-specific ADCs that allow for more precise drug attachment, bispecific ADCs that can bind to two targets at once, and even dual-payload ADCs that deliver two different toxic agents into cancer cells to increase potency and reduce the chance of resistance. Researchers are also experimenting with non-traditional payloads, such as drugs that stimulate the immune system or trigger cancer cell suicide without relying on direct toxicity.
In summary, while ADCs have already shown impressive potential in lung cancer and other tumor types, their full impact will depend on solving these challenges—understanding resistance, improving patient selection, designing smarter drug combinations, and advancing new generations of ADC technology.
Sources
Assessed and Endorsed by the MedReport Medical Review Board
