The 2026 European Lung Cancer Congress (ELCC) in March in Copenhagen, Denmark, opened with a Keynote Address exploring the future directions and current challenges of antibody-drug conjugates (ADCs).
Fred R. Hirsch, MD, PhD, who will become director of Dartmouth Cancer Center on July 13, began by highlighting the rapid development of ADCs, noting that thousands of clinical trials are evaluating them for the treatment of various malignancies, and many have recently received regulatory approval. However, he emphasized that the basis behind some of these approvals—specifically those targeting MET, HER2, and TROP2—is somewhat complex.
“For MET, approval is based on overexpression at the protein level in second‑line treatment,” Dr. Hirsch said. “For HER2, we have approvals based on HER2 mutation, and we have other approvals based on HER2 protein expression. For TROP2, we also have approval for EGFR‑mutant non-small cell lung cancer (NSCLC).”
Posing a question for the audience, Dr. Hirsch asked: How do we select the right biomarkers for the right patients?
Some patients are selected based on protein expression or mutation expression, while others are biomarker-agnostic—that is, not selected based on any biomarker. Therefore, it is important to consider the complexities of ADCs, Dr. Hirsch said.
“We know that TKIs are strongly associated with mutations and fusions; we have learned that over decades. For antibodies, what is the optimal target?” he asked. “We have learned from many studies that EGFR protein expression and EGFR copy number seem to play a clear predictive role when we talk about monoclonal antibodies. In my opinion, that is a key difference we need to keep in mind when we talk about ADCs.
“We have also learned from other studies that protein expression does not predict mutation status. More recent studies have shown that copy number amplification can be a clear predictive marker.”
He highlighted varying definitions of MET amplification across three trials as another hurdle. The INSIGHT trial defined MET amplification as a copy number of five or more. In contrast, the SAVANNAH and SACHI trials defined MET amplification as 10 or more, particularly for patients treated with osimertinib monotherapy.
“There is a difference between using 10 copies as the definition of amplification versus five copies or other cut‑offs,” Dr. Hirsch said. “This lack of harmonization is, in my opinion, an important issue in itself.”
Potential for Combination Therapies
Dr. Hirsch discussed the potential for developing rational combination therapies, while suggesting there may be overlap between candidates for different ADCs, such as those with co-expression of ADC targets and potential ADC targets based on EGFR expression.
He highlighted two studies evaluating osimertinib with ADCs, one of which used two biomarkers (EGFR mutation and c-MET expression), while others only relied on one biomarker.
“When we combine therapies, we need to keep in mind that a combination of predictive biomarkers might play a role,” Dr. Hirsch said. “We shouldn’t just focus on biomarkers for one component when we make those combinations.”
Regarding TROP2, Dr. Hirsch explained that initial studies have found no clear difference in outcomes based on TROP2 protein expression. He argued that protein expression is a dynamic process without fixed cut-offs and needs to be analyzed continuously.
One such approach is implementing the use of artificial intelligence (AI) platforms, such as an normalized membrane ratio (NMR)-based quantitative continuous scoring system (QCS). The program derives a scoring system by analyzing pure membranous expression of the protein versus the combination of membranous and cytoplasmic expression.
“So far, it is clear that using the NMR/QCS scoring system separates the curves and predicts who will benefit from TROP2‑directed ADCs versus who will not. This is a very promising technology, and it incorporates continuous assessment, which I think we have missed for many years,” Dr. Hirsch said.
Future Directions: The Bystander Effect
Dr. Hirsch said it is important to remember that some ADC payloads will be released extracellularly, which can create a “bystander effect” on nearby cells and affect the immune landscape around the tumor.
He said further study is needed to understand the role of liquid biopsy in determining predictive biomarkers. He also called for a multifactorial biomarker approach to address resistance and better define targets in order to overcome heterogeneity in protein expression.
“ADCs induce tumor-specific adaptive immunity, increase T-cell infiltration in the tumor microenvironment, and reinvigorate exhausted T cells,” Dr. Hirsch said. “Several other immunologic mechanisms are coming into play. In the future, we need to keep that in mind when we talk about biomarkers for ADCs, because the biomarker composition will be multifactorial. I don’t think one single biomarker can do the job.”
His overall take-home message: ADCs are very complex. They include the antibody, the linker, and the payload. Each of these components might, in the future, provide a biomarker clue that can help predict the efficacy of these drugs. It’s important to consider how each step—mutations, gene copy number, and protein expression—may help select the right biomarker for the right patients.
“We need the tissue. We need to study and understand the mechanisms so we can make a good predictive biomarker concept,” Dr. Hirsch said.
Before delivering the lecture, Dr. Hirsch paid tribute to Masahiro Tsuboi, MD, PhD, a renowned thoracic oncologist and surgeon. Dr. Tsuboi, a prominent leader in the international thoracic oncology community, died in March.
“[Dr. Tsuboi] made a huge impact on the way we treat lung cancer today. He was also a very loved colleague and friend, and very active in the international community,” Dr. Hirsch said. “He helped us bring the international community together in a family concept. We will all miss him in many ways, both personally and professionally. May his memory be a blessing for all of us.”
