Editor’s Note: The 27th National Clinical Oncology Conference and 2024 CSCO Annual Meeting, co-hosted by the Chinese Society of Clinical Oncology and the Beijing Health Management Development Foundation, took place in Xiamen from September 25-29, 2024. During the conference, several lung cancer-focused forums highlighted cutting-edge research and progress in the field both domestically and internationally. During the event, Oncology Frontier had the opportunity to interview Dr. Tony Mok from the Faculty of Medicine at The Chinese University of Hong Kong. He shared his insights on the current role and future outlook of biomarker testing in clinical practice for lung cancer.01
Oncology Frontier: Biomarkers play a significant role in lung cancer research and treatment, serving as a cornerstone for precision therapy. For example, identifying relevant gene mutations allows us to select appropriate targeted therapies for patients. Could you discuss the importance of biomarker testing for lung cancer patients prior to treatment?
Dr. Tony Mok: This is an important question. Over the past two decades, advancements in lung cancer therapy have been revolutionary, and biomarkers have enabled us to select the right medication for each patient. It began with the discovery of the EGFR mutation, which we now routinely test for in adenocarcinoma patients, reshaping the treatment landscape. Additionally, since the introduction of ALK inhibitors in 2014, ALK gene testing has become common practice. The range of genes we test for continues to grow, currently encompassing around ten distinct genetic abnormalities. Many drugs developed for these driver mutations are now approved as first-line therapies. Even for rare mutations, recent studies have shown clinical benefits, such as RET-selective inhibitors and the EGFR-MET bispecific antibody amivantamab for treating NSCLC with EGFR exon 20 insertions. Thus, I believe comprehensive genetic testing before initiating treatment provides clarity on the patient’s condition and guides the development of an optimal clinical strategy.
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Oncology Frontier: Immunotherapy has proven effective in improving outcomes for NSCLC patients in recent years, but not all patients benefit. Could you tell us about your team’s research and exploration of lung cancer biomarkers?
Dr. Tony Mok: This is indeed a critical area of research. The discovery of EGFR mutations marked the start of targeted therapy for lung cancer, and immunotherapy brought new hope for long-term survival. Following these advancements, the development of antibody-drug conjugates (ADCs) has gained significant attention, targeting various receptors such as HER2, HER3, TROP-2, and MET. However, current data are less encouraging than anticipated, with only modest improvements in progression-free survival (PFS) for certain targets like TROP-2. This raises the question of how to discover clinically valuable biomarkers. At this year’s World Conference on Lung Cancer (WCLC), Professor Marina Chiara Garassino’s team presented a study on TROP2, using a quantitative continuous scoring method to standardize the TROP2 membrane ratio, which could predict clinical outcomes in the TROPION-Lung 01 study. This research demonstrated that a positive TROP2 membrane ratio correlated with higher overall response rate (ORR) and PFS in NSCLC patients treated with datopotamab deruxtecan (dato-DXd), a TROP2-targeting ADC. The TROP2 membrane standardized ratio (QCS-NMR) measures the ratio of TROP2 expression in the tumor cell membrane relative to the cytoplasm, with a QCS-NMR positive status defined as at least 75% of tumor cells having a TROP2 ratio of ≤0.5585. I believe the future of biomarker research lies in leveraging digital technologies, such as AI, to develop these biomarkers.
Additionally, ongoing research at The Chinese University of Hong Kong is employing 3D quantification technology to measure protein expression within three-dimensional tumor blocks, rather than traditional two-dimensional slides. Quantifying protein expression from a three-dimensional perspective represents a promising direction for future exploration.
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Oncology Frontier: Biomarkers play an essential role in predicting clinical efficacy and disease prognosis, making them a research hotspot in lung cancer. Could you share your views on future directions for biomarker research in this field?
Dr. Tony Mok: First, genomic-based biomarker exploration has been a successful approach since targeted drugs act on abnormal genes and their products. For the future, we must look beyond molecular genomics, especially regarding ADC development, where proteomics and methods for calculating protein levels are crucial. Additionally, novel treatments such as cancer vaccines, CAR-T cells, and other cell therapies leverage the immune system to combat cancer. This presents complexities because the immune system interacts with both cancer and normal cells, making differentiation challenging. A basic concept to start with is HLA typing. Since HLA’s role is to present neoantigens on cell surfaces for T-cell recognition, it forms the foundation of T-cell interactions with antigens. However, HLA typing varies significantly across ethnic groups, necessitating further research into HLA typing and its relationship with immunotherapy.
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Oncology Frontier: With the continuous progress in biomarker research, it is foreseeable that more biomarkers will be applied to clinical practice for lung cancer. Could you discuss how this might change lung cancer diagnosis and treatment?
Dr. Tony Mok: This question is broad, covering both diagnosis and treatment. First, early detection of lung cancer is crucial, as patients with early-stage disease have curative surgery options that significantly improve survival and quality of life. Unfortunately, most lung cancer patients are diagnosed at advanced stages, making surgical resection impossible. Low-dose CT (LDCT) scans are among the most effective tools for early detection; however, they are expensive and require large equipment. One possible approach is to combine LDCT with plasma-based biomarkers, such as plasma DNA genomic testing, although previous tests have shown limited sensitivity. Current fragmentomics technology, which examines cfDNA fragmentation patterns and calculates methylation, is emerging as a promising tool for early cancer screening, with higher sensitivity in early lung cancer detection. Integrating LDCT with fragmentomics may be an exciting direction to explore in the future.
As for prognosis, although many prognostic factors and genes have been identified, they are not always clinically useful since prognostic genes are not necessarily predictive. In my opinion, clinically relevant biomarkers should be predictive, such as the genomic and immune biomarkers currently in use.
Professor Tony Mok
Chair, Department of Oncology Li Shu Fan Medical Foundation Professor of Clinical Oncology Fellow of the American Society of Clinical Oncology (FASCO) Board Member of ASCO (June 2018-May 2022) Past President, International Association for the Study of Lung Cancer Academician, Hong Kong Academy of Sciences
Professor Tony Mok’s research focuses on biomarkers and molecular targeted therapies in lung cancer. He is a founding member of the Lung Cancer Research Group and has led numerous key multinational clinical studies, establishing a foundation for personalized lung cancer treatment.
