Editor's Note: On July 2, 2024, the "ADC High-Level Closed-Door Seminar," chaired by Vice President Yong Yang of China Pharmaceutical University and President Jin Li of Shanghai Gaobo Oncology Hospital, was grandly held in Shanghai. The seminar explored the current status and future of ADC development. During the event, Oncology Frontier interviewed Professor Baohui Han from the Shanghai Chest Hospital . Combining recent ASCO conference updates, Professor Han analyzed the efficacy results and safety management points of ADC treatment in NSCLC and shared insights on the future prospects of ADC development.

Unmet Needs in Lung Cancer and the Value of ADC

Oncology Frontier: Antibody-drug conjugates (ADC) have become a research hotspot in recent years. Could you share the unmet needs in the field of lung cancer in China and the value of ADC in lung cancer treatment?

Professor Baohui Han: Lung cancer is the leading killer among malignant tumors in China. According to the latest cancer epidemiology report from the National Cancer Center, China sees 1.06 million new lung cancer cases and 730,000 deaths annually. As a clinical doctor specializing in lung tumors, we face many challenges and unmet clinical needs. In the treatment of advanced lung cancer, primary resistant populations, patients without precise therapeutic targets, and PD-L1-negative populations present significant challenges, with ample room for improvement in treatment efficacy. New treatment strategies are urgently needed.

In recent years, ADCs have made significant breakthroughs in lung cancer treatment. At this year’s American Society of Clinical Oncology (ASCO) annual meeting, the final results of the phase II DESTINY-Lung02 study on Trastuzumab Deruxtecan (T-DXd, DS-8201) for treating non-small cell lung cancer (NSCLC) were reported, showing a median progression-free survival (PFS) of 10.0 months, which is quite satisfactory. Additionally, more drugs targeting HER2, HER3, TROP-2, and MET are under development, promising exciting future prospects.

In the development and application of ADC drugs, it is crucial to precisely target a membrane surface antibody so that the drug can bind to the surface of tumor cells. The drug payload should be highly cytotoxic, ensuring high efficacy while maintaining safety. For example, T-DXd has a narrow therapeutic window; increasing the dosage from 5.4 mg/kg to 6.4 mg/kg significantly raises the incidence of interstitial lung disease (ILD). Making ADCs more effective and less toxic is a challenge we need to address in the future.

Key Lung Cancer Developments from ASCO

Oncology Frontier: As you mentioned, T-DXd performed well at ASCO. Could you summarize other important lung cancer-related developments from the recent ASCO meeting?

Professor Baohui Han: Lung cancer is one of the fastest-progressing cancers in the field of solid tumors. Besides T-DXd, two other studies presented at ASCO are particularly noteworthy. One is the use of HER3-DXd targeting HER3 after resistance to EGFR mutations, achieving an impressive 30% objective response rate (ORR). Another is the HARMONi-A study, which reported positive results for combining Ivosidenib with chemotherapy for EGFR mutation NSCLC after progression on EGFR-TKIs. Ivosidenib is a PD-1/VEGF bispecific antibody, offering a new treatment strategy for patients resistant to EGFR-TKIs.

Managing ADC Toxicities

Oncology Frontier: You mentioned the importance of managing ADC’s safety. Could you share your clinical experience in handling ADC-related toxicities?

Professor Baohui Han: One significant reason ADCs are effective is their ability to carry potent cytotoxic drugs that are intolerable as single agents, such as topoisomerase inhibitors, taxanes, and ricin, which are highly toxic even in minimal doses. In lung cancer treatment, ADCs can precisely target lung sites, resulting in high drug concentrations in the lungs. However, the cytotoxic drugs released by ADCs can leak into the tumor’s surrounding tissues, causing ILD. Additionally, the cytotoxic load can lead to chemotherapy-induced bone marrow suppression, including reductions in hemoglobin and white blood cells.

Since ADC indications are developed from late-line to frontline treatments, no frontline indications have been achieved yet. Considering patients’ medical and treatment history when applying ADCs is crucial for ensuring drug safety. Patients with chronic obstructive pulmonary disease (COPD), chronic ILD, or immune diseases are at higher risk for ILD. Patients who experienced grade 3 or higher adverse reactions such as bone marrow suppression in previous treatments need careful monitoring when using ADCs. Given ADCs’ dual effects as monoclonal antibodies and chemotherapy drugs, with specific organ toxicities, thorough patient screening and assessment are essential for safe clinical use.

Future Prospects for ADC in Lung Cancer

Oncology Frontier: In the lung cancer field, ADCs targeting TROP2, HER2, HER3, B7-H3, EGFR, and cMET are at the forefront. How do you view the application prospects of ADCs in lung cancer? Can ADC drugs make it to frontline treatments and change the current clinical treatment landscape?

Professor Baohui Han: The efficacy of ADCs in late-line treatments has driven their advancement to frontline therapies. ADCs have shown a median PFS of about 10 months in EGFR-resistant NSCLC patients, a significant improvement from the past, but not yet a revolutionary breakthrough. It is entirely possible for ADCs to become a supplementary strategy for frontline treatments in the future, but more evidence is needed to fully replace existing regimens.

For NSCLC patients receiving frontline treatments, their performance status (PS) scores, treatment tolerance, and compliance are far better than those of patients undergoing late-line treatments. Late-line patients often have deteriorated bone marrow and organ function due to multiple lines of treatment. When ADCs reach frontline treatment status, their efficacy may improve due to better patient tolerance and compliance. We hope ADCs can partially replace chemotherapy in the future, reducing chemotherapy-induced adverse reactions. We also look forward to more optimized ADC drugs and ADC combination therapy regimens, benefiting patients.

Professor Baohui Han

• Second-level Professor
• Chief Physician/Professor/Doctoral Supervisor
• Honorary Vice President of Shanghai Gaobo Oncology Hospital, Affiliated with China Pharmaceutical University
• Discipline Leader at the Affiliated Chest Hospital of Shanghai Jiao Tong University
• Vice President and Director of the Oncology Branch of the Asia-Pacific Society of Medical Immunology
• Executive Chairman of the Chinese Academy of Lung Cancer
• Review Expert for the National Medical Products Administration (NMPA)
• Former Chairman of the CSCO Tumor Vascular Targeting Committee
• Vice Chairman of the CSCO Tumor NSCLC Committee
• Chairman of the China Primary Health Care Foundation Tumor Precision Diagnosis and Treatment Committee
• Vice Chairman of the Chinese Anti-Cancer Association Tumor Precision Treatment Committee
• Standing Committee Member of the Chinese Medical Association Respiratory Branch
• Standing Committee Member of the Chinese Medical Doctor Association Tumor Branch
• Chairman of the Shanghai Medical Association Tumor Target Molecular Branch
• Vice Chairman of the Eighth Council of the Shanghai Anti-Cancer Association
• Chief Consultant of the Tumor Chemotherapy Branch of the Shandong Anti-Cancer Association