At the 2025 European Lung Cancer Congress (ELCC), new data from the ORCHARD study were presented, highlighting the potential of osimertinib in combination with Dato-DXd as a post-progression strategy following first-line osimertinib treatment in patients with EGFR-mutant non-small cell lung cancer (NSCLC). This marks the first public release of efficacy and safety findings for this combination in the treatment of EGFR-TKI resistant NSCLC.Professor Gen Lin and Dr. Hongxia Li：Resistance mechanisms following osimertinib treatment are heterogeneous and complex. Current post-progression strategies include both targeted therapies addressing known resistance pathways and non-targeted drug approaches. Among patients with MET amplification or overexpression following osimertinib, combination treatment with MET inhibitors has become an established standard. For the majority of patients without identifiable resistance mutations, chemotherapy-based combinations and the development of novel antibody-drug conjugates (ADCs) represent emerging areas of promise.
Previous phase III studies have shown that in EGFR-mutant advanced NSCLC resistant to osimertinib, median progression-free survival (PFS) with chemotherapy is typically 4–5 months. Combinations of chemotherapy with immunotherapy or anti-angiogenic agents (as in ORIENT-31, IMpower151, HARMONi-A) have shown consistent results, with objective response rates (ORR) around 45–50% and median PFS of 7–8 months.
Recent studies have further confirmed that novel ADCs exhibit strong antitumor activity in this treatment-resistant population. For example, patritumab deruxtecan as monotherapy in previously treated EGFR-mutant advanced NSCLC demonstrated an ORR of 60% and a median PFS of 11.5 months. In a phase I trial of BL-B01D1, a HER3/EGFR bispecific ADC developed by Betta Pharma, the ORR exceeded 50% with a median PFS of 6.8 months in patients with EGFR-TKI-resistant disease. Combined data from TROPION-Lung01 and TL05 suggest that Dato-DXd monotherapy yields an ORR of 43% and median PFS of 5.7 months in this population.
These findings underscore the broad therapeutic potential of ADCs in the post-EGFR TKI setting and establish ADC-based combination therapy as a current focus in clinical research.
The newly presented Module 10 results from the ORCHARD study are particularly encouraging. In the 4 mg/kg Dato-DXd + osimertinib group, the ORR reached 43% with a median PFS of 9.5 months. In the 6 mg/kg group, the ORR was 36%, with a median PFS of 11.7 months, closely aligning with results observed in patritumab deruxtecan monotherapy in similar settings (median PFS ~11.1 months).
It is important to note that in combination regimens involving third-generation EGFR-TKIs and ADCs, patients often have pre-existing interstitial lung abnormalities or pulmonary fibrosis due to prolonged TKI exposure, which may increase the risk of ILD compared to treatment-naïve populations.
Looking ahead, optimization of combination strategies will be a key focus. Whether using a TKI-based backbone or an ADC-based backbone, exploration of combinations with anti-angiogenic agents also holds significant promise.
Professor Gen Lin
Doctor, Chief Physician, Doctoral Supervisor
Director of the Cancer Center, Beijing Chest Hospital, Capital Medical University
Young and Middle-Aged Expert with Outstanding Contributions to the Health System of Fujian Province
Deputy Chairman of the Committee on Malignant Mesothelioma of the Chinese Anti-Cancer Association
Chairman of the Lung Cancer Special Committee of CSWOG (China Southern Oncology Group)
Deputy Chairman of the Patient Education Special Committee of CSCO (Chinese Society of Clinical Oncology)
Executive Committee Member of the Immune Therapy Expert Committee of CSCO
Executive Committee Member of the Nervous System Tumor Expert Committee of CSCO
Professor Hongxia Li, MD, PhD
- Deputy Chief Physician and Master’s Supervisor, Beijing Chest Hospital, Capital Medical University
- Visiting Scholar, Department of Thoracic Oncology, MD Anderson Cancer Center, USA
- Member, Youth Committee, Chemotherapy and Targeted Therapy Branch, Chinese Pharmacological Society
- Member, Lung Cancer Screening and Prevention Committee, Beijing Health Promotion Association
- Member, Lung Cancer Committee, Beijing Integrative Medicine Association
