preface
The 2024 European Society for Medical Oncology (ESMO) Annual Meeting is in full swing in Barceló, Spain. This medical event covers basic research, translational research and the latest clinical research progress, like a rally in the fight against diseases, constantly breaking the survival records of multiple tumor types. As the world's largest cancer, lung cancer has a high incidence and mortality rate of the most common type, non-small cell lung cancer (NSCLC), which puts a heavy burden on patients' families and the public healthcare system.
At the just-concluded 2024 World Congress on Lung Cancer (WCLC), the latest data on trophoblast cell surface antigen 2 (TROP2) antibody conjugates (ADCs) were presented in several studies in the field of lung cancer. Among them, TROPION-Lung01, as the first Phase III clinical study in the field of TROP2 ADC lung cancer, further announced its overall survival (OS) results, demonstrating the clinical benefit of Dato-DXd in advanced treatment-based non-squamous NSCLC, and is expected to become a new treatment option¹. At this ESMO conference, the researchers further revealed the therapeutic effect of Dato-DXd in patients with brain metastases in the TROPION-Lung01 study. Yimaitong specially invited Professor Heng Xinyu from the First Affiliated Hospital of Air Force Medical University to share the latest data of patients with brain metastases in the TROPION-Lung01 study at the ESMO conference, and discuss the future research direction of Dato-DXd in the field of lung cancer treatment.
Expert Profile
Professor Heng Xinyu
- Deputy Director of the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of the Air Force Medical University
- Deputy Director of the Institute of Respiratory Diseases, Air Force Medical University
- Postdoctoral Fellow, Texas A&M University, United States
- Member of the All-Army Respiratory Professional Committee
- Deputy head of the interventional group of the All-Army Respiratory Professional Committee
- Vice Chairman of Shaanxi Chronic Obstructive Pulmonary Disease Alliance
- Secretary of the Infectious Diseases Group of Shaanxi Respiratory and Tuberculosis Branch of the Chinese Medical Association
TROPION-Lung01研究全面改写NSCLC治疗格局
At the 2024 WCLC Annual Meeting held not long ago, the results of the OS benefit of the TROPION-Lung01 study attracted much attention. The data showed that Dato-DXd achieved a median OS of 14.6 months (95% CI, 12.4-16.0) in non-scaly patients, a 2.3-month extension compared with docetaxel, a 16% reduction in the risk of disease mortality (HR = 0.84, 95% CI 0.68-1.05), and a clinically meaningful improvement¹. In addition, previously published data on progression-free survival (PFS) in non-scaly patients showed that PFS was significantly superior in the Dato-DXd arm over docetaxel (5.5 versus 3.6 months, HR=0.63, 95% CI: 0.51-0.79)². Based on the efficacy and safety profile of the TROPION-Lung01 study, Dato-DXd is expected to be a new option for the post-line treatment of patients with advanced non-squamous NSCLC in the future. The full text of the study was published in the Journal of Clinical Oncology (IF=42.1)³ during the 2024WCLC.
At the ESMO Annual Meeting, the research team further announced the treatment efficacy⁴ of the TROPION-Lung01 study in patients with brain metastases. As of March 29, 2023, 84 of the 468 patients with nonsquamous NSCLC in the TROPION-Lung01 study had brain metastases, of whom 43 were randomized to Dato-DXd (Dato-DXd, 6 mg/kg Q3W) and 41 to docetaxel (75 mg/m2 Q3W). The baseline characteristics of patients were basically balanced between the two groups. Median follow-up was 12.9 months and 12.7 months in the Dato-DXd and docetaxel arms, respectively. Results showed that a trend of efficacy-benefit was observed in the Dato-DXd monotherapy group compared to docetaxel group, regardless of baseline brain metastasis status. In patients with brain metastases, the median PFS of Dato-DXd versus docetaxel was 4.9 months vs. 3.6 months; HR=0.59(95%CI 0.35-1.00）； Median OS was 12.9 months vs. 8.9 months; HR=0.94（95%CI 0.56-1.57）。 In addition, the objective response rate (ORR) was 30 percent (95% CI 17 percent, 46 percent) in the Dato-DXd arm, compared with 12 percent (95% CI 4 %, 26 percent) in the docetaxel arm; The disease control rate (DCR) was 84 percent (95% CI 69 percent, 93 percent) in the Dato-DXd group, which was also better than 46 percent (95% CI 31 percent, 63 percent) in the docetaxel group.
图1 TROPION-Lung01研究脑转移患者PFS
图2 TROPION-Lung01研究脑转移患者OS
In terms of safety, there were fewer grade 3 treatment-related adverse events (TRAEs) and dose reduction or discontinuation in the Dato-DXd group than in the docetaxel group, regardless ≥of brain metastasis status. In patients with brain metastases, Dato-DXd versus docetaxel were associated with 7% vs. 27% of grade ≥3 TRAEs, respectively; The incidence of TRAEs resulting in dose reduction was 12% vs. 19%; The incidence of TRAEs leading to discontinuation was 7% versus 14%.
表1 TROPION-Lung01研究脑转移患者安全性
Dato-DXd not only demonstrated significant and durable systemic efficacy in patients with advanced treatment-previously treated non-squamous NSCLC, but also effectively prolonged the progression-free survival of patients with brain metastases. In patients with brain metastases, the median PFS was 1.3 months longer and the risk of disease mortality was reduced by 41% in the Dato-DXd group compared with docetaxel (HR = 0.59, 95% CI 0.35–1.00). In addition, Dato-DXd achieved an ORR of 30% and a DCR of 84% in patients with brain metastases. These results indicate that Dato-DXd has great therapeutic potential in patients with brain metastases in NSCLC, and further expands its research and application prospects in patients with advanced non-squamous NSCLC.
Precise force and unique mechanism of action are the key factors for the intracranial efficacy of Dato-DXd
Brain metastases are one of the most common distant metastatic sites in NSCLC. Studies have shown that nearly 30% of patients with advanced NSCLC have concomitant brain metastases at initial diagnosis, while approximately 60% of patients with NSCLC develop central nervous system (CNS) involvement during the disease⁵. Brain metastases can seriously affect cognitive function, survival time, and quality of life. However, due to the presence of the blood-brain barrier, it is difficult for systemic therapeutic drugs to reach effective concentrations in the central nervous system⁶. Therefore, there is an urgent need for new treatment options to improve the efficacy of brain tumors. In the past, the treatment regimen for patients with brain metastases in NSCLC mostly focused on small molecule tyrosine kinase inhibitors, while ADC drugs, as large molecules, are considered to be unable to penetrate the blood-brain barrier, so there are few relevant studies. In practice, however, larger molecules may also penetrate the brain parenchyma as the blood-brain barrier at the metastasis site is disrupted and replaced by a highly permeable blood-tumor barrier⁷. A preclinical study presented at the 2024 Annual Meeting of the United States Association for Cancer Research (AACR) showed that Dato-DXd demonstrated significant antitumor activity in intracranial lesions in a mouse tumor model with positive TROP2 expression⁸.
In addition, it has been shown that factors such as drug-antibody ratio (DAR), linker, and load of ADC drugs may have an impact on their efficacy in intracranial tumors⁶. Dato-DXd is a drug conjugated from a humanized anti-TROP2 IgG1 monoclonal antibody to a potent topoisomerase I inhibitor through a stable tetrapeptide-cleavable linker. Its highly active drug load, specific tetrapeptide cleavable linkers, and efficacy- and safety-assessed DAR values make Dato-DXd an excellent performer in the treatment of intracranial tumors.
Sprint Winner: Dato-DXd Shows Superior Efficacy in Patients With AGA-Positive Brain Metastases NSCLC
Patients with EGFR and other targetable genomic alterations (AGA)-positive advanced NSCLC have a higher proportion of brain metastases compared with those with negative driver genes. TROPION-Lung05 is an investigational study of Dato-DXd for the posterior treatment of AGA-positive advanced NSCLC. Intracranial efficacy analysis data from the TROPION-Lung05 study were presented at the 2024 United States Society of Clinical Oncology (ASCO) Annual Meeting. A total of 53 patients with stable brain metastases at baseline were included, of whom 29 (55%) were EGFR mutation-positive patients and the remainder had ALK, ROS1, NTRK, BRAF, RET, or MET14 skipping mutations⁹. The results showed that the intracranial objective response rate (IC-ORR) and disease control rate (IC-DCR) of Dato-DXd in patients with AGA-positive advanced NSCLC reached 22% and 72%, respectively, and 56% of patients achieved intracranial lesion shrinkage, further supporting its potential application in the population of brain metastatic NSCLC.
表2 TROPION-Lung05研究中Data-DXd的颅内疗效数据
brief summary
At the ESMO Annual Meeting, patients with brain metastases from the TROPION-Lung01 study demonstrated a 1.3-month longer median PFS and a 41% lower risk of disease mortality in the Dato-DXd arm compared with docetaxel (HR = 0.59, 95% CI 0.35–1.00). This result further highlights the therapeutic potential of Dato-DXd in patients with brain metastases in NSCLC and expands its application prospect in patients with advanced non-squamous NSCLC. We look forward to the results of further analysis of the intracranial efficacy of the TROPION-Lung01 study in order to expand the treatment beneficiary population." It is hoped that this "magic bullet" can bring the benefits of precision treatment to more lung cancer patients.
Bibliography:
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Written by: Myka
Reviewer: Myka
Typography: Babel
Executive: Babel
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