Editor's Note: The development of modern oncology has provided multiple breakthrough treatment options for lung cancer, making it one of the fastest-evolving solid tumors. To help clinicians comprehensively grasp the significant advancements in this field, "Oncology Frontier" collaborates with Dr. Hua Zhong and Dr. Baohui Han from the Department of Respiratory and Critical Care Medicine at Shanghai Chest Hospital, Shanghai JiaoTong University School of Medicine, to present the clinical progress series "Zhong" Sound "Hui" Words. Through high-quality interpretations of clinical research in lung cancer, this series aims to enhance clinical practice. In the 22nd episode, the Dr. present "Evaluation of the Efficacy and Safety of Entrectinib Targeted Therapy for ROS1 Fusion Detected in Peripheral Blood," based on data from the BFAST clinical study's D cohort, recently published in Nature Medicine.

Evaluation of the Efficacy and Safety of Entrectinib Targeted Therapy for ROS1 Fusion Detected in Peripheral Blood

Dr. Baohui Han: ROS1 fusion defines a specific molecular subtype of non-small cell lung cancer (NSCLC) patients. Approximately 2% of advanced NSCLC patients harbor this mutation. Unlike EGFR, there is no significant difference in the incidence of ROS1 fusion between Caucasian and Asian populations. With the development of next-generation sequencing (NGS) technology, nearly a hundred different ROS1 fusion variants have been identified, with CD74 being the most common fusion partner. ROS1 fusion frequently occurs in females, non-smokers, and adenocarcinoma patients. The 2014 New England Journal of Medicine published the PROFILE-1001 study, the first targeted therapy study for ROS1 fusion-positive lung cancer patients. Data showed that patients receiving crizotinib achieved an ORR of 72%, with a median duration of response of 17.6 months and a median PFS of 19.2 months. In subsequent data updates, with 49% of patients experiencing death events, the median OS for the entire cohort reached 51.4 months. Thus, crizotinib, as a targeted drug, has ushered ROS1 fusion-positive NSCLC patients into the era of precision medicine, significantly improving patient prognosis. In the Chinese population, the largest sample size study comes from the OO-1201 study, which included 127 ROS1-positive NSCLC patients treated with crizotinib, showing a median PFS of 15.9 months and an ORR of 71.7%. Crizotinib was the first targeted therapy drug approved in China for ROS1 fusion-positive NSCLC patients.

Entrectinib is the second drug approved for ROS1 fusion-positive NSCLC patients. A pooled analysis included 161 NSCLC patients, with 37.3%, 39.8%, and 23.0% of patients being treatment-naive, previously treated with one line, and more than two lines of therapy, respectively. The ORR, median PFS, and median OS for the entire cohort were 67.1%, 15.7 months, and not reached, respectively. For treatment-naive patients, the ORR and median PFS were 78% and 19.0 months, respectively.

This year, the publication of efficacy data for the next-generation ROS1-TKIs, Repotrectinib and Taletrectinib, has the potential to further extend patient survival. For treatment-naive patients receiving the standard dose of Repotrectinib, the ORR was 79%, and the median PFS reached 35.7 months. For previously treated patients, the overall ORR was 38%, with a median PFS of 9.0 months and a median OS of 25.1 months.

For patients receiving the standard dose of Taletrectinib, the ORR for treatment-naive patients was 90.6%, with the median PFS not reached, and a 24-month PFS rate of 70.5%. Even for patients previously treated with crizotinib, the ORR was 51.5%, with a median PFS of 7.6 months.

Regarding brain metastases, different drugs have shown varying intracranial efficacy. In the EUCROSS study, for ROS1 fusion-positive NSCLC patients with and without baseline brain metastases treated with crizotinib, the median PFS was 9.4 months and 20.0 months, respectively. In the registrational clinical study for entrectinib, among 20 patients with baseline brain metastases, the ORR was 55%, with an intracranial PFS of 13.6 months. Both next-generation ROS1-TKIs have shown excellent intracranial efficacy. For Taletrectinib, among 12 patients with measurable baseline brain metastases, the ORR was 91.7%. For Repotrectinib, the ORR was 89% for treatment-naive and 38% for previously treated patients.

Overall, with the support of multiple effective targeted therapies, ROS1 fusion-positive NSCLC patients may become the second “diamond mutation” group after ALK-positive patients, achieving long-term survival.

Dr. Hua Zhong: Identifying the driver gene mutation status in patients is crucial for providing precision treatment. However, in clinical practice, some patients face material constraints after routine tissue pathology tests, leaving insufficient samples for subsequent genetic typing, complicating individualized treatment. Liquid biopsy technology offers a solution to this problem. In the EGFR pathway, studies have found that liquid biopsy has a sensitivity of about 60%, specificity over 95%, and consistency of around 70%, providing a good complement to tissue pathology, though data for other driver gene pathways are limited.

The BFAST study prospectively evaluated the feasibility of treating patients with different driver gene mutations guided by liquid biopsy technology. The study found that patients with ROS1 fusion, detected through peripheral blood and given corresponding targeted therapy, achieved good efficacy. Due to tumor heterogeneity, the molecular pathological status at the sampling site may not reflect the entire tumor. Thus, tissue pathology testing may yield false-negative results, while circulating tumor DNA in peripheral blood, representing the overall tumor shedding, can provide a good complement to tissue testing. Director Han has reviewed several key targeted therapies for the ROS1 pathway. With these drugs’ support and advancements in liquid biopsy technology, precision treatment for patients will likely see further breakthroughs.

However, several challenges remain in this field: firstly, next-generation TKI drugs still face resistance, and managing post-resistance treatment remains difficult. In the EGFR pathway, immunotherapy combined with chemotherapy is approved for treating patients with targeted resistance. Whether similar strategies are feasible for the ROS1 pathway is unclear. Secondly, liquid biopsy still misses some patients. Improving detection sensitivity requires technical advancements. Lastly, improving drug safety remains an area for further exploration.

Dr. Baohui Han

• Leading Talent in Shanghai, Honorary Director of the Department of Respiratory Medicine at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
• Outstanding Academic Leader in Shanghai
• Director of the Drug Clinical Trial Institution, Recipient of the State Council Special Allowance
• Member of the Lung Cancer Professional Committee, Chinese Anti-Cancer Association
• Executive Member of the Clinical Oncology Collaboration Professional Committee, Chinese Anti-Cancer Association (CSCO)
• Chairman of the CSCO Tumor Vascular Targeting Professional Committee
• Director of the Respiratory Endoscopy Training Base, Ministry of Health
• Standing Member of the Tumor Professional Committee, Chinese Medical Association
• Vice President of the Chinese Medical Association Biological Immunology Society
• Chairman of the Tumor Branch, Chinese Medical Association Biological Immunology Society
• Deputy Chairman of the Tumor Targeted Molecular Professional Committee, Shanghai Medical Association
• Vice President of the 8th Council, Shanghai Anti-Cancer Association
• Vice President of the Respiratory Medicine Branch, Shanghai Medical Association

Dr. Hua Zhong

• Director of the Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
• Chief Physician
• Doctoral Supervisor
• Reviewer for the National Natural Science Foundation of China
• Member of the Biological Immunology Society, Chinese Medical Association
• Member of the Non-Small Cell Lung Cancer Committee, CSCO
• Member of the 8th Council, Shanghai Anti-Cancer Association
• Member and Secretary of the Tumor Targeted Molecular Specialty Branch, Shanghai Medical Association
• Member of the Chinese Clinical Oncology Association
• Member of the American Society of Clinical Oncology
• Conducted fundamental and translational research in lung cancer immunotherapy as a visiting scholar at the University of Pittsburgh
• Principal Investigator for three National Natural Science Foundation projects, four Shanghai Science and Technology Commission projects, one key project of the Ministry of Science and Technology, and one joint project of emerging frontier technologies in municipal hospitals
• Multiple awards, including: Chinese Medical Science and Technology Award, Second Prize Shanghai Anti-Cancer Science and Technology Award Research Physician Award from Shanghai Jiao Tong University School of Medicine