Intracranial Efficacy of Crizotinib and Postprogression Therapeutic Strategies in Advanced c-ros Oncogene 1 (ROS1)-Positive Non–Small Cell Lung Cancer (NSCLC), a Multicenter Real-World Study

Abstract

Intracranial efficacy of crizotinib and optimal postprogression therapies in c-ros oncogene 1 (ROS1)-positive non–small cell lung cancer(NSCLC) remain under-explored. We performed a multicenter real-world study across 17 Chinese hospitals (2015–2024) in 325 ROS1-positive NSCLC patients to evaluate the intracranial efficacy of crizotinib and postprogression treatment strategies. Crizotinib achieved an overall response rate(ORR) of 78.5% and a median progression-free survival (PFS) of 22.4 months. Patients with baseline brain metastases had a 66.7% intracranial response rate and a median central nervous system (CNS)-PFS of 22.2 months, demonstrating intracranial benefit. After progression, next-generation ROS1 inhibitors (active against the G2032R resistance mutation, for example, taletrectinib and repotrectinib) significantly prolonged PFS compared to older-generation targeted agents (median 13.9 vs. 4.4 months), especially among patients with secondary ROS1 resistance mutations (ORR 66.7% vs. 14.3%). However, due to greater availability in China, earlier agents like lorlatinib and entrectinib were commonly used after crizotinib failure. In our cohort, lorlatinib demonstrated superior efficacy to entrectinib, with a trend toward longer PFS and higher overall (34% vs. 7%) and intracranial (50% vs. 0%) response rates. This large real-world study confirms crizotinib's intracranial benefit and underscores the importance of next-generation ROS1 inhibitors and older-generation agents like lorlatinib—for improved patient outcomes after crizotinib resistance.

Keywords

c-ros oncogene 1 / central nervous system efficacy / Crizotinib / non–small cell lung cancer / subsequent treatments

References

[1] A. Drilon, C. Jenkins, S. Iyer, A. Schoenfeld, C. Keddy, and M. A. Davare, “ROS1-Dependent Cancers—Biology, Diagnostics and Therapeutics,” Nature Reviews Clinical Oncology 18, no. 1 (2021): 35–55.

[2] S. Park, B. C. Ahn, S. W. Lim, et al., “Characteristics and Outcome of ROS1-Positive Non-Small Cell Lung Cancer Patients in Routine Clinical Practice,” Journal of Thoracic Oncology 13, no. 9 (2018): 1373–1382.

[3] A. T. Shaw, S. H. Ou, Y. J. Bang, et al., “Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer,” The New England Journal of Medicine 371, no. 21 (2014): 1963–1971.

[4] A. T. Shaw, G. J. Riely, Y. J. Bang, et al., “Crizotinib in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer (NSCLC): Updated Results, Including Overall Survival, From PROFILE 1001,” Annals of Oncology 30, no. 7 (2019): 1121–1126.

[5] Y. L. Wu, S. Lu, J. C. Yang, et al., “Final Overall Survival, Safety, and Quality of Life Results from a Phase 2 Study of Crizotinib in East Asian Patients with ROS1-Positive Advanced NSCLC,” JTO Clinical and Research Reports 3, no. 10 (2022): 100406.

[6] J. Mazieres, G. Zalcman, L. Crino, et al., “Crizotinib Therapy for Advanced Lung Adenocarcinoma and a ROS1 Rearrangement: Results From the EUROS1 Cohort,” Journal of Clinical Oncology 33, no. 9 (2015): 992–999.

[7] S. Michels, B. Massuti, H. U. Schildhaus, et al., “Safety and Efficacy of Crizotinib in Patients with Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial,” Journal of Thoracic Oncology 14, no. 7 (2019): 1266–1276.

[8] Y. L. Wu, J. C. Yang, D. W. Kim, et al., “Phase II Study of Crizotinib in East Asian Patients with ROS1-Positive Advanced Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology 36, no. 14 (2018): 1405–1411.

[9] A. Drilon, S. Siena, R. Dziadziuszko, et al., “Entrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer: Integrated Analysis of Three Phase 1–2 Trials,” Lancet Oncology 21, no. 2 (2020): 261–270.

[10] R. Dziadziuszko, M. G. Krebs, F. De Braud, et al., “Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion–Positive Non–Small-Cell Lung Cancer,” Journal of Clinical Oncology 39 (2021): 1253–1263.

[11] A. Drilon, C. H. Chiu, Y. Fan, et al., “Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC,” JTO Clinical and Research Reports 3, no. 6 (2022): 100332.

[12] A. T. Shaw, B. J. Solomon, R. Chiari, et al., “Lorlatinib in Advanced ROS1-Positive Non-Small-Cell Lung Cancer: A Multicentre, Open-Label, Single-Arm, Phase 1–2 Trial,” Lancet Oncology 20, no. 12 (2019): 1691–1701.

[13] H. Chen, Y. L. Wu, Z. Huang, et al., “MA06.05 A Phase II Study of Lorlatinib in Advanced ROS1+ NSCLC Pre-Treated With Crizotinib and Platinum-Based Chemotherapy,” Journal of Thoracic Oncology 19, no. 10 (2024): S74.

[14] B. C. Ahn, Y. J. Kim, D.-W. Kim, K. H. Lee, Y. Lee, and J.-Y. Han, “Lorlatinib in TKI-Naïve, Advanced ROS1-Positive Non-Small-Cell Lung Cancer a Multicenter, Open-Label, Single-Arm, Phase 2 Trial,” Journal of Clinical Oncology 42, no. 16_suppl (2024): 8519.

[15] A. Drilon, S. I. Ou, B. C. Cho, et al., “Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent-Front Mutations,” Cancer Discovery 8, no. 10 (2018): 1227–1236.

[16] A. Drilon, D. R. Camidge, J. J. Lin, et al., “Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer,” New England Journal of Medicine 390, no. 2 (2024): 118–131.

[17] W. Li, A. Xiong, N. Yang, et al., “Efficacy and Safety of Taletrectinib in Chinese Patients with ROS1+ Non-Small Cell Lung Cancer: The Phase II TRUST-I Study,” Journal of Clinical Oncology 42, no. 22 (2024): 2660–2670.

[18] L. Shen, T. Qiang, Z. Li, D. Ding, Y. Yu, and S. Lu, “First-Line Crizotinib Versus Platinum-Pemetrexed Chemotherapy in Patients With Advanced ROS1-Rearranged Non-Small-Cell Lung Cancer,” Cancer Medicine 9, no. 10 (2020): 3310–3318.

[19] K. Masuda, Y. Fujiwara, Y. Shinno, et al., “Efficacy and Safety of Crizotinib in Patients With ROS1 Rearranged Non-Small Cell Lung Cancer: A Retrospective Analysis,” Journal of Thoracic Disease 11, no. 7 (2019): 2965–2972.

[20] H. Xu, Q. Zhang, L. Liang, et al., “Crizotinib vs Platinum-Based Chemotherapy as First-Line Treatment For Advanced Non-Small Cell Lung Cancer With Different ROS1 Fusion Variants,” Cancer Medicine 9, no. 10 (2020): 3328–3336.

[21] C. Liu, H. Yu, J. Chang, et al., “Crizotinib in Chinese Patients With ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer in Routine Clinical Practice,” Target Oncology 14, no. 3 (2019): 315–323.

[22] E. Nadal, N. Rifi, S. Kane, et al., “Efficacy and Safety of Crizotinib in the Treatment of Advanced Non-Small Cell Lung Cancer With ROS1 Gene Fusion: A Systematic Literature Review and Meta-Analysis of Real-World Evidence,” Lung Cancer (Amsterdam, Netherlands) 192 (2024): 107816.

[23] Y. Xu, Y. Zhang, H. Qiang, H. Zhong, J. Xu, and R. Zhong, “Impact of PD-L1 Expression on the Efficacy of First-Line Crizotinib in Advanced ROS1-Rearranged NSCLC,” Lung Cancer (Amsterdam, Netherlands) 194 (2024): 107892.

[24] Y. He, W. Sheng, W. Hu, et al., “Different Types of ROS1 Fusion Partners Yield Comparable Efficacy to Crizotinib,” Oncology Research 27, no. 8 (2019): 901–910.

[25] Z. Li, L. Shen, D. Ding, et al., “Efficacy of Crizotinib Among Different Types of ROS1 Fusion Partners in Patients With ROS1-Rearranged Non-Small Cell Lung Cancer,” Journal of Thoracic Oncology 13, no. 7 (2018): 987–995.

[26] Y. Zhang, X. Zhang, R. Zhang, et al., “Clinical and Molecular Factors That Impact the Efficacy of First-Line Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer: A Large Multicenter Retrospective Study,” BMC Medicine 19, no. 1 (2021): 206.

[27] Z. Huang, Y. Zhang, Q. Xu, et al., “Clinical Treatment Patterns, Molecular Characteristics and Survival Outcomes of ROS1-Rearranged Non-Small Cell Lung Cancer: A Large Multicenter Retrospective Study,” Lung cancer (Amsterdam, Netherlands) 192 (2024): 107827.

[28] J. F. Gainor, D. Tseng, S. Yoda, et al., “Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non-Small-Cell Lung Cancer,” JCO Precision Oncology 2017 (2017): 1; PO.17.00063.

[29] C. E. McCoach, A. T. Le, K. Gowan, et al., “Resistance Mechanisms to Targeted Therapies in ROS1(+) and ALK(+) Non-Small Cell Lung Cancer,” Clinical Cancer Research 24, no. 14 (Jul 15 2018): 3334–3347.

[30] F. Facchinetti, Y. Loriot, M. S. Kuo, et al., “Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers,” Clinical Cancer Research 22, no. 24 (2016): 5983–5991.

[31] D. B. Costa, S. Kobayashi, S. S. Pandya, et al., “CSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor crizotinib,” Journal of Clinical Oncology 29, no. 15 (2011): e443-5.

[32] D. B. Costa, A. T. Shaw, S. H. Ou, et al., “Clinical Experience with Crizotinib in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases,” Journal of Clinical Oncology 33, no. 17 (2015): 1881–1888.

[33] G. Metro, G. Lunardi, P. Floridi, et al., “CSF Concentration of Crizotinib in Two ALK-Positive Non-Small-Cell Lung Cancer Patients With CNS Metastases Deriving Clinical Benefit From Treatment,” Journal of Thoracic Oncology 10, no. 5 (2015): e26–e27.

[34] B. J. Solomon, F. Cappuzzo, E. Felip, et al., “Intracranial Efficacy of Crizotinib versus Chemotherapy in Patients with Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results from PROFILE 1014,” Journal of Clinical Oncology 34, no. 24 (2016): 2858–2865.

[35] J. Mazieres, A. Drilon, A. Lusque, et al., “Immune Checkpoint Inhibitors for Patients With Advanced Lung Cancer and Oncogenic Driver Alterations: Results From the IMMUNOTARGET Registry,” Annals of Oncology 30, no. 8 (2019): 1321–1328.

[36] F. Guisier, C. Dubos-Arvis, F. Vinas, et al., “Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients with Advanced NSCLC with BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01–2018,” Journal of Thoracic Oncology 15, no. 4 (2020): 628–636.

[37] S. Lu, L. Wu, H. Jian, et al., “Sintilimab plus Bevacizumab Biosimilar IBI305 and Chemotherapy for Patients With EGFR-Mutated Non-Squamous Non-Small-Cell Lung Cancer Who Progressed on EGFR Tyrosine-Kinase Inhibitor Therapy (ORIENT-31): First Interim Results From a Randomised, Double-Blind, Multicentre, Phase 3 Trial,” The Lancet Oncology 23, no. 9 (2022): 1167–1179.

[38] W. Fang, Y. Zhao, Y. Luo, et al., “Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer with EGFR Variant: A Randomized Clinical Trial,” JAMA 332, no. 7 (2024): 561–570.

[39] R. Katayama, Y. Kobayashi, L. Friboulet, et al., “Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion-Positive Cancer,” Clinical Cancer Research 21, no. 1 (2015): 166–174.

Rights & permissions

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.