Alexander Drilon1, Jessica J Lin2, Thomas Filleron3, Ai Ni4, Julie Milia5, Isabella Bergagnini4, Vaios Hatzoglou4, Vamsidhar Velcheti6, Michael Offin7, Bob Li7, David P Carbone8, Benjamin Besse9, Tony Mok10, Mark M Awad11, Jurgen Wolf12, Dwight Owen8, D Ross Camidge13, Gregory J Riely7, Nir Peled14, Mark G Kris7, Julien Mazieres3, Justin F Gainor2, Oliver Gautschi15. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY. Electronic address: drilona@mskcc.org. 2. Department of Medicine, Massachusetts General Hospital, Boston, MA. 3. Department of Medicine, Oncopole University Cancer Institute, Toulouse, France. 4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 5. Department of Medicine, France Larrey Center University Hospital Toulouse, Toulouse, France. 6. Department of Medicine, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH. 7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY. 8. Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH. 9. Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France. 10. Department of Medicine, Chinese University of Hong Kong, Hong Kong, China. 11. Department of Medicine, Dana Farber Cancer Institute, Cambridge, MA. 12. Department of Medicine, Lung Cancer Group Cologne, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. 13. Department of Medicine, University of Colorado-Denver, Aurora, CO. 14. Department of Medicine, Davidoff Cancer Center, Petah Tikva, Israel. 15. Department of Medicine, Cantonal Hospital Lucerne, Luzern, Switzerland.
Abstract
INTRODUCTION: In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. METHODS: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. RESULTS: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months). CONCLUSIONS: Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.
INTRODUCTION: In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. METHODS: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancerpatients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. RESULTS: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months). CONCLUSIONS:Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.
Authors: Alexander Drilon; Geoffrey R Oxnard; Daniel S W Tan; Herbert H F Loong; Melissa Johnson; Justin Gainor; Caroline E McCoach; Oliver Gautschi; Benjamin Besse; Byoung C Cho; Nir Peled; Jared Weiss; Yu-Jung Kim; Yuichiro Ohe; Makoto Nishio; Keunchil Park; Jyoti Patel; Takashi Seto; Tomohiro Sakamoto; Ezra Rosen; Manisha H Shah; Fabrice Barlesi; Philippe A Cassier; Lyudmila Bazhenova; Filippo De Braud; Elena Garralda; Vamsidhar Velcheti; Miyako Satouchi; Kadoaki Ohashi; Nathan A Pennell; Karen L Reckamp; Grace K Dy; Jürgen Wolf; Benjamin Solomon; Gerald Falchook; Kevin Ebata; Michele Nguyen; Binoj Nair; Edward Y Zhu; Luxi Yang; Xin Huang; Elizabeth Olek; S Michael Rothenberg; Koichi Goto; Vivek Subbiah Journal: N Engl J Med Date: 2020-08-27 Impact factor: 91.245
Authors: Vivek Subbiah; Justin F Gainor; Geoffrey R Oxnard; Daniel S W Tan; Dwight H Owen; Byoung Chul Cho; Herbert H Loong; Caroline E McCoach; Jared Weiss; Yu Jung Kim; Lyudmila Bazhenova; Keunchil Park; Haruko Daga; Benjamin Besse; Oliver Gautschi; Christian Rolfo; Edward Y Zhu; Jennifer F Kherani; Xin Huang; Suhyun Kang; Alexander Drilon Journal: Clin Cancer Res Date: 2021-06-04 Impact factor: 12.531