Justin F Gainor1, Giuseppe Curigliano2, Dong-Wan Kim3, Dae Ho Lee4, Benjamin Besse5, Christina S Baik6, Robert C Doebele7, Philippe A Cassier8, Gilberto Lopes9, Daniel S W Tan10, Elena Garralda11, Luis G Paz-Ares12, Byoung Chul Cho13, Shirish M Gadgeel14, Michael Thomas15, Stephen V Liu16, Matthew H Taylor17, Aaron S Mansfield18, Viola W Zhu19, Corinne Clifford20, Hui Zhang21, Michael Palmer22, Jennifer Green23, Christopher D Turner23, Vivek Subbiah24. 1. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Electronic address: jgainor@partners.org. 2. Department of Oncology and Hemato-Oncology, University of Milan and European Institute of Oncology, IRCCS, Milan, Italy. 3. Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea. 4. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. 5. Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France; Paris-Saclay University, Orsay, France. 6. Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA. 7. Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA. 8. Department of Medicine, Centre Léon Bérard, Lyon, France. 9. Miller School of Medicine and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. 10. Division of Medical Oncology, National Cancer Centre Singapore, Singapore. 11. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 12. Medical Oncology Department, Hospital Universitario 12 de Octubre and Spanish National Cancer Research Center, Madrid, Spain. 13. Division of Medical Oncology, Department of Internal Medicine and Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. 14. Division of Hematology and Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA. 15. Department of Thoracic Oncology, Translational Lung Research Center Heidelberg, Thoraxklinik Heidelberg University Hospital, Heidelberg, Germany. 16. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. 17. Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. 18. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA. 19. Division of Hematology-Oncology, Department of Medicine, University of California Irvine, Orange, CA, USA. 20. Clinical Operations, Blueprint Medicines, Cambridge, MA, USA. 21. Biostatistics, Blueprint Medicines, Cambridge, MA, USA. 22. Translational Medicine, Blueprint Medicines, Cambridge, MA, USA. 23. Clinical Development, Blueprint Medicines, Cambridge, MA, USA. 24. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. FUNDING: Blueprint Medicines.
BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. FUNDING: Blueprint Medicines.
Authors: Jacob J Adashek; Aakash P Desai; Alexander Y Andreev-Drakhlin; Jason Roszik; Gilbert J Cote; Vivek Subbiah Journal: Mol Cancer Ther Date: 2021-09-06 Impact factor: 6.261
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