Vivek Subbiah1, Mimi I Hu2, Lori J Wirth3, Martin Schuler4, Aaron S Mansfield5, Giuseppe Curigliano6, Marcia S Brose7, Viola W Zhu8, Sophie Leboulleux9, Daniel W Bowles10, Christina S Baik11, Douglas Adkins12, Bhumsuk Keam13, Ignacio Matos14, Elena Garralda14, Justin F Gainor15, Gilberto Lopes16, Chia-Chi Lin17, Yann Godbert18, Debashis Sarker19, Stephen G Miller20, Corinne Clifford20, Hui Zhang20, Christopher D Turner20, Matthew H Taylor21. 1. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vsubbiah@mdanderson.org. 2. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 4. West German Cancer Center Essen, Department of Medical Oncology, University Hospital Essen and German Cancer Consortium, Partner site University Hospital Essen, Essen, Germany. 5. Mayo Clinic, Rochester, MN, USA. 6. European Institute of Oncology, IRCCS and University of Milano, Milano, Italy. 7. Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA. 8. Department of Medicine, University of California Irvine School of Medicine, Orange, CA, USA. 9. Department of Nuclear Medicine and Endocrine Oncology, Gustav Roussy and University Paris Saclay, Villejuif, France. 10. Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA. 11. University of Washington School of Medicine, Seattle, WA, USA. 12. Washington University School of Medicine, St Louis, MO, USA. 13. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. 14. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 15. Massachusetts General Hospital, Boston, MA, USA. 16. Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA. 17. National Taiwan University Hospital, Taipei, Taiwan. 18. Bergonié Institute Cancer Center, Bordeaux, France. 19. Guy's Hospital, King's College London, London, UK. 20. Blueprint Medicines, Cambridge, MA, USA. 21. Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
Abstract
BACKGROUND: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. METHODS: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. FINDINGS: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. INTERPRETATION: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. FUNDING: Blueprint Medicines.
BACKGROUND: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. METHODS: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. FINDINGS: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. INTERPRETATION: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. FUNDING: Blueprint Medicines.
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