G R Oxnard1, J C-H Yang2, H Yu3, S-W Kim4, H Saka5, L Horn6, K Goto7, Y Ohe8, H Mann9, K S Thress10, M M Frigault10, K Vishwanathan11, D Ghiorghiu9, S S Ramalingam12, M-J Ahn13. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. Electronic address: geoffrey_oxnard@dfci.harvard.edu. 2. Department of Oncology, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan. 3. Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, USA. 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 5. Clinical Research Center, Nagoya Medical Center, Nagoya, Japan. 6. Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, USA. 7. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 8. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. 9. AstraZeneca R&D, Cambridge, UK. 10. Translational Medicine, Research and Early Development, Oncology R&D, AstraZeneca, Boston, USA. 11. Clinical Pharmacology and Safety Science, R&D, AstraZeneca, Boston, USA. 12. Department of Hematology and Medical Oncology, Emory University, Winship Cancer Institute, Atlanta, USA. 13. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Abstract
BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. CLINICAL TRIALS NUMBER: NCT02143466.
BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. CLINICAL TRIALS NUMBER: NCT02143466.
Authors: Michael Zhang; Adrian J Rodrigues; Erqi L Pollom; Iris C Gibbs; Scott G Soltys; Steven L Hancock; Joel W Neal; Sukhmani K Padda; Kavitha J Ramchandran; Heather A Wakelee; Steven D Chang; Michael Lim; Melanie Hayden Gephart; Gordon Li Journal: J Neurooncol Date: 2021-01-07 Impact factor: 4.130
Authors: Jia Luo; Alex Makhnin; Yosef Tobi; Linda Ahn; Sara A Hayes; Afsheen Iqbal; Kenneth Ng; Maria E Arcila; Gregory J Riely; Mark G Kris; Helena A Yu Journal: JCO Precis Oncol Date: 2021-01-11
Authors: Julie R Brahmer; Hamzah Abu-Sbeih; Paolo Antonio Ascierto; Jill Brufsky; Laura C Cappelli; Frank B Cortazar; David E Gerber; Lamya Hamad; Eric Hansen; Douglas B Johnson; Mario E Lacouture; Gregory A Masters; Jarushka Naidoo; Michele Nanni; Miguel-Angel Perales; Igor Puzanov; Bianca D Santomasso; Satish P Shanbhag; Rajeev Sharma; Dimitra Skondra; Jeffrey A Sosman; Michelle Turner; Marc S Ernstoff Journal: J Immunother Cancer Date: 2021-06 Impact factor: 13.751