TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer
| Autor: | Hideo Saka, Dana Ghiorghiu, Yuichiro Ohe, Helena A. Yu, Leora Horn, Suresh S. Ramalingam, Geoffrey R. Oxnard, J.C.-H. Yang, Helen Mann, Kenneth S. Thress, Karthick Vishwanathan, Melanie M. Frigault, Myung-Ju Ahn, Sang We Kim, Koichi Goto |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Lung Neoplasms Durvalumab Nausea Gastroenterology 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Osimertinib Lung cancer Protein Kinase Inhibitors Acrylamides Aniline Compounds Triazines business.industry Antibodies Monoclonal Hematology medicine.disease Rash ErbB Receptors 030104 developmental biology Oncology Tolerability Savolitinib Pyrazines 030220 oncology & carcinogenesis Mutation Selumetinib Benzimidazoles medicine.symptom business |
| Zdroj: | Annals of Oncology. 31:507-516 |
| ISSN: | 0923-7534 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|