TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer
Journal
Annals of Oncology
Journal Volume
31
Journal Issue
4
Pages
507-516
Date Issued
2020
Author(s)
Oxnard G.R.
Yu H.
Kim S.-W.
Saka H.
Horn L.
Goto K.
Ohe Y.
Mann H.
Thress K.S.
Frigault M.M.
Vishwanathan K.
Ghiorghiu D.
Ramalingam S.S.
Ahn M.-J.
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. ? 2020 European Society for Medical Oncology
Subjects
combination; EGFR mutation; non-small cell lung cancer; osimertinib; phase I
SDGs
Other Subjects
alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; durvalumab; epidermal growth factor receptor; osimertinib; programmed death 1 ligand 1; savolitinib; scatter factor receptor; selumetinib; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; acrylamide derivative; aniline derivative; antineoplastic agent; benzimidazole derivative; durvalumab; EGFR protein, human; epidermal growth factor receptor; monoclonal antibody; osimertinib; protein kinase inhibitor; pyrazine derivative; selumetinib; triazine derivative; adult; aged; anemia; Article; asthenia; constipation; controlled clinical trial; controlled study; coughing; decreased appetite; dermatitis; diarrhea; dizziness; drug dose escalation; drug intermittent therapy; drug safety; drug tolerability; drug withdrawal; dry skin; dyspnea; fatigue; female; fever; gene mutation; headache; human; hyperglycemia; hypertransaminasemia; hypoalbuminemia; hyponatremia; interstitial lung disease; leukocyte count; lung embolism; major clinical study; male; molecularly targeted therapy; multicenter study; nausea; neutropenia; neutrophil count; non small cell lung cancer; open study; paronychia; peripheral edema; phase 1 clinical trial; pneumonia; priority journal; pruritus; rash; side effect; stomatitis; thrombocytopenia; vomiting; clinical trial; genetics; lung tumor; mutation; Acrylamides; Aniline Compounds; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrazines; Triazines
Publisher
Elsevier Ltd
Type
journal article