TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

• Published in: Annals of oncology Vol. 31; no. 4; pp. 507 - 516
• Main Authors: Oxnard, G.R., Yang, J.C.-H., 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.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2020
• Subjects: Acrylamides; Aniline Compounds - therapeutic use; Antibodies, Monoclonal - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Benzimidazoles; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; combination; EGFR mutation; ErbB Receptors - genetics; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Mutation; non-small cell lung cancer; osimertinib; phase I; Protein Kinase Inhibitors - adverse effects; Pyrazines; Triazines; EGFR mutation; non-small cell lung cancer; phase I; osimertinib; combination
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1016/j.annonc.2020.01.013

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 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).
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.
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.
NCT02143466.
•Patients with advanced EGFR-mutant NSCLC received osimertinib 80 mg combined with selumetinib, savolitinib or durvalumab.•Feasible dosing strategies were identified for osimertinib plus selumetinib or savolitinib.•Osimertinib plus durvalumab was not feasible due to increased reporting of interstitial lung disease.•Responses were seen in all treatment arms, warranting further analysis of the feasible combinations identified.•Osimertinib-based combinations represent a compelling approach now being investigated broadly to further improve outcomes.