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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., Competing Interests: Disclosure GO has declared honoraria from Chugai Pharma, Bio-Rad, Sysmex, and Guardant Health, and consultancy fees from AstraZeneca, Inivata, Takeda, LOXO, Ignyta, DropWorks, and GRAIL. JY has declared honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharma, MSD, Novartis, and Roche; and consulting or advisory fees from Astellas Pharma, AstraZeneca, AstraZeneca (Inst), Bayer, Boehringer Ingelheim, Boehringer Ingelheim (Inst), Bristol-Myers Squibb, Celgene, Clovis Oncology, Hansoh, Lilly, Merck Serono, MSD Oncology, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, and Yuhan. HY has declared consultancy fees from AstraZeneca and Lilly Oncology; and research funding from AstraZeneca, Daiichi, Lilly Oncology, and Novartis. HS has declared honoraria and research funding from AstraZeneca. LH has declared consultancy fees from AstraZeneca, Lilly, Merck, Roche-Genentech, EMD Serono, Incyte, and Xcovery; and research funding from Boehringer Ingelheim and Xcovery. KG has declared honoraria from Bristol-Myers Squibb, AstraZeneca, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Lilly, Boehringher Ingelheim, Quintiles, Merck Serono, Life Technologies, MSD, AbbVie, Riken Genesis, Nippon Kayaku, Takeda, and Otsuka Pharmaceutical; consulting or advisory fees from Otskua; and research funding from MSD, AstraZeneca, Taiho Pharmaceutical, Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon, Takeda, Novartis, Daiichi Sankyo, Kyowa Hakko Kirin, Astellas Pharma, Eisai, Lilly, Pfizer, Riken Genesis, Bristol-Myers Squibb, Merck Serono, Ignyta, Life Technologies, Research Triangle Institue d/b/a RTI Health Solutions, Janssen, Xcoo, and Loxo. YO has declared grants and honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai, Pfizer, Lilly, MSD, Novartis, Ono Pharmaceutical; grants from Dainippon-Sumitomo and Kyorin; and honoraria from Bayer, Boehringer Ingelheim, and Nippon Kayaku. SR has declared grants and honoraria from Merck, Tesaro, Amgen, AstraZeneca, Abbvie, Bristol-Myers Squibb, Lilly, Genentech, Takeda, Merck, Luxo, and Tesaro. M-JA has declared honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, and Roche; and consulting or advisory fees from AstraZeneca, Bristol-Myers Squibb, Takeda, MSD, Ono Pharmaceutical, Roche, and Alpha Pharmaceutical. KT is an employee and stockholder at AstraZeneca and Tesaro. HM, MF, KV, and DG are employees and stockholders at AstraZeneca. S-WK has declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)