A Phase 1b Study of Osimertinib Plus Savolitinib in Patients with EGFR Mutation-Positive, MET-Amplified, Non-Small Cell Lung Cancer after Progression on EGFR-Tyrosine Kinase Inhibitors

Background: Preliminary data from the TATTON study (NCT02143466) suggested that savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET-tyrosine kinase inhibitor (TKI), plus osimertinib, a third-generation, irreversible EGFR-TKI which selectively inhibits both EGFR-TKI sensitising and T790M resistance mutations, may overcome MET-driven resistance to EGFR-TKIs in non-small cell lung cancer. Methods: Patients were ≥18 years with locally advanced/metastatic, METpositive, EGFR mutation-positive non-small cell lung cancer, whose disease had progressed on a prior EGFR-TKI. In Part B, patients received osimertinib 80 mg plus savolitinib 600 mg orally once daily; after a protocol amendment, some patients received savolitinib at 300 mg through weight-based dosing. In Part D, patients had received no prior thirdgeneration EGFR-TKI and were EGFR T790M-negative, and received osimertinib plus savolitinib 300 mg, regardless of weight. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate. Findings: In Part B, 138 patients received osimertinib plus savolitinib 600/300 mg. In Part D, 42 patients received osimertinib plus savolitinib 300 mg. In Parts B and D, 57% and 38% of patients experienced ≥Grade 3 adverse events (AEs), respectively. More patients in Part B had AEs possibly causally related to savolitinib (83% vs 60%), and serious AEs (45% vs 26%) vs Part D. Overall objective response rate (95% CI) was 48% (39-56) in Part B (30% [20-43] for patients with prior third-generation EGFR-TKI; 65% [50-78] and 67% [41-87] for patients with no prior thirdgeneration EGFR-TKI who were T790M-negative and T790M-positive, respectively). Objective response rate was 64% (46-79) in the T790Mnegative patients in Part D. Interpretation: This combination may address the unmet need for a targeted treatment option for patients with MET-driven resistance to EGFR-TKI treatment. Trial Registration: NCT02143466. Funding Statement: TATTON (NCT02143466) was funded by AstraZeneca, Cambridge, UK, manufacturers of savolitinib and osimertinib. Declaration of Interests: LVS has received research funding from AstraZeneca, Boehringer Ingelheim, Blueprint Medicines, Genentech, LOXO, Merrimack Pharmaceuticals, and Novartis; and received personal fees from AstraZeneca, Blueprint Medicines, Genentech, Janssen, and Merrimack Pharmceuticals. In addition, Dr. Sequist has a patent on treating EGFR-mutant cancer with osimertinib and BLU-667 pending. J-YH has received honoraria from MSD Oncology, Roche, AstraZeneca, and Takeda; received fees for consulting or advisory roles from Novartis, MSD Oncology, AstraZeneca, Lilly, and Takeda; and received research funding from Roche, Pfizer, and Ono Pharmaceutical. M-JA has received honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, and Roche; and received fees for consulting or advisory roles for AstraZeneca, Bristol-Myers Squibb, Takeda, MSD, Ono Pharmaceutical, Roche, and Alpha Pharmaceutical. BCC has received research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, and MSD; has received fees for consultancy from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BristolMyers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; and has stock ownership in TheraCanVac Inc, Gencurix Inc, and Bridgebio Therapeutics. In addition, Dr. Cho has a patent with Champions Oncology with royalties paid. HY has received fees for consultancy from AstraZeneca; and received research funding from AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, and Astellas. S-WK has recieved research funding and fees for consulting or advisory roles from AstraZeneca. JC-HY has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceuticals; and received honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, and Blueprint. JSL, W-CS, DK, and SO declare no competing interests. MC is an AstraZeneca contract employee and shareholder. RBV is an AstraZeneca employee and shareholder, and holds shares in Aduro Biotech. AM, PF are AstraZeneca employees and shareholders. XO is an AstraZeneca contract employee. GO has received honoraria from Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, and Foundation Medicine; and received fees for consulting or advisory roles from AstraZeneca, Inviata, Takeda, LOXO, Ignyta, DropWorks, GRAIL, Illumina, and Janssen. In addition, Dr. Oxnard has a patent with DFCI pending. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki Good Clinical Practice guidelines (as defined by the International Conference on Harmonisation), applicable regulatory requirements, and the policy on bioethics and human biological samples of the trial sponsor, AstraZeneca. All patients provided written informed consent.