Background: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. Methods: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466. Findings: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39–56) patients in part B and 23 (64%; 46–79) in part D. Interpretation: The combination of osimertinib and savolitinib has acceptable risk–benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. Funding: AstraZeneca.
Bibliographical noteFunding Information:
LVS has received research funding from AstraZeneca, Boehringer Ingelheim, Blueprint Medicines, Genentech, LOXO, Merrimack Pharmaceuticals, and Novartis; has received personal fees from AstraZeneca, Blueprint Medicines, Genentech, Janssen, and Merrimack Pharmaceuticals; and 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; fees for consulting or advisory roles from Novartis, MSD Oncology, AstraZeneca, Lilly, and Takeda; and research funding from Roche, Takeda, Pfizer, and Ono Pharmaceutical. M-JA has received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Ono Pharmaceutical, and Roche; and fees for consulting or advisory roles from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Ono Pharmaceutical, Roche, Takeda, 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 Merck Sharp & Dohme; has received personal fees from Novartis, AstraZeneca, Janssen, Yuhan, Ono Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Pfizer, Eli Lilly, and Takeda; has stock ownership in TheraCanVac, Gencurix, and Bridgebio Therapeutics; and has a patent with Champions Oncology with royalties paid. HY has received fees for consultancy from AstraZeneca; and research funding from AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, and Astellas. S-WK has received research funding and fees for consulting or advisory roles from AstraZeneca. JC-HY has received honoraria for speeches and advisory boards from Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Merck Sharp & Dohme, Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceutical; and honoraria for advisory boards from AstraZeneca, Astellas, Merck Serono, Celgene, Merrimack, Yuhan Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, and Blueprint Medicines. MC is an AstraZeneca contract employee and shareholder. RBV is an AstraZeneca employee and shareholder, and holds shares in Aduro Biotech. AM and PF are AstraZeneca employees and shareholders. LO is an AstraZeneca employee. XO is an AstraZeneca contract employee. GO has received honoraria from Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, and Foundation Medicine; has received fees for consulting or advisory roles from AstraZeneca, Inviata, Takeda, LOXO, Ignyta, DropWorks, GRAIL, Illumina, and Janssen; and has a patent with Dana-Farber Cancer Institute pending. JSL, W-CS, DK, and SO declare no competing interests.
The study was funded by AstraZeneca, the manufacturers of savolitinib and osimertinib. We thank all of the patients and their families, as well as the staff and investigators at all of the study sites. We acknowledge Indira Hara and Hugo Xavier of AstraZeneca (Cambridge, UK) for patient safety input, and Bernadette Tynan of iMed Comms (Macclesfield, UK; an Ashfield Company, part of UDG Healthcare) for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines.
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