Preliminary data suggest that combining savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a 3rd generation, irreversible, oral epidermal growth factor receptor (EGFR) TKI that potently and selectively inhibits both EGFR mutations (EGFRm) and EGFR T790M, may overcome MET-driven resistance to EGFR-TKIs. The maximum tolerated dose (MTD) of savolitinib regimens in Japanese pts was evaluated in Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study (NCT02143466).
Two dose-finding cohorts of pts (≥20 years) received savolitinib monotherapy (pts with advanced solid malignancies; savolitinib 400/600 mg once daily [QD]) or savolitinib/osimertinib combination therapy (pts with EGFRm non-small cell lung cancer [NSCLC] who progressed on 1st/2nd-generation EGFR-TKI; osimertinib 80 mg + savolitinib 300/400/600 mg QD). Primary endpoints were safety/tolerability and to define the combination dose(s) for further clinical evaluation. Secondary endpoints for combination included evaluation of tumor response.
Seventeen pts received savolitinib monotherapy (400 mg, n=7/17; 600 mg, n=10/17) and 12 received the combination (savolitinib dose 300 mg, n=2/12; 400 mg, n=6/12; 600 mg, n=4/12). Serious adverse events (AE) were reported in 5/17 and 3/12 of pts, and AEs possibly causally related to savolitinib leading to its discontinuation were reported in 3/17 and 6/12 respectively. Dose-limiting toxicities data are included in the table, all except one were reversible. Pts receiving the combination (across doses) had an objective response rate of 42% (95% confidence interval 15.2, 72.3).
The MTD of savolitinib was 400 mg QD in both monotherapy and combination cohorts. Preliminary data demonstrate an acceptable safety profile for savolitinib and suggest antitumor activity in combination with osimertinib in Japanese pts with EGFRm NSCLC *n=1 for all events #Not recovered/not resolved †Guidelines are now in place regarding hypersensitivity-related AEs ALT, alanine aminotransferase; AST, aspartate aminotransferase; DLT, Dose-limiting toxicity
Dose Evaluable patients with DLT DLT* Monotherapy Savolitinib 400 mg 0/6 Savolitinib 600 mg 3/9 Grade 3 ALT increase, Grade 3 AST increase Grade 4 ALT increase, Grade 4 AST increase Grade 4 drug-induced liver injury# Combination therapy Savolitinib 300 mg + Osimertinib 80 mg 0/2 Savolitinib 400 mg + Osimertinib 80 mg 1/6 Grade 2 fatigue, Grade 2 nausea, Grade 2 myalgia Savolitinib 600 mg + Osimertinib 80 mg 3/4 Grade 2 pyrexia† Grade 3 skin reaction Grade 3 anaphylactic shock†
NCT02143466.
Bernadette Tynan, MSc, of Ashfield Healthcare Communications, Macclesfield, UK, for medical writing support that was funded by AstraZeneca, Cambridge, UK, in accordance with Good Publications Practice (GPP3) guidelines.
AstraZeneca.
AstraZeneca.
T. Hirashima: Honoraria (self), Research grant/Funding (self): Ono Pharmaceutical Co. Ltd; Honoraria (self), Research grant/Funding (self): Lilly Japan Co. Ltd.; Honoraria (self), Research grant/Funding (self): AstraZeneca Co. Ltd.; Honoraria (self), Research grant/Funding (self): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant/Funding (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant/Funding (self): MSD Oncology Co.; Honoraria (self), Research grant/Funding (self): Boehringer Ingelheim; Research grant/Funding (self): Merck Serono Co. Ltd. K. Yoh: Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Lilly Japan; Honoraria (self): Novartis; Honoraria (self): Kirin; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Taiho. H. Saka: Honoraria (self), Research grant/Funding (self): AstraZeneca. T. Kurata: Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): Eli lilly; Honoraria (self), Research grant/Funding (self): MSD; Honoraria (self): Ono; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai; Honoraria (self), Research grant/Funding (self): Bristol-Myers; Research grant/Funding (self): Takeda; Research grant/Funding (self): Novartis. Y. Ohe: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca, Chugai, ONO, Bristol-Myers Squibb; Research grant/Funding (self): Takeda; Advisory/Consultancy, Research grant/Funding (self): Kyorin; Advisory/Consultancy: Celltrion; Advisory/Consultancy: Amgen; Advisory/Consultancy: Nippon Kayaku; Honoraria (self): Eli Lilly; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bayer; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self): MSD; Honoraria (self), Research grant/Funding (self): Taiho; Honoraria (self): Nippon Kayaku; Honoraria (self): Kyowa Hakko Kirin; Research grant/Funding (self): Lilly; Research grant/Funding (self): Dainippon- Sumitomo; Research grant/Funding (self): Novartis; Research grant/Funding (self): Ignyta; Research grant/Funding (self): Kissei; Research grant/Funding (self): Daiichi-Sankyo, Janssen, Loxo. T. Hida: Honoraria (self): Ono Pharmaceutical; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Meyers Squibb; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Novartis. A. Mellemgaard: Full/Part-time employment: AstraZeneca. R.B. Verheijen: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca; Full/Part-time employment: Johnson&Johnson; Shareholder/Stockholder/Stock options: Aduro Biotech. X. Ou: Full/Part-time employment, Contracted with AstraZeneca through Phastar: AstraZeneca. M. Hayama, K. Sugibayashi: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. G. Oxnard: Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Honoraria (self): Sysmex; Advisory/Consultancy: AbbVie; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: DropWorks; Advisory/Consultancy: GRAIL; Advisory/Consultancy: Illumina; Advisory/Consultancy: Inviata; Advisory/Consultancy: Janssen; Advisory/Consultancy: Loxo; Advisory/Consultancy: Takeda; Licensing/Royalties, DCFI patent describing blood-based cancer monitoring: DFCI; Full/Part-time employment, Commencing June 15th: Foundation Medicine.