Savolitinib ± Osimertinib in Japanese Patients with Advanced Solid Malignancies or EGFRm NSCLC: Ph1b TATTON Part C

Kiyotaka Yoh, Tomonori Hirashima, Hideo Saka, Takayasu Kurata, Yuichiro Ohe, Toyoaki Hida, Anders Mellemgaard, Remy B Verheijen, Xiaoling Ou, Ghada F Ahmed, Manabu Hayama, Ko Sugibayashi, Geoffrey R Oxnard, Kiyotaka Yoh, Tomonori Hirashima, Hideo Saka, Takayasu Kurata, Yuichiro Ohe, Toyoaki Hida, Anders Mellemgaard, Remy B Verheijen, Xiaoling Ou, Ghada F Ahmed, Manabu Hayama, Ko Sugibayashi, Geoffrey R Oxnard

Abstract

Background: Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs.

Objective: To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies.

Patients and methods: In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition.

Results: Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients.

Conclusions: The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib.

Trial registration: Clinicaltrials.gov; NCT02143466; 21 May 2014.

Conflict of interest statement

KY received honoraria and research funds from AstraZeneca. TH received honoraria from Ono, Eli Lilly, AstraZeneca, Taiho, Chugai, MSD and Boehringer Ingelheim; research funds from Ono, Eli Lilly, AstraZeneca, Taiho, Chugai, Merck Serono, MSD and Boehringer Ingelheim. HS received honoraria from AstraZeneca and research funds from MSD, AstraZeneca, BMS, Takeda, Ono and Parexel. TK received honoraria from AstraZeneca, Eli Lilly, MSD, Ono, Boehringer Ingelheim, Chugai and Bristol Myers; research funds from Bristol Myers, Takeda, MSD, AstraZeneca and Novartis. YO received honoraria from AstraZeneca and Chugai; research funds from AstraZeneca, Chugai, ONO, BMS, Kyorin, Dainippon- Sumitomo, Taiho, Kissei, Ignyta, Takeda, Janssen and LOXO. TH received honoraria and research funds from AstraZeneca and Novartis. AM reports employment for AstraZeneca. RBV reports former employment for AstraZeneca and current employment for Johnson & Johnson; holding shares of AstraZeneca, Aduro Biotech and Johnson & Johnson. GFA reports former employment for AstraZeneca and current employment for UCB Pharma Ltd. MH, XO, KS report employment for AstraZeneca. GO reports employment for Foundation Medicine and honoraria from AstraZeneca.

Figures

Fig. 1
Fig. 1
Patient disposition. “Other” included progression of disease clinically. AE adverse event, PD progressive disease, PK pharmacokinetics
Fig. 2
Fig. 2
Dose-limiting toxicities (DLTs) across doses in (a) monotherapy in patients with advanced solid malignancies and (b) combination therapy in patients with epidermal growth factor receptor mutation positive advanced non-small cell lung cancer. ALT alanine aminotransferase, AST aspartate aminotransferase. *Not recovered/not resolved
Fig. 3
Fig. 3
Waterfall plot of the best percentage change in target lesion size in (a) patients with advanced solid malignancies receiving savolitinib monotherapy and (b) patients with epidermal growth factor receptor mutation positive advanced non-small-cell lung cancer receiving savolitinib + osimertinib combination therapy (by dose of savolitinib)

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