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

Autor: Anders Mellemgaard, Ghada F. Ahmed, Xiaoling Ou, Geoffrey R. Oxnard, Kiyotaka Yoh, Toyoaki Hida, Yuichiro Ohe, Hideo Saka, Manabu Hayama, Tomonori Hirashima, Ko Sugibayashi, Takayasu Kurata, Remy B. Verheijen
Rok vydání: 2021
Předmět:
Zdroj: Targeted Oncology
ISSN: 1776-260X
1776-2596
Popis: 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. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00806-5.
Plain Language Summary For patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors, like osimertinib, are the standard treatment. However, for most patients, these treatments eventually stop working, as tumors develop resistance to them. Early studies suggest that combining osimertinib with savolitinib can overcome this resistance. We report Part C of the four-part TATTON study, in which two groups of Japanese adult patients received treatment. One group received savolitinib 400 mg once daily, then 600 mg. The other group received osimertinib 80 mg with savolitinib 300/400/600 mg once daily. The main objective of the study was to determine the maximum dose of savolitinib that patients could receive (maximum tolerated dose) and to monitor the safety of the combination. Overall, 17 patients received savolitinib alone and 12 received the combination. The maximum tolerated dose of savolitinib was found to be 400 mg once daily in both groups of patients. The data demonstrated that savolitinib had acceptable safety outcomes either alone, or in combination with osimertinib. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00806-5.
Databáze: OpenAIRE
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