First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity

Abstract

Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). Patients and Methods: This open-label, multicenter doseescalation and-expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 þ 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N ¼ 1, 800 mg N ¼ 1, and 1,000 mg N ¼ 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 hÁng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

“…Indeed, there is clinical rationale for exploring ALK/MET combinations besides lorlatinib/crizotinib. For example, while cross-trial comparisons suggest that most adverse events, including nausea/vomiting and edema, occur at comparable rates with the three MET TKIs evaluated in cell lines (crizotinib, capmatinib, savolitinib), 4,27,28 the blood-brain barrier penetration of capmatinib is superior to crizotinib. Capmatinib may therefore be a more optimal partner for lorlatinib in patients with brain metastases.…”

Comprehensive review of targeted therapy for colorectal cancer

“…AMG 337, an oral ATP-competitive TKI specific to MET, caused a strong response in patients with MET-amplified upper gastrointestinal tract cancer in phase I and II trials. 325,326 Savolitinib, a selective MET inhibitor, displayed marked antitumour potential under experimental conditions and appeared to be effective against renal cell cancer 327,328 and is being investigated in a metastatic CRC phase I trial. Capmatinib, another selective MET inhibitor, has been demonstrated as a good supplementary agent to gefitinib in patients with EGFR-mutant, MET-amplified NSCLC.…”

First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer

“…The most common AEs were increased blood creatinine (52%), nausea (48), decreased appetite (41%), vomiting (39%), and diarrhea (25%). The gastrointestinal symptoms, such as vomiting and diarrhea, were also observed frequently with savolitinib [17], while less reported (≤ 10%) with BIP-9016M. Furthermore, the ATTENTION trial was terminated because of an increased incidence of interstitial lung disease in the tivantinib group [30].…”

“…Monoclonal antibodies that directly against HGF or MET, such as onartuzumab, rilotumumab, and emibetuzumab, have entered early phase clinical trials and demonstrated promising activity [13,14]. Several small-molecule tyrosine kinase inhibitors that inhibit a number of intracellular pathways including MET, such as cabozantinib, savolitinib, and capmatinib, are also under development [15][16][17].…”