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Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors
Xiaorong Dong1, Xingya Li2, Jianhua Chen3
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Introduction:
c-MET is an important therapeutic target for various cancers; however, the People's Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors.
Methods:
Patients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics.
Results:
A total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, Css,max was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET (MET exon 14-skipping, MET amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%.
Conclusions:
The selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.
Insights
The novel c-MET inhibitor HS-10241 shows good tolerability and antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). This selective inhibitor demonstrates therapeutic potential, particularly in patients with MET-positive tumors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- c-MET is a key therapeutic target in various cancers.
- Limited c-MET inhibitors are available in China.
- HS-10241 is a novel, highly selective c-MET inhibitor identified in preclinical studies.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HS-10241.
- To determine the maximal tolerated dose (MTD) of HS-10241 in patients with advanced solid tumors.
Main Methods:
- Phase 1 clinical trial involving 27 patients with advanced NSCLC.
- Oral administration of HS-10241 in six different dose regimens (once or twice daily).
- Treatment continued until disease progression or unacceptable toxicity; primary endpoints were dose-limiting toxicity and MTD.
Main Results:
- The MTD for once-daily dosing was 400 mg; MTD was not reached for twice-daily dosing (300 mg was the maximal safe escalated dose).
- Most frequent adverse events included nausea, fatigue, and anemia.
- A disease control rate of 80% was observed in 5 MET-positive patients, including one partial response.
Conclusions:
- HS-10241 is well-tolerated and exhibits clinical activity in advanced NSCLC patients.
- The drug shows particular promise in patients with MET-positive tumors.
- HS-10241 warrants further investigation for its therapeutic potential in cancer treatment.
