Safety, efficacy, and pharmacokinetics of SH‐1028 in EGFR T790M‐positive advanced non–small cell lung cancer patients: A dose‐escalation phase 1 study

• Published in: Cancer 2023-05, Vol.129 (10), p.1513-1522
• Main Authors: He, Jing, Ma, Pei, Zhao, Dongmei, Shi, Xinsheng, Guo, Renhua, Gao, Wen, Shu, Yongqian
• Format: Article
• Language: English
• Subjects: Adverse events; Anticancer properties; Antineoplastic Agents - adverse effects; Antitumor activity; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Diarrhea; Disease control; Drug resistance; Effectiveness; efficacy; EGFRT790M mutation; Epidermal growth factor receptors; ErbB Receptors - genetics; Health services; Humans; Kinases; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Metastases; Morbidity; Mutation; Non-small cell lung carcinoma; NSCLC; Oncology; Patients; Pharmacokinetics; Protein Kinase Inhibitors - adverse effects; Protein-tyrosine kinase; Safety; Safety management; SH‐1028; Small cell lung carcinoma; Toxic diseases; Toxicity; Tyrosine
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.34697

Background SH‐1028 is a new third‐generation EGFR tyrosine kinase inhibitors (TKI) to benefit patients with EGFR T790M‐mutated NSCLC. Here, the authors report its clinical safety, preliminary efficacy, and pharmacokinetic (PK) profile for the first time. Methods Patients with EGFR T790M mutation, locally advanced non–small cell lung cancer (NSCLC), or metastatic NSCLC who had progressed after previous EGFR TKI therapy were eligible. Patients received SH‐1028 at five oral dose levels (60 mg, 100 mg, 200 mg, 300 mg, and 400 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were the safety, dose‐limiting toxicity (DLT), maximum‐tolerated dose (MTD), and PK profile. Secondary end points included objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), etc. Results Data cut off on December 31, 2020, a total of 20 patients were enrolled during the trial, two of three patients in 300 mg cohort experienced a DLT, and no DLT was observed in 240 mg cohort, 240 mg was determined to be the MTD of SH‐1028. A total of 95.0% (19 of 20) of patients reported treatment‐related adverse events (TRAEs), and the incidence of serious adverse events was 20.0% (4 of 20). The ORR and DCR of the 200 mg cohort were 75% (95% confidence interval [CI], 19.41–99.37) and 75.0% (95% CI, 19.41–99.37), respectively. The overall ORR was 40% (95% CI, 19.12–63.95), and DCR was 70.0% (95% CI, 45.72–88.11). According to the PK profile, the dosage regimen for future studies was determined as 200 mg once daily. Conclusions SH‐1028 showed a manageable safety and promising antitumor activity in patients with EGFR T790M mutation at the dose of 200 mg once daily. Plain language summary Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non–small cell lung cancer accounts for approximately 85% of lung cancer. First‐ or second‐generation EGFR TKIs' weak selectivity often led to the occurrence of treatment‐related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year. A dose of 200 mg of SH‐1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation. SH‐1028 and its active metabolite Imp3 have a weak inhibitory effect on wild‐type EGFR, which may ensure the targeted efficacy of the drug for EGFR‐mutated non–small cell lung cancer pa