Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial
Open accessAbstract
Introduction As a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation.Methods This was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first- or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intolerable toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tumors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on.Results A total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 patients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee-assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4-68.8) in part A and 60.4% (95% CI: 53.7-66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3-20.8) in part A and 12.6 months (95% CI: 9.7-15.3) in part B. The median OS was 26.0 months (95% CI: 23.3-not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study.Conclusions SH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M.
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Oritinib binds irreversibly to EGFR kinase by covalently bonding to Cys797 residues targeting ATP binding sites.
“Oritinib binds irreversibly to EGFR kinase by covalently bonding to form Cys797 residues targeting ATP binding sites.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [164]
Oritinib overcomes T790M-mediated drug resistance in NSCLC and inhibits WT-EGFR, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750, and EGFRd746-750/T790M kinases, with IC50 values of 18, 0.7, 4, 0.1, 1.4, and 0.89 nM, respectively.
“Oritinib overcomes T790M-mediated drug resistance in NSCLC and inhibits WT-EGFR, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750, and EGFRd746-750/T790M kinases. IC50 were 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [164]
Oritinib effectively and selectively targets mutated EGFR cell lines in vitro.
“Oritinib effectively and selectively targets mutated EGFR cell lines in vitro.142,163–165”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [164]
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- Authors
- Xiong, A., Ren, S., Liu, H., Miao, L., Wang, L., Chen, J., Li, W., Li, R., Wang, X., Lu, Z., Wang, D., Wu, X., Liu, Z., Xing, L., Mao, Y., Liu, C., Zeng, A., Niu, H., Du, Y., Sun, Y., Pan, Y., Hu, Y., Zhang, X., Chen, X., Ma, Z., Li, N., Zhang, J., Zhao, M., Li, X., Ye, F., Li, M., Yu, G., Zhang, X., Min, J., Han, D., Li, J., & Zhou, C.
- Affiliations
- Tongji University (CN)
- Zhengzhou University (CN)
- Nanjing Drum Tower Hospital (CN)
- Central South University (CN)
- Xuzhou Central Hospital (CN)
- Wannan Medical College (CN)
- Chongqing University (CN)
- Wuxi Fourth People's Hospital (CN)
- Jiangxi Provincial Cancer Hospital (CN)
- Shandong Tumor Hospital (CN)
- First Affiliated Hospital of Henan University of Science and Technology (CN)
- Xinjiang Medical University (CN)
- Tumor Hospital of Guangxi Medical University (CN)
- First Affiliated Hospital of Xinxiang Medical University (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Jinan Central Hospital (CN)
- Anhui Provincial Hospital (CN)
- Hubei Cancer Hospital (CN)
- Nantong University (CN)
- Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN)
- Zunyi Medical University (CN)
- Liaoning Cancer Hospital & Institute (CN)
- First Affiliated Hospital of Xiamen University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Weifang People's Hospital (CN)
- Nanjing Sanhome Pharmaceutical Co., Ltd. (China) (CN)
- Corresponding author
- Zhou, Caicun
- ORCID
- Ren, Shengxiang
- Liu, Huaimin
- Miao, Liyun
- Wang, Lei
- Chen, Jianhua
- Wang, Xiang
- Lu, Zhiwei
- Wang, Donglin
- Wu, Xiaohong
- Liu, Zhihua
- Xing, Ligang
- Mao, Yimin
- Liu, Chunling
- Du, Yingying
- Sun, Yuping
- Pan, Yueyin
- Hu, Yanping
- Zhang, Xiaodong
- Chen, Xueqin
- Ma, Zhiyong
- Li, Na
- Zhang, Jianyong
- Zhao, Min
- Li, Xiaoling
- Ye, Feng
- Li, Mingjun
- Yu, Guohua
- Zhang, Xiaomeng
- Han, Dong
- Li, Jin
- Zhou, Caicun
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2022-10
- Volume
- 17
- Issue
- 10
- Pages
- 1216-1226
- ISSN
- 1556-0864 (ISSN-L)
- OpenAlex
- W4283812058
- Cited by
- 20
- References
- 23
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 2 · 2023: 6 · 2022: 3
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Merck Sharp and Dohme
- Innovent Biologics
- Merck
- Program of Shanghai Academic Research Leader (21XD1423200)
- Roche
- Tongji University Affiliated Shanghai Pulmonary Hospital
- Sanofi
- Boehringer Ingelheim
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- T790M mutation, non-small cell lung cancer, third-generation EGFR tyrosine kinase inhibitors, second-line therapy, objective response rate, progression-free survival, overall survival, drug safety, adverse events, dose-limiting toxicity, central nervous system metastasis, brain metastases, pharmacokinetics
- MeSH terms
- Aniline Compounds, Carcinoma, Non-Small-Cell Lung, Creatinine, Humans, Lung Neoplasms, Mutation, Protein Kinase Inhibitors, ErbB Receptors
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