| Citation: |
TAN Dengxu, LIU Ke, MA Yifan, WANG Yongfeng, ZHANG Yanying, SHI Changhong. Efficacy and Safety of KRASG12C Inhibitors in Advanced Solid Tumors with KRASG12C-mutated: A Single-arm Meta-analysis[J]. Cancer Research on Prevention and Treatment, 2023, 50(7): 688-693. DOI: 10.3971/j.issn.1000-8578.2023.22.1524
|
To systematically study the efficacy and safety of KRASG12C inhibitors in advanced solid tumors with KRASG12C-mutated.
Computer searches from PubMed, The Cochrane Library, Web of Science, Embase, CNKI, and CBM databases were conducted to collect clinical studies on KRASG12C inhibitors in advanced solid tumors with KRASG12C-mutated, with a search time from inception to October 12, 2022. Then, two investigators independently screened the literature, extracted information, assessed the risk of bias in included studies, and performed meta-analyses using RevMan 5.4 software.
There were four publications included, all of which were single-arm clinical studies. The KRASG12C inhibitors that completed clinical phase Ⅰ and Ⅱ trials were sotorasib and adagrasib, with two publications each. A total of 388 and 394 patients were included in the efficacy evaluation and safety evaluation, respectively. Resultsof the Meta-analysis showed that the patients had objective response rate, overall disease control, and disease stabilization rates of 35%, 82%, and 45%, respectively. In addition, the rate of serious adverse events, general adverse events, and all adverse events in patients was 2%, 28%, and 79%, respectively. Moreover, the rate of partial remission of disease in NSCLC patients was 38%.
The KRASG12C inhibitors sotorasib and adagrasib exhibited good efficacy and high safety in advanced solid tumors.
Competing interests: The authors declare that they have no competing interests.
| [1] |
Blechacz B, Komuta M, Roskams T, et al. Clinical diagnosis and staging of cholangiocarcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(9): 512-522. doi: 10.1038/nrgastro.2011.131
|
| [2] |
Parameswaran S, Kundapur D, Vizeacoumar FS, et al. A Road Map to Personalizing Targeted Cancer Therapies Using Synthetic Lethality[J]. Trends Cancer, 2019, 5(1): 11-29. doi: 10.1016/j.trecan.2018.11.001
|
| [3] |
Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies[J]. Nat Rev Drug Discov, 2019, 18(3): 197-218. doi: 10.1038/s41573-018-0007-y
|
| [4] |
Xu K, Park D, Magis AT, et al. Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy[J]. Mol Cancer, 2019, 18(1): 85. doi: 10.1186/s12943-019-1012-4
|
| [5] |
Hofmann MH, Gerlach D, Misale S, et al. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants[J]. Cancer Discov, 2022, 12(4): 924-937. doi: 10.1158/2159-8290.CD-21-1331
|
| [6] |
Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy[J]. Acta Pharm Sin B, 2019, 9(5): 871-879. doi: 10.1016/j.apsb.2019.03.002
|
| [7] |
Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions[J]. Nature, 2013, 503(7477): 548-551. doi: 10.1038/nature12796
|
| [8] |
Hallin J, Engstrom LD, Hargis L, et al. The KRAS(G12C) Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients[J]. Cancer Discov, 2020, 10(1): 54-71. doi: 10.1158/2159-8290.CD-19-1167
|
| [9] |
Papke B, Der CJ. Drugging RAS: Know the enemy[J]. Science, 2017, 355(6330): 1158-1163. doi: 10.1126/science.aam7622
|
| [10] |
Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web[J]. Nat Rev Cancer, 2011, 11(11): 761-774. doi: 10.1038/nrc3106
|
| [11] |
Janes MR, Zhang J, Li LS, et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor[J]. Cell, 2018, 172(3): 578-589. e17. doi: 10.1016/j.cell.2018.01.006
|
| [12] |
Lito P, Solomon M, Li LS, et al. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism[J]. Science, 2016, 351(6273): 604-608. doi: 10.1126/science.aad6204
|
| [13] |
Biernacka A, Tsongalis PD, Peterson JD, et al. The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma[J]. Cancer Genet, 2016, 209(5): 195-198. doi: 10.1016/j.cancergen.2016.03.001
|
| [14] |
Neumann J, Zeindl-Eberhart E, Kirchner T, et al. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer[J]. Pathol Res Pract, 2009, 205(12): 858-862. doi: 10.1016/j.prp.2009.07.010
|
| [15] |
Kim D, Xue JY, Lito P. Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients[J]. Cell, 2020, 183(4): 850-859. doi: 10.1016/j.cell.2020.09.044
|
| [16] |
Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors[J]. N Engl J Med, 2020, 383(13): 1207-1217. doi: 10.1056/NEJMoa1917239
|
| [17] |
Skoulidis F, Li BT, Dy GK, et al. Sotorasib for Lung Cancers with KRAS p. G12C Mutation[J]. N Engl J Med, 2021, 384(25): 2371-2381. doi: 10.1056/NEJMoa2103695
|
| [18] |
Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation[J]. N Engl J Med, 2022, 387(2): 120-131. doi: 10.1056/NEJMoa2204619
|
| [19] |
Ou SI, Jänne PA, Leal TA, et al. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1)[J]. J Clin Oncol, 2022, 40(23): 2530-2538. doi: 10.1200/JCO.21.02752
|
| [20] |
Molina-Arcas M, Moore C, Rana S, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer[J]. Sci Transl Med, 2019, 11(510): eaaw7999. doi: 10.1126/scitranslmed.aaw7999
|
| [21] |
Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity[J]. Nature, 2019, 575(7781): 217-223. doi: 10.1038/s41586-019-1694-1
|
| [22] |
Dunnett-Kane V, Nicola P, Blackhall F, et al. Mechanisms of Resistance to KRAS(G12C) Inhibitors[J]. Cancers (Basel), 2021, 13(1): 151. doi: 10.3390/cancers13010151
|
| [23] |
Kemp SB, Cheng N, Markosyan N, et al. Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer[J]. Cancer Discov, 2023, 13(2): 298-311. doi: 10.1158/2159-8290.CD-22-1066
|
| [24] |
Hofmann MH, Gerlach D, Misale S, et al. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants[J]. Cancer Discov, 2022, 12(4): 924-937. doi: 10.1158/2159-8290.CD-21-1331
|
Figures(9) / Tables(2)
This work is licensed under a Creative Commons Attribution 3.0 License.
Copyright © Editorial Department of Cancer Prevention Research 鄂公网安备 42011102005013号 鄂ICP备2022015867号
Supported by: Beijing Renhe Information Technology Co., Ltd. 
DownLoad: