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索托拉西布治疗有KRAS p.G12C突变的肺癌
Sotorasib for Lung Cancers with KRAS p.G12C Mutation


Ferdinandos Skoulidis ... 肿瘤 • 2021.06.24
相关阅读
• 通过sotorasib抑制KRASG12C治疗晚期实体瘤

CodeBreaK100:精准医学和创新设计的胜利

 

梁乃新

北京协和医院胸外科

 

从精准医学研究思路看CodeBreaK100

在精准医学的basket和umbrella研究类型中,肺癌领域进展最快,也最先结合两种研究思路进行探索。在传统1~3期研究逐步探索安全性、有效性的基础上,换个角度看,本文即在1期(可看为basket研究阶段)的基础上,迅速进入2期阶段。而在2期研究中就充分利用精准医学检测技术对共突变亚组进行分层分析,将会极大加速3期进入真正精准医学理念指导下的临床研究设计,并提供重要参考依据。

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摘要


背景

索托拉西布(sotorasib)在一项1期研究中对携带KRAS p.G12C突变的晚期实体瘤患者显示出抗癌活性,而且对非小细胞肺癌(NSCLC)患者亚组的抗癌活性尤其有前景。

 

方法

在单组2期试验中,我们研究了口服索托拉西布(每日一次,每次960 mg)对接受过标准治疗的KRAS p.G12C突变晚期NSCLC患者的抗癌活性。主要终点是经独立集中审核后确定的客观缓解(完全或部分缓解)。关键次要终点包括缓解持续时间、疾病控制(定义为完全缓解、部分缓解或疾病稳定)、无进展生存期、总生存期和安全性。本试验评估了探索性生物标志物与索托拉西布应答情况之间的关联。

 

结果

在本试验纳入的126例患者中,大多数(81.0%)既往接受过铂类化疗及程序性死亡受体1(PD-1)或程序性死亡受体配体1(PD-L1)抑制剂治疗。根据集中审核结果,124例患者在基线时有可测量病变,并进行了应答情况评估。本试验观察到46例患者达到客观缓解(37.1%;95%置信区间[CI],28.6~46.2),其中4例(3.2%)完全缓解,42例(33.9%)部分缓解。中位缓解持续时间为11.1个月(95% CI,6.9~无法评估)。100例患者(80.6%;95% CI,72.6~87.2)达到疾病控制。中位无进展生存期为6.8个月(95% CI,5.1~8.2),中位总生存期为12.5个月(95% CI,10.0~无法评估)。126例患者中有88例(69.8%)发生了与治疗相关的不良事件,其中25例发生了3级事件(19.8%),1例发生了4级事件(0.8%)。本试验在根据PD-L1表达、肿瘤突变负荷及STK11KEAP1TP53共现突变定义的亚组中观察到缓解。

 

结论

在此项2期试验中,索托拉西布使既往接受过治疗的KRAS p.G12C突变NSCLC患者在临床上持久获益,且无新的安全信号(由安进公司和美国国立卫生研究院资助,CodeBreaK100在ClinicalTrials.gov注册号为NCT03600883)。





作者信息

Ferdinandos Skoulidis, M.D., Ph.D., Bob T. Li, M.D., Ph.D., M.P.H., Grace K. Dy, M.D., Timothy J. Price, M.B., B.S., D.H.Sc., Gerald S. Falchook, M.D., Jürgen Wolf, M.D., Antoine Italiano, M.D., Martin Schuler, M.D., Hossein Borghaei, D.O., Fabrice Barlesi, M.D., Ph.D., Terufumi Kato, M.D., Alessandra Curioni-Fontecedro, M.D., Adrian Sacher, M.D., Alexander Spira, M.D., Ph.D., Suresh S. Ramalingam, M.D., Toshiaki Takahashi, M.D., Ph.D., Benjamin Besse, M.D., Ph.D., Abraham Anderson, Ph.D., Agnes Ang, Ph.D., Qui Tran, Ph.D., Omar Mather, M.D., Haby Henary, M.D., Gataree Ngarmchamnanrith, M.D., Gregory Friberg, M.D., Vamsidhar Velcheti, M.D., and Ramaswamy Govindan, M.D.
From the University of Texas M.D. Anderson Cancer Center, Houston (F.S.), and U.S. Oncology Research, the Woodlands (A. Spira) — both in Texas; Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (B.T.L.) and Thoracic Medical Oncology, Perlmutter Cancer Center, New York University (V.V.), New York, and Roswell Park Cancer Institute, Buffalo (G.K.D.) — all in New York; the Queen Elizabeth Hospital and University of Adelaide, Woodville, SA, Australia (T.J.P.); Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), the West German Cancer Center, University Hospital Essen, University Duisburg–Essen, Essen (M.S.), and the German Cancer Consortium, Heidelberg (M.S.) — all in Germany; the Early Phase Trials and Sarcoma Units, Bergonie Cancer Institute, Bordeaux (A.I.), and Gustave Roussy Institute, Villejuif (F.B., B.B.) — both in France; Fox Chase Cancer Center, Philadelphia (H.B.); Kanagawa Cancer Center, Yokohama (T.K.), and the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka (T.T.) — both in Japan; the Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (A.C.-F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A. Sacher); Virginia Cancer Specialists, Fairfax (A. Spira); Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore (A. Spira); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Amgen, Thousand Oaks, CA (A. Anderson, A. Ang, Q.T., O.M., H.H., G.N., G.F.); and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis (R.G.). Address reprint requests to Dr. Skoulidis at the Department of Thoracic and Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 432, Houston, TX 77030, or at fskoulidis@mdanderson.org; or to Dr. Govindan at the Alvin J. Siteman Cancer Center, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8056, St. Louis, MO 63110, or at rgovindan@wustl.edu.

 

参考文献

1. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med 2020;383:640-649.

2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021;71:7-33.

3. Black RC, Khurshid H. NSCLC: an update of driver mutations, their role in pathogenesis and clinical significance. R I Med J (2013) 2015;98:25-28.

4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 2018;378:2078-2092.

5. Mok TSK, Wu Y-L, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-1830.

6. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non–small-cell lung cancer. N Engl J Med 2017;376:2415-2426.

7. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 2015;373:1627-1639.

8. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-1550.

9. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-265.

10. Pallis AG, Agelaki S, Agelidou A, et al. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer 2010;10:633-633.

11. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-2103.

12. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-1597.

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. Cancer Genet 2016;209:195-198.

14. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008;14:5731-5734.

15. Boch C, Kollmeier J, Roth A, et al. The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study. BMJ Open 2013;3(4):e002560-e002560.

16. Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5:860-877.

17. Jänne PA, van den Heuvel MM, Barlesi F, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA 2017;317:1844-1853.

18. Singh A, Daemen A, Nickles D, et al. NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin Cancer Res 2021;27:877-888.

19. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548-551.

20. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov 2014;13:828-851.

21. Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov 2016;15:771-785.

22. Lito P, Solomon M, Li L-S, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016;351:604-608.

23. Patricelli MP, Janes MR, Li L-S, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 2016;6:316-329.

24. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019;575:217-223.

25. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020;383:1207-1217.

26. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384:665-673.

27. Arbour KC, Jordan E, Kim HR, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res 2018;24:334-340.

28. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143-155.

29. Scheffler M, Ihle MA, Hein R, et al. K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways. J Thorac Oncol 2019;14:606-616.

30. Xue JY, Zhao Y, Aronowitz J, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 2020;577:421-425.

31.Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012;18:6169-6177.

32. Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer 2019;19:495-509.

33. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018;8:822-835.

34. Negrao MV, Lam VK, Reuben A, et al. PD-L1 expression, tumor mutational burden, and cancer gene mutations are stronger predictors of benefit from immune checkpoint blockade than HLA class I genotype in non-small cell lung cancer. J Thorac Oncol 2019;14:1021-1031.

35. Chen X, Su C, Ren S, Zhou C, Jiang T. Pan-cancer analysis of KEAP1 mutations as biomarkers for immunotherapy outcomes. Ann Transl Med 2020;8:141-141.

36. Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res 2020;26:274-281.

37. La Fleur L, Falk-Sörqvist E, Smeds P, et al. Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11. Lung Cancer 2019;130:50-58.

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