提示: 手机请竖屏浏览!

selpercatinib对RET融合阳性非小细胞肺癌的疗效
Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer


Alexander Drilon ... 肿瘤 • 2020.08.27
相关阅读
• 晚期非小细胞肺癌的精确诊断和治疗 • 患者整个癌症病程中的基因组测序 • 追踪非小细胞肺癌的进化

旧致癌驱动基因,新标准靶向疗法:selpercatinib治疗RET融合阳性非小细胞肺癌

 

乐秀宁*,张建军

Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, TX, USA

*通讯作者

 

过去20年间,晚期疾病患者肿瘤分子表达谱分析和治疗分层的成功使非小细胞肺癌(NSCLC)成为精准医学时代的典型代表。每种致癌驱动基因都定义了一个独特的患者群体。依据EGFRALKROS1等致癌驱动基因选择治疗方法,改变了接受有效抑制剂治疗的NSCLC患者生存期和生活质量。

查看更多

摘要


背景

RET融合是1%~2%非小细胞肺癌(NSCLC)的致癌驱动基因。在RET融合阳性NSCLC患者中,选择性抑制RET的疗效和安全性尚不清楚。

 

方法

我们在selpercatinib的1~2期试验中分别纳入了接受过铂类化疗和未接受过治疗的RET融合阳性晚期NSCLC患者。主要终点是由独立的审核委员会确定的客观缓解(完全或部分缓解)。次要终点包括缓解持续时间、无进展生存期和安全性。

 

结果

在前105例连续纳入的至少接受过铂类化疗的RET融合阳性NSCLC患者中,达到客观缓解的百分比为64%(95%置信区间[CI],54%~73%)。中位缓解持续时间为17.5个月(95% CI,12.0~无法评估);中位随访12.1个月时,63%的缓解仍持续。在39例未接受过治疗的患者中,达到客观缓解的百分比为85%(95% CI,70%~94%);在6个月时,90%的缓解仍持续。在纳入时有可测量的中枢神经系统转移的11例患者中,达到颅内客观缓解的百分比为91%(95% CI,59%~100%)。最常见的3级或更高级别的不良事件包括高血压(14%的患者)、丙氨酸转氨酶水平升高(12%)、天冬氨酸转氨酶水平升高(10%)、低钠血症(6%)和淋巴细胞减少(6%)。531例患者中共有12例(2%)因药物相关不良事件而将selpercatinib停药。

 

结论

在接受过铂类化疗和未接受过治疗的RET融合阳性NSCLC患者中,selpercatinib具有持久疗效(包括对颅内病变的疗效),且毒性作用多为低级别(由Loxo Oncology等资助;LIBRETTO-001在ClinicalTrials.gov注册号为NCT03157128)。





作者信息

Alexander Drilon, M.D., Geoffrey R. Oxnard, M.D., Daniel S.W. Tan, M.B., B.S., Ph.D., Herbert H.F. Loong, M.B., B.S., Melissa Johnson, M.D., Justin Gainor, M.D., Caroline E. McCoach, M.D., Ph.D., Oliver Gautschi, M.D., Benjamin Besse, M.D., Ph.D., Byoung C. Cho, M.D., Ph.D., Nir Peled, M.D., Ph.D., Jared Weiss, M.D., Yu-Jung Kim, M.D., Ph.D., Yuichiro Ohe, M.D., Ph.D., Makoto Nishio, M.D., Keunchil Park, M.D., Ph.D., Jyoti Patel, M.D., Takashi Seto, M.D., Tomohiro Sakamoto, M.D., Ezra Rosen, M.D., Ph.D., Manisha H. Shah, M.D., Fabrice Barlesi, M.D., Ph.D., Philippe A. Cassier, M.D., Lyudmila Bazhenova, M.D., Filippo De Braud, M.D., Elena Garralda, M.D., Vamsidhar Velcheti, M.D., Miyako Satouchi, M.D., Ph.D., Kadoaki Ohashi, M.D., Ph.D., Nathan A. Pennell, M.D., Ph.D., Karen L. Reckamp, M.D., Grace K. Dy, M.D., Jürgen Wolf, M.D., Benjamin Solomon, M.B., B.S., Ph.D., Gerald Falchook, M.D., Kevin Ebata, Ph.D., Michele Nguyen, B.S., Binoj Nair, Ph.D., Edward Y. Zhu, Ph.D., Luxi Yang, M.P.H., Xin Huang, Ph.D., Elizabeth Olek, M.D., S. Michael Rothenberg, M.D., Ph.D., Koichi Goto, M.D., Ph.D., and Vivek Subbiah, M.D.
From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D., E.R.) and New York University Langone Medical Center (V.V.), New York, and Roswell Park Comprehensive Cancer Center, Buffalo (G.K.D.) — all in New York; Dana–Farber Cancer Institute (G.R.O.) and Massachusetts General Hospital (J.G.), Boston; National Cancer Centre Singapore, Singapore (D.S.W.T.); the Chinese University of Hong Kong, Hong Kong, China (H.H.F.L.); Sarah Cannon Research Institute, Nashville (M.J.); University of California, San Francisco–Helen Diller Family Comprehensive Cancer Center, San Francisco (C.E.M.), University of California, San Diego, Moores Cancer Center, La Jolla (L.B.), and City of Hope Comprehensive Cancer Center, Duarte (K.L.R.) — all in California; University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne — both in Switzerland (O.G.); Institut Gustave Roussy, Villejuif (B.B.), Hospital La Timone, Marseille (F.B.), and Centre Léon Bérard, Lyon (P.A.C.) — all in France; Severance Hospital, Yonsei University Health System (B.C.C.), and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), Seoul, and Seoul National University Bundang Hospital, Seongnam (Y.J.K.) — all in South Korea; Soroka University Medical Center, Beer-Sheva, Israel (N.P.); University of North Carolina–Chapel Hill, Chapel Hill (J. Weiss); National Cancer Center Hospital (Y.O.) and Cancer Institute Hospital of the Japanese Foundation for Cancer Research (M. Nishio), Tokyo, National Hospital Organization Kyushu Cancer Center, Fukuoka (T. Seto), Tottori University Hospital, Tottori (T. Sakamoto), Hyogo Cancer Center, Akashi (M.S.), Okayama University Hospital, Okayama (K.O.), and National Cancer Center Hospital East, Chiba (K.G.) — all in Japan; University of Chicago, Chicago (J.P.); the Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.), and Cleveland Clinic, Cleveland (N.A.P.); Istituto Nazionale Tumori–National Cancer Institute, Università degli Studi di Milano, Milan (F.D.B.); Vall d’Hebron Institute of Oncology, Hospital Universitario Vall d’Hebron, Barcelona (E.G.); Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany (J. Wolf); Peter MacCallum Cancer Institute, Melbourne, VIC, Australia (B.S.); Sarah Cannon Research Institute at HealthONE, Denver (G.F.); Loxo Oncology, Stamford, CT (K.E., M. Nguyen, B.N., E.Y.Z., L.Y., X.H., E.O., S.M.R.); and the University of Texas M.D. Anderson Cancer Center, Houston (V.S.). Address reprint requests to Dr. Drilon at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, or at drilona@mskcc.org; or to Dr. Subbiah at the University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 455, Houston, TX 77030, or at vsubbiah@mdanderson.org.

 

参考文献

1. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 2014;14:173-186.

2. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol 2018;15:151-167.

3. Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 2012;30:4352-4359.

4. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014;159:676-690.

5. Tsuta K, Kohno T, Yoshida A, et al. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer 2014;110:1571-1578.

6. Takeuchi K. Discovery stories of RET fusions in lung cancer: a mini-review. Front Physiol 2019;10:216-216.

7. Drilon A, Lin JJ, Filleron T, et al. Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers. J Thorac Oncol 2018;13:1595-1601.

8. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol 2017;35:1403-1410.

9. Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 2016;17:1653-1660.

10. Lee S-H, Lee J-K, Ahn M-J, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol 2017;28:292-297.

11. Yoh K, Seto T, Satouchi M, et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med 2017;5:42-50.

12. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2018;13:27-45.

13. Subbiah V, Velcheti V, Tuch BB, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 2018;29:1869-1876.

14. Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.

15. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012;18:382-384.

16. Hida T, Velcheti V, Reckamp KL, et al. A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. Lung Cancer 2019;138:124-130.

17. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med 2018;378:113-125.

18. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med 2010;363:1693-1703.

19. Shaw AT, Ou S-H, Bang Y-J, et al. Crizotinib in ROS1-rearranged non–small-cell lung cancer. N Engl J Med 2014;371:1963-1971.

20. Farago A, Kummar S, Moreno V, et al. Activity of larotrectinib in TRK fusion lung cancer. J Thorac Oncol 2019;14:Suppl:S283-S284. abstract.

21. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med 2018;378:731-739.

22. National Comprehensive Cancer Network. Non-small cell lung cancer, version 2.2020 (https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. opens in new tab).

服务条款 | 隐私政策 | 联系我们