提示: 手机请竖屏浏览!

奥拉帕利联合贝伐珠单抗作为卵巢癌的一线维持治疗
Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer


Isabelle Ray-Coquard ... 肿瘤 妇产科和儿科 • 2019.12.19
相关阅读
• 卵巢癌的维利帕利联合一线化疗和随后的维利帕利维持治疗 • 尼拉帕利治疗新诊断的晚期卵巢癌 • 新诊断晚期卵巢癌患者的奥拉帕利维持治疗

续写卵巢癌治疗模式新篇章——PARP抑制剂一线治疗

 

胡争

中山大学附属第一医院妇产科

 

时至今日,卵巢癌死亡率仍高居女性生殖系统恶性肿瘤首位1,铂类药物与紫杉醇的联合化疗一直是晚期卵巢癌患者的一线治疗方案2,但高达70%的晚期卵巢癌患者在完全缓解或部分缓解后3年内复发3。如何有效提高患者生存率,寻找新的治疗策略是当前卵巢癌研究亟需解决的问题。

查看更多

摘要


背景

在有BRCA突变的新诊断晚期卵巢癌患者中,作为维持治疗的奥拉帕利产生了显著的临床益处。在不考虑BRCA突变状态的情况下,奥拉帕利+贝伐珠单抗联合维持治疗的效果尚未明确。

 

方法

我们开展了一项随机、双盲、国际性3期试验。患者纳入标准是新诊断出晚期高级别卵巢癌,并且对一线铂类-紫杉类药物化疗+贝伐珠单抗治疗产生应答。纳入标准未考虑手术结局,也未考虑BRCA突变状态。我们以2∶1的比例将患者随机分组,分别接受最长24个月的奥拉帕利片剂(每日2次,每次300 mg)或安慰剂治疗;所有患者均接受最长15个月的贝伐珠单抗治疗(每3周1次,每次15 mg/kg)。主要终点是从随机分组至研究者判定疾病进展或死亡的时间。

 

结果

在被随机分组的806例患者中,537例被分配接受奥拉帕利治疗,269例被分配接受安慰剂治疗。中位随访22.9个月后,奥拉帕利+贝伐珠单抗组和安慰剂+贝伐珠单抗组的中位无进展生存期分别为22.1个月和16.6个月(疾病进展或死亡的风险比,0.59;95%置信区间[CI],0.49~0.72;P<0.001)。在同源重组缺陷(HRD)阳性的肿瘤(包括有BRCA突变的肿瘤)患者中,疾病进展或死亡的风险比(奥拉帕利组vs.安慰剂组)为0.33(95% CI,0.25~0.45)(中位无进展生存期,37.2个月 vs. 17.7个月),在无BRCA突变的HRD阳性肿瘤患者中,疾病进展或死亡的风险比为0.43(95% CI,0.28~0.66)(中位无进展生存期,28.1 个月vs. 16.6个月)。不良事件符合奥拉帕利和贝伐珠单抗的已知安全性特征。

 

结论

在接受包括贝伐珠单抗的一线标准治疗的晚期卵巢癌患者中,加用奥拉帕利维持治疗在无进展生存期方面产生了显著益处,这一益处在HRD阳性肿瘤(包括无BRCA突变的肿瘤)患者中显著(由ARCAGY Research等资助;在ClinicalTrials.gov注册号为NCT02477644)。





作者信息

Isabelle Ray-Coquard, M.D., Ph.D., Patricia Pautier, M.D., Sandro Pignata, M.D., Ph.D., David Pérol, M.D., Antonio González-Martín, M.D., Ph.D., Regina Berger, Ph.D., Keiichi Fujiwara, M.D., Ph.D., Ignace Vergote, M.D., Ph.D., Nicoletta Colombo, M.D., Johanna Mäenpää, M.D., Ph.D., Frédéric Selle, M.D., Jalid Sehouli, M.D., Domenica Lorusso, M.D., Eva M. Guerra Alía, M.D., Alexander Reinthaller, M.D., Shoji Nagao, M.D., Ph.D., Claudia Lefeuvre-Plesse, M.D., Ulrich Canzler, M.D., Giovanni Scambia, M.D., Alain Lortholary, M.D., Frederik Marmé, M.D., Pierre Combe, M.D., Nikolaus de Gregorio, M.D., Ph.D., Manuel Rodrigues, M.D., Ph.D., Paul Buderath, M.D., Coraline Dubot, M.D., Alexander Burges, M.D., Benoît You, M.D., Eric Pujade-Lauraine, M.D., Ph.D., and Philipp Harter, M.D., Ph.D. for the PAOLA-1 Investigators*
From Centre Léon Bérard (I.R.-C., D.P.), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y.), Lyon, Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) (I.R.-C., P.P., F.S., C.L.-P., A.L., P.C., M.R., C.D., B.Y., E.P.-L.), Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S.), Hôpital Européen Georges Pompidou (P.C.), Institut Curie, Hôpital Claudius Régaud (M.R.), and Association de Recherche Cancers Gynécologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P.), Centre Eugène Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hôpital Privé du Confluent, Nantes (A.L.), and Institut Curie, Hôpital René Huguenin, Saint Cloud (C.D.) — all in France; the Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples (S.P.), University of Milan–Bicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L.), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica, and MITO, Rome (G.S.) — all in Italy; M.D. Anderson Cancer Center Madrid (A.G.-M.), Grupo Español de Investigación en Cáncer de Ovario (GEICO) (A.G.-M., E.M.G.A.), and Hospital Universitario Ramón y Cajal (E.M.G.A.) — all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B.), and Arbeitsgemeinschaft Gynäkologische Onkologie Study Group (AGO)–Austria (R.B., A.R.), Innsbruck, and Medical University of Vienna, Vienna (A.R.) — all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F.), Gynecologic Oncology Trial and Investigation Consortium (GOTIC), Moroyama-cho (K.F., S.N.), and Hyogo Cancer Center, Akashi (S.N.) — all in Japan; University Hospital Leuven, Leuven Cancer Institute, and Belgium and Luxembourg Gynecologic Oncology Group (BGOG) — both in Leuven, Belgium (I.V.); Tampere University and University Hospital, Tampere, Finland (J.M.); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M.); and Charité–Medical University of Berlin (Campus Virchow Klinikum), Berlin (J.S.), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H.), Universitätsklinikum Essen (P.B.), and Kliniken Essen Mitte (P.H.), Essen, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden (U.C.), Universitätsklinikum Heidelberg, Heidelberg (F.M.), Universitätsklinikum Ulm, Ulm (N.G.), and Klinikum der Universität München, Munich (A.B.) — all in Germany. Address reprint requests to Dr. Ray-Coquard at Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, Lyon 69008, France, or at isabelle.ray-coquard@lyon.unicancer.fr. *A list of the PAOLA-1 principal investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484-2496.

2. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-2483.

3. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:Suppl 6:vi24-vi32.

4. Colombo N, Sessa C, du Bois A, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol 2019;30:672-705.

5. Karam A, Ledermann JA, Kim JW, et al. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions. Ann Oncol 2017;28:711-717.

6. Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol 2019;37:2317-2328.

7. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015;16:928-936.

8. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495-2505.

9. O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell 2015;60:547-560.

10. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-615.

11. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852-861.

12. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154-2164.

13. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-1961.

14. Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: a randomized controlled chemotherapy-free study — NSGO-AVANOVA2/ENGOT-OV24. J Clin Oncol 2019;37:Suppl:5505-5505. abstract.

15. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 2014;15:1207-1214.

16. Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol 2019;30:551-557.

17. Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Eur J Cancer 2012;48:1713-1721.

18. Vergote I, Pujade-Lauraine E, Pignata S, et al. European Network of Gynaecological Oncological Trial Groups’ requirements for trials between academic groups and pharmaceutical companies. Int J Gynecol Cancer 2010;20:476-478.

19. du Bois A, Reuss A, Pujade-Lauraine E, et al. European Network of Gynaecological Oncological Trial Groups’ requirements for trials between academic groups and industry partners — first update 2015. Int J Gynecol Cancer 2015;25:1328-1330.

20. Herzog TJ, Armstrong DK, Brady MF, et al. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper. Gynecol Oncol 2014;132:8-17.

21. Cnaan A, Laird NM, Slasor P. Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. Stat Med 1997;16:2349-2380.

22. Norquist BM, Brady MF, Harrell MI, et al. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group study. Clin Cancer Res 2018;24:777-783.

23. Chan N, Pires IM, Bencokova Z, et al. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 2010;70:8045-8054.

24. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274-1284.

25. Ledermann JA, Harter P, Gourley C, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 2016;17:1579-1589.

服务条款 | 隐私政策 | 联系我们