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【35 under 35】赵志强医生:瑞格非尼&阿帕替尼—转移性骨肉瘤治疗的新曙光?

2018年08月01日
编译:赵志强    中山大学附属第一医院    骨与软组织肿瘤    
来源:肿瘤资讯

第二届“35 under 35”CSCO-良医汇2018优秀青年肿瘤医师风采大赛评选活动”报名及筛选阶段已正式结束!在众多参与报名筛选的医生中,有100位优秀青年医生脱颖而出!他们将在近期进行三轮PK,展示青年医生风采!第一轮为ASCO最新摘要解读,候选人在主办方指定的2018ASCO口头报告专题中自由选择一份口头报告进行点评(如:背景,结果的评价,对临床的意义,和其他研究的对照,优点和不足等等),目前100位青年医生在规定的时间内已将解读提交,解读很精彩,现展示出来,供各位品读!欢迎转发,让更多的医生同道看到青年力量!欢迎评论,发表您的见解,与青年医师同台论道!

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Results of randomized, placebo (PL)-controlled phase II study evaluating efficacy and safety of regorafenib (REG) in patients (pts) with metastatic osteosarcoma (metOS), on behalf of the French Sarcoma Group (FSG) and Unicancer.

Sub-category:

Bone Tumors

Category:

Sarcoma

Meeting:

2018 ASCO Annual Meeting

Abstract No:

11504

Citation:

J Clin Oncol 36, 2018 (suppl; abstr 11504)

Author(s): Florence Duffaud, Jean-Yves Blay, Olivier Mir, Pascaline Boudou-Rouquette, Sophie Piperno-Neumann, Nicolas Penel, Emmanuelle Bompas, Corinne Delcambre, Elsa Kalbacher, Antoine Italiano, Olivier Collard, Christine Chevreau, Antoine Thyss, Nicolas Isambert, Jessy Delaye, Nicolas De Sousa Carvalho, Camille Schiffler, Corinne Bouvier, Vincent Vidal, Sylvie Chabaud; La Timone University Hospital, Marseille, France; Centre Léon Bérard, Lyon, France; Gustave Roussy Cancer Campus, Villejuif, France; Department of Medical Oncology, Hopital Cochin, Université Paris Descartes, CARPEM, APHP, Paris, France; Institut Curie, Paris, France; Oscar Lambret Cancer Center, Lille, France; Institut de Cancerologie de l'Ouest, Nantes, France; Centre François Baclesse, Caen, France; CHU Jean Minjoz, Besançon, France; Institut Bergonié, Bordeaux, France; Institut de Cancérologie de la Loire, St. Priest En Jarez, France; IUCT-Oncopôle Institut Claudius Regaud, Toulouse, France; Centre Antoine-Lacassagne, Nice, France; Service d'oncologie médicale CLCC Georges-François Leclerc, Dijon, France; UNICANCER, Paris, France; Unicancer, Paris, France; Centre Léon-Bérard, Lyon, France; Assistance Publique - Hopitaux De Marseille, Marseille, France; Assistance Publique - Hôpitaux de Marseille, Marseille, France


Abstract Disclosures

 

Abstract:

Background: Oral multikinase inhibitor REG has shown activity in GIST and non-adipocytic soft tissue sarcomas. We designed REGOBONE as a non-comparative phase II, double-blind, PL-controlled trial to study the efficacy and safety of REG for pts with metOS and other types of bone sarcomas. This trial consisted of 4 independent cohorts : metOS, Ewing sarcoma, chondrosarcoma, and chordoma. We report here the metOS cohort results.

背景:口服多激酶抑制剂瑞格非尼在治疗胃肠道间质瘤(GIST)及非脂肪源性软组织肉瘤中展现出良好的疗效。本研究设计了非对照双盲安慰剂二期临床研究来评估REG在治疗转移性骨肉瘤,尤文肉瘤,软骨肉瘤及脊索瘤中等4个独立分组中的安全性及疗效。此次摘要主要报道转移性骨肉瘤中的研究结果。

方法:该临床研究招募转移性骨肉瘤患者,并随机分配接受REG(160mg/天,21/28天)治疗或安慰剂治疗(2:1),明确进展后允许从安慰剂组交叉至REG治疗组。。入组标准主要为:年龄大于10岁,病例确诊骨肉瘤,接受1-2种化疗药物治疗后持续进展的转移性骨肉瘤患者。根据A’Hern’s 单阶段二期临床试验设计,24例ECOG评分0-1分患者纳入REG治疗组,8周时观察到27%无进展率。次要终点为PFS,OS和安全性。

Methods: metOS pts were randomized (2:1) to receive either REG (160 mg/d, 21/28d) or PL with optional cross-over at the time of confirmed central review of progressive disease (PD). Key-eligibility criteria were age ≥10 years, histologically confirmed diagnosis of OS, confirmed measurable PD not amenable to curative-intent, 1-2 previous chemotherapy (CT) regimen(s) for metastatic disease, and ECOG 0-1. 24 pts were planned in the REG arm based on A’Hern’s single-stage design for phase II trials (1-sided α = 0.05, and 80% power) to detect a 27% benefit in the progression-free rate at 8 weeks (P0 = 40%). Major secondary endpoints were PFS (per modified RECIST1.1), OS and safety.


Results: From June 2014 to April 2017, 43 metOS pts were included. Five pts were not eligible for efficacy analysis. Of 38 efficacy-evaluable pts (12 in PL arm and 26 in REG arm) ; 24 were men, median age was 33 (18-74) years, 28 (74%) had 1 previous CT regimen. 17 pts (65.4% ; one-sided CI95% = [47.4%-]) were non-progressive at 8 weeks in the REG arm vs. 0 in the PL arm. Median PFS was 13.7 (CI95% = 8.0-27.3) vs. 4 (CI95% = 3.0-5.7) weeks for REG and PL arms, respectively. PFS rate at 24 weeks was 35% (CI95% = 17-52) in the REG arm vs. 0 in the PL arm. 1-year OS was 53% (CI95% = 31-71) and 33% (CI95% = 10-59) for REG and PL arms, respectively. Ten pts crossed-over to REG after centrally-confirmed PD on PL. The most common ≥Gr3 REG-related AEs during the double blind period were hypertension (24%), hand-foot skin reaction (17%), asthenia (10%) and diarrhea (7%). Conclusions: REG demonstrates very promising activity, with acceptable toxicity, in metOS after failure of conventional chemotherapy, justifying confirmatory trials. Clinical trial information: NCT02389244

背景:口服多激酶抑制剂瑞格非尼(REG)在治疗胃肠道间质瘤(GIST)及非脂肪源性软组织肉瘤中展现出良好的疗效。本研究设计了非对照双盲安慰剂二期临床研究来评估REG在治疗转移性骨肉瘤,尤文肉瘤,软骨肉瘤及脊索瘤中等4个独立分组中的安全性及疗效。此次摘要主要报道转移性骨肉瘤中的研究结果。

方法:该临床研究招募转移性骨肉瘤患者,并随机分配接受REG(160mg/天,21/28天)治疗或安慰剂治疗(2:1),明确进展后允许从安慰剂组交叉至REG治疗组。入组标准主要为:年龄大于10岁,病例确诊骨肉瘤,接受1-2种化疗药物治疗后持续进展的转移性骨肉瘤患者。根据A’Hern’s 单阶段二期临床试验设计,24例ECOG评分0-1分患者纳入REG治疗组,8周时观察到27%无进展率。次要终点为PFS,OS和安全性。

结果:从2014年6月到2017年4月,共纳入43例转移性骨肉瘤患者。5例患者未能进行

有效性分析。38例进行有效性分析患者中包括12例安慰剂治疗患者及26例REG治疗患者。24例男性,中位年龄33岁,28例之前接受1中化疗药物治疗。8周时,REG组中17例肿瘤无进展,安慰剂组为0.中位无进展时间为13.7周(REG组) VS 4周(安慰剂组)。24周PFS为35%(REG组)VS 0%(安慰剂组)。10例安慰剂治疗患者确定进展后交叉之REG组。REG治疗中最常见3级以上不良反应包括:高血压(24%),手足皮肤毒性(17%),疲劳(10%),腹泻(7%)。

结论:对于传统化疗失败的转移性骨肉瘤患者,REG显示出了理想的效果,且无严重不良反应。NCT02389244

点评:

瑞格非尼&阿帕替尼—转移性骨肉瘤治疗的新曙光?

      骨肉瘤治疗中亟待解决的问题仍然是治疗过程中出现转移的病例,其5年总体生存率低于30%。对于一线化疗治疗失败的复发或转移病例,当前二线治疗方案经多年大规模临床试验的研究,亦难以取得较理想的疗效。随着对骨肉瘤研究的深入,分子靶向治疗、免疫治疗等也为转移性骨肉瘤患者带来新的希望。尤其是小分子抗血管生成治疗药物的相继研发上市,激发了骨与软组织肿瘤专家开展一系列临床研究和探索,期望能够为转移性或进展性骨与软组织肉瘤患者带来新曙光。

       瑞格非尼(REG)为一个多靶点抑制剂,作用于VEGFR1,VEGFR2,VEGFR3,PDGFR-β,Kit,RET和Raf-1等肿瘤微环境中的多种激酶。在转移性结直肠癌,胃肠道间质瘤(GIST),肝癌等肿瘤中开展了多项前瞻性或回顾性临床研究,并展示出独特的治疗反应和安全性。而一项针对REG在治疗进展性软组织肉瘤患者的安全性和有效性评估的二期临床试验中(NCT01900743.),瑞格非尼在多种软组织肉瘤(平滑肌肉瘤,滑膜肉瘤等,除外脂肪肉瘤)治疗中,明显改善患者PFS。安全性方面,3级或以上不良反应包括:高血压(19%),手足皮肤反应15%,疲劳12%,1例REG治疗患者因肝功能衰竭死亡。而研究者设计的此项针对转移性骨肉瘤II期临床试验中,24周的PFS为35%,对于传统治疗失败的转移性骨肉瘤带来一丝希望。

       相较于瑞格非尼,近2年ASCO展示研究数据中,另一针对骨肉瘤研究较多明星药物阿帕替尼也显示出良好的治疗反应。其通过高选择性抑制血管内皮生长因子受体 2(VEGFR-2)的活性、抑制肿瘤血管生成,进而达到抗肿瘤作用,具有更高的靶点特异性。2017年ASCO收录的研究中,一项多中心回顾性研究显示:26 例不可切除的高级别恶性骨肉瘤患者在标准化疗后使用阿帕替尼治疗可达到 42.3% 的 ORR 和 80.8% 的 CBR,中位 PFS 为 8 个月;【摘要号:11031】。另一项回顾性研究纳入了 34 例接受阿帕替尼治疗的骨肉瘤患者,总体的 ORR 为 20.5%,DCR 为 94.1%,而 18 例在阿帕替尼治疗前发生肺转移的患者对阿帕替尼反应性相对更好,其 ORR 和 DCR 分别达到 33.3% 和 88.9%【摘要号:e22500】。2018年ASCO,一项关于阿帕替尼治疗一线方案治疗失败的复发或不可切除骨肉瘤的前瞻性Ⅱ期临床研究显示:4个月和6个月的PFS率分别为56.76%和36.77%。中位PFS和总生存期(OS)分别为4.50个月和9.87个月。

        无论瑞格非尼或阿帕替尼在转移性骨肉瘤治疗中的初步临床研究数据都显示出可观的治疗反应及安全性。然而,肿瘤的发生发展是多基因、多阶段的过程,每种激酶单独和联合调控肿瘤的生长、基质微环境的形成及疾病的进展。究竟高选择性靶向药物阿帕替尼,还是多靶点药物瑞格菲尼,亦或联合当前化疗方案能为进展或转移性骨肉瘤患者带来希望,仍需进一步的大规模临床试验数据支持。

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参考文献

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3. Safety and effi cacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1732-1742.

4. Xie L, Ji T, Guo W. Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Oncol Rep. 2017;38(2):625-636.

5. Zhou Y, Zhang W, Tang F, et al. A case report of apatinib in treating osteosarcoma with pulmonary metastases. Medicine (Baltimore). 2017;96(15):e6578.

6. Apatinib for advanced sarcoma: results from multiple institutions' off-label use in China. BMC Cancer. 2018 Apr 6;18(1):396.

7. Results of randomized, placebo (PL)-controlled phase II study evaluating efficacy and safety of regorafenib (REG) in patients (pts) with metastatic osteosarcoma (metOS), on behalf of the French Sarcoma Group (FSG) and Unicancer. 2018 ASCO Annual Meeting.

Abstract No:11504

8. Response to apatinib in patients with osteosarcoma: Updated evidence of efficacy and safety. 2018 ASCO Annual Meeting.Abstract No:e23500

9. Efficacy and safety of apatinib in osteosarcoma lung metastasis. 2018 ASCO Annual Meeting. Abstract No: e23527

10. Apatinib for advanced osteosarcoma after failure of standard multimodal therapy: An open label phase 2 clinical trial. 2018 ASCO Annual Meeting. Abstract No:11520


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