甲磺酸伊马替尼治疗胃肠道间质瘤的疗效及安全性分析

胃肠道间质瘤(gastrointestinalStromal tumor,GIST)是最常见的消化道间质肿瘤,这些肿瘤通常存在酪氨酸受体激酶KIT(75%～80%)或PDGFRA(5%～10%)激活性突变[1].激活性突变使配体独立激活,然后激发KIT或PDG-FRA组成性激活介导的信号转导通路,从而发生不可控制的细胞增生,同时抑制细胞凋亡,最终GIST形成.GIST对传统的化疗和放疗高度耐药,在甲磺酸伊马替尼(imatinibmesvlate.Glivec,preyiotislv called STI571)出现以前,手术是治疗GIST的主要方式,但手术治疗往往并不足够,甚至完全切除肿瘤后,大部分晚期GIST患者还是出现复发,而出现复发和(或)转移的患者往往预后不良[2].GIST分子遗传学与靶向治疗方面的相互结合,使小分子激酶抑制剂伊马替尼治疗复发性或转移性胃肠道问质瘤,成为其他实体瘤靶向治疗的典范.到日前为此,甲磺酸伊马替尼在美国、中国及许多国家被批准用于不可切除和(或)转移性GIST治疗的一线药物.本文回顾性分析复旦大学附属肿瘤医院甲磺酸伊马替尼治疗的39例GIST患者,并就伊乌替尼疗效和安全性作一总结.     

甲磺酸伊马替尼治疗不能切除和/或转移的胃肠道间质瘤的临床分析

目的：评价甲磺酸伊马替尼(ST1571)治疗不能手术切除和／或转移的胃肠道间质瘤疗效和毒性。方法：口服甲磺酸伊马替尼400mg/日治疗10例不能手术切除和／或转移的胃肠道间质瘤患者。结果：9例可评价疗效，4例部分缓解，4例稳定。10例评价不良反应，非血液学毒性有水肿(主要是眼眶周围水肿)、腹痛、腹泻、恶心呕吐、乏力、腹腔肿瘤出血、间歇性肌肉痉挛和结膜炎，大多为I～Ⅱ度。血液学毒性少见。结论：酪氨酸激酶抑制剂甲磺酸伊马替尼治疗不能手术切除和／或转移的胃肠道间质瘤有一定疗效，且毒性可耐受。     

甲磺酸伊马替尼治疗胃肠道间质瘤的研究进展

胃肠道间质瘤（GIST）是胃肠道及腹腔最常见的间叶源性肿瘤,对常规的放疗、化疗均不敏感。外科手术是局限性GIST患者的主要治疗方式,但术后复发率较高。对于术前、术后辅助、复发、转移及不能手术切除的患者,酪氨酸激酶抑制剂甲磺酸伊马替尼对其有较好的治疗效果。本文对甲磺酸伊马替尼治疗胃肠道间质瘤的研究进展作一综述。     

伊马替尼新辅助治疗直肠间质瘤的疗效及安全性分析

目的 探讨甲磺酸伊马替尼新辅助治疗原发直肠胃肠间质瘤（GIST）的疗效及安全性。方法40例直肠GIST患者口服甲磺酸伊马替尼片400mg/天, 连续口服6个月后评估手术指征。根据肿瘤大小和位置分别采用局部切除术、直肠低位前切除术和腹会阴联合直肠癌根治术。结果按RECIST 1.1版标准评价,获CR 3例,PR 31例,SD 4例,PD 2例;有效率（RR）为850%,疾病控制率（DCR）为95.0%;按Choi标准评价,获CR 3例,PR 28例,SD 7例,PD 2例;RR为77.5%,DCR为95.0%。治疗后获R0切除38例。40例患者的1年生存率为1000%,2年生存率为950%。不良反应以轻度水肿发生率最高,为72.5%,其次为白细胞减少（47.5%）;其他不良反应包括乏力、腹痛、胃肠道反应等,均可耐受。结论 直肠GIST患者术前使用甲磺酸伊马替尼辅助治疗,能够扩大患者的手术指征,提高R0切除率,疗效确切,安全性高,可以作为直肠GIST个体化治疗方案之一。     

国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期的临床观察

目的 观察国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期(CML-CP)的效果及安全性.方法 回顾性分析东莞市人民医院2014年10月至2016年10月收治的23例年龄＞18岁、初次确诊、除羟基脲外未接受其他任何抗CML治疗的CML-CP患者临床资料,所有患者均接受国产甲磺酸伊马替尼400 mg/次,1次/d口服治疗,评价3、6、12个月时的血液学、分子生物学反应及安全性.结果 23例患者治疗后均达到血液学完全缓解.在可评估的20例患者中,在3个月时15例bcr-abl国际标准化(IS)值＜10％;治疗6个月时16例达bcr-abl＜ 1％;治疗12个月时8例bcr-abl＜0.1％.不良反应均可耐受.结论 国产甲磺酸伊马替尼治疗初诊CML-CP疗效可靠,不良反应可耐受.     

甲磺酸伊马替尼治疗复发或转移性胃肠间质瘤

目的 评价甲磺酸伊马替尼进行术前辅助治疗及治疗术后复发和(或)转移性胃肠间质瘤(GISTs)的临床疗效及不良反应。方法 经病理组织学证实的GISTs 30例,其中29例CD117阳性。行术前辅助化疗2例,术后复发或已转移并失去手术机会者28例,给予甲磺酸伊马替尼200～600mg／d口服。结果 30例患者中,3例失访,25例可评价客观疗效。部分缓解(PR)15例,占60．0％;病情稳定(SD)5例,占20．0％;疾病进展(PD)5例,占20．0％。患者获益(CR PR SD)率80．0％,获益者中位无进展生存期(TTP)超过13个月。随访1年以上者22例,1年生存率为86．4％。27例可评价不良反应,其中轻度水肿23例(85.2％),Ⅰ、Ⅱ度白细胞减少11例(40．7％),Ⅰ、Ⅱ度乏力8例(29．6％),轻度腹痛4例(14．8％),Ⅰ、Ⅱ度恶心呕吐5例(18．5％),轻度皮疹3例(11．1％),出血2例(7．4％)。结论 甲磺酸伊马替尼治疗进展期GISTs疗效肯定,不良反应较轻．患者能够耐受,可以较长时期用于转移性和(或)不能手术的GISTs治疗。     

苹果酸舒尼替尼二线治疗国人晚期胃肠间质瘤的临床观察

的 探讨苹果酸舒尼替尼二线治疗甲磺酸伊马替尼治疗失败的国内胃肠间质瘤（GIST）患者的疗效和安全性,并初步分析后续治疗对生存的影响。方法 回顾性分析2008年11月至2009年12月应用舒尼替尼二线治疗伊马替尼失败的24例GIST患者资料,口服舒尼替尼50mg／日,连续4周,停药2周,6周为1周期。按照RECIST 1.1版进行疗效评价,根据NCI CTC 3.0版进行毒性评价。结果 24例患者共接受治疗232个周期,平均9.7个周期（2～29个周期）。获PR 6例,SD 12例,PD 6例,有效率为 25％,疾病控制率为75％。舒尼替尼二线治疗进展后有8例接受后续治疗。中位随访时间为378天（190～1554天）,中位无进展生存时间（PFS）为336天（95％CI：223.2～448.8天）,中位总生存时间（OS）为655天（95％CI：359.7～950.3天）。其中未接受后续治疗组的中位OS为392天（95％CI： 190.1～593.9天）,接受后续治疗组的中位OS为1303天（95％CI：661.2～1544.8天）,两组差异有统计学意义（P=0.000）。毒副反应多为1～2级,未发生治疗相关性死亡。结论 舒尼替尼二线治疗伊马替尼失败的国内GIST患者有效,不良反应轻微,安全可控;对于二线治疗失败的患者采取后续治疗可能有生存获益。     

伊马替尼治疗晚期胃肠间质瘤的疗效分析及不良反应

目的 评价靶向药物伊马替尼治疗晚期(不可切除或复发转移)胃肠间质瘤(GIST)患者的临床疗效并总结所有胃肠间质瘤患者服用伊马替尼后的不良反应.方法 回顾分析我院自2004年6月至2009年12月接受伊马替尼治疗的GIST患者154例,其中晚期患者96例.完全切除术后辅助治疗58例.对晚期患者的治疗疗效进行分析,并统计所有患者服药后的不良反应.结果 资料完整的晚期患者73例,接受伊马替尼治疗中位时间23个月,其中完全缓解0例,部分缓解53例(72.6%),疾病稳定15例(20.5%),原发耐药疾病进展5例(6.8%),客观有效率为72.6%,疾病控制率为93.2%.中位无进展生存期45.0个月,患者1、3、5年无进展生存率分别为86%、61%和34%,患者1、3、5年总体生存率分别为98%、88%和72%.154例患者接受过至少一次伊马替尼治疗,起始剂量400 mg/d,绝大多数患者不良反应为1～2级,耐受良好.最常见的不良反应分别为水肿(75.3%)、消化道反应(37.7%)和贫血(22.7%).3级或以上不良反应发生率15.6%(24/154).结论 伊马替尼治疗晚期GIST疗效肯定;患者对于400 mg/d的治疗剂量耐受良好.     

甲磺酸伊马替尼治疗国人胃肠间质瘤的临床研究

 目的 观察和评价甲磺酸伊马替尼（Imatinib mesylate）治疗国人胃肠间质瘤（GIST）的有效性和安全性。方法 2002年8月至2004年12月，在本院通过病理形态学及免疫组化确诊的GIST共52例，其中36例应用伊马替尼治疗，用法为伊马替尼400mg，口服，1／日。参照WHO实体瘤客观疗效标准观察和判定疗效，NCI-CTC2．0版抗癌药的毒性标准观察和判定毒性。结果 伊马替尼治疗的36例患者中，包括新辅助治疗和姑息治疗在内可以评价疗效的有28例，用药后获得部分缓解为14例（50％），疾病稳定10例（35．7％），疾病进展4例（14．3％）；即有效率（RR）为50％，疾病控制率（DCR）达到85．7％。36例均可进行毒性评价，除了1例因胃部GIST合并脾脏B细胞型非霍奇金淋巴瘤，姑息切除术后口服格列卫同时进行CHOP方案化疗，结果 发生了Ⅲ级骨髓抑制外，其他35例中毒副反应均为Ⅰ～Ⅱ级，而且大多数毒性可以控制或恢复正常。结论 与国外文献报道一致，甲磺酸伊马替尼治疗国人GIST安全高效，耐受性好。     

甲磺酸伊马替尼治疗晚期胃肠间质瘤的疗效及预后因素

目的:探讨口服甲磺酸伊马替尼治疗晚期胃肠间质瘤患者的疗效及预后相关因素。方法:102例复发和(或)转移性胃肠间质瘤患者接受甲磺酸伊马替尼口服治疗(起始剂量为400mg/d,病情进展者加量至600mg/d)。结果:99例患者可评价疗效,其中8例(8.1%)完全缓解,68例(68.7%)部分缓解,20例(20.2%)疾病稳定,3例(3.0%)疾病进展;客观缓解率(完全缓解+部分缓解)为76.8%。中位无进展生存期(progression-free survival,PFS)为32.0个月,1、2和3年生存率分别为96.1%、81.2%和70.8%。居住在城市、美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)体能状况(performance status,PS)<2分或客观缓解的患者有更长的PFS(P<0.05),而年龄<65岁、居住在城市、ECOG PS<2分、单纯肝转移或治疗后病灶密度降低的患者有更长的总生存期(P<0.05)。结论:口服甲磺酸伊马替尼治疗晚期胃肠间质瘤患者安全而有效。年龄、基线PS、近期疗效和治疗后病灶密度的变化是晚期胃肠间质瘤预后的重要相关因素。     

Imatinib . Sunitinib

Imatinib mesilate, which efficiently inhibits BCR-ABL,and KIT as well as platelet-derived growth factor receptor (PDGF-R) kinases, is highly effective for clinical treatment of CML, Ph+ALL, and advanced GIST with good tolerability, respectively. Acquired resistance to the drug,however, becomes an clinically emerging problem with long-standing use. Meanwhile, sunitinib malate,which inhibits three VEGF-Rs and FLT 3 in addition to KIT as well as PDGF-R, was clinically evaluated in the phase II clinical trials for imatinib-resistant or intolerant GIST, and advanced renal cell carcinoma in Japan. Sunitinib is therapeutically effective for both on imatinib-resistant GIST and advanced renal cell carcinoma with modest tolerability, and is now under review for approval in Japan.     

KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway

Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition with imatinib, yet will eventually exhibit resistance. Imatinib-resistance mechanisms are heterogeneous, and little is known about KIT functional roles in imatinib-resistant GIST. Biological consequences of biochemical inhibition of KIT, phosphatidyl-inositol-3-kinase (PI3-K), PLCgamma, MAPK/ERK kinase/mitogen-activated protein kinase (MEK/MAPK), mammalian target of rapamycin (mTOR) and JAK were determined by immunoblotting for protein activation, and by cell proliferation and apoptosis assays in GIST cell lines from imatinib-sensitive GIST (GIST882), imatinib-resistant GISTs (GIST430 and GIST48) and KIT-negative GIST (GIST62). KIT activation was 3- to 6-fold higher in GIST430 and GIST48 than in GIST882, whereas total KIT expression was comparable in these three GIST lines. In addition to the higher set point for KIT activation, GIST430 and GIST48 had intrinsic imatinib resistance. After treatment with 1 muM imatinib, residual KIT activation was 6- and 2.8-fold higher in GIST430 and GIST48, respectively, compared to GIST882. In all GIST lines, cell growth arrest resulted from PI3-K inhibition, and - to a lesser extent - from MEK/MAPK and mTOR inhibition. Inhibition of JAK/STAT or PLCgamma did not affect cell proliferation. Similarly, only PI3-K inhibition resulted in substantial apoptosis in the imatinib-resistant GISTs. We conclude that GIST secondary KIT mutations can be associated with KIT hyperactivation and imatinib resistance. Targeting critical downstream signaling proteins, such as PI3-K, is a promising therapeutic strategy in imatinib-resistant GISTs.     

Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor

Inhibition of KIT oncoproteins by imatinib induces clinical responses in most gastrointestinal stromal tumor (GIST) patients. However, many patients develop imatinib resistance due to secondary KIT mutations. Heat shock protein 90 (HSP90) protects KIT oncoproteins from proteasome-mediated degradation, and we therefore did preclinical validations of the HSP90 inhibitor, 17-allylamino-18-demethoxy-geldanamycin (17-AAG), in an imatinib-sensitive GIST cell line (GIST882) and in novel imatinib-resistant GIST lines that are either dependent on (GIST430 and GIST48) or independent of (GIST62) KIT oncoproteins. 17AAG (>100 nmol/L) inhibited imatinib-sensitive and imatinib-resistant KIT oncoproteins, with substantially reduced phospho-KIT and total KIT expression after 30 minutes and 6 hours, respectively. KIT signaling intermediates, including AKT and mitogen-activated protein kinase, were inactivated by 17-AAG in the KIT-positive GIST lines, but not in the KIT-negative GIST62. Likewise, cell proliferation and survival were inhibited in the KIT-positive GISTs but not in GIST62. These findings suggest that 17-AAG biological effects in KIT-positive GISTs result mainly from KIT oncoprotein inhibition. The dramatic inactivation of imatinib-resistant KIT oncoproteins suggests that HSP90 inhibition provides a therapeutic solution to the challenge of heterogeneous imatinib resistance mutations in GIST patients.     

青少年胃肠道间质瘤研究进展

胃肠道间质瘤是一种胃肠道最常见的间叶组织来源的肿瘤,多见于中老年人,青少年罕见。青少年胃肠间质瘤临床诊断参考成人胃肠间质瘤的诊断标准,更加注重基因诊断。青少年胃肠间质瘤主要依靠外科治疗,对于晚期不可切除的患者根据基因检测结果可考虑伊马替尼或索尼替尼靶向治疗。     

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.     

Evidence-based treatment of gastrointestinal stromal tumor (GIST) with tyrosine kinase inhibitors-imatinib and sunitinib

Gastrointestinal stromal tumors (GIST) are sarcoma in the gastrointestinal tract which may be caused by somatic gain-of-function mutations in the KIT or PDGFRA gene. Imatinib mesylate has shown significant safety and great effectiveness for patients with KIT-positive unresectable, advanced, or metastatic GIST. The response rate (RR) was no less than 50%, disease control rate (DCR) of more than 85%, and the median progression-free survival (PFS) has been nearly two years. Also, imatinib has been shown to improve the prognosis of GIST patients. Meanwhile, sunitinib malate, used for patients with imatinib-resistant GIST or imatinib-intolerant patients, has also shown modest tolerability and fairly good outcomes. Sunitinib shows a less than 10% RR, a 30% to 40% DCR, and a median of nearly 8 months of PFS. Molecularly targeted therapy has prolonged overall survival of advanced GIST patients from 1. 5 years in the pre-imatinib era to 5 years after the introduction of imatinib. There remains, however, a great unmet medical need for new agents and/or multidisciplinary treatments for advanced GIST patients.     

Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers

BackgroundMasitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib.MethodsThis dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib’s activity in cancer patients and establishment of a pharmacokinetic profile.ResultsForty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2 mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic results showed a linear, dose-dependent increase of C_max and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1 mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable disease.ConclusionsThe safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients.     

Contemporary treatment of gastrointestinal stromal tumors

Great revolutionary changes have occurred in the diagnosis and treatment of gastrointestinal stromal tumor(GIST) due to the discovery and development of molecularly targeted therapy with imatinib and sunitinib, which have led to publication of several clinical guidelines for GIST. However, despite enhanced understanding of the clinical and molecular nature of GIST, there are many problems still remain. In this paper, I will focus on three GIST issues of great interest including: 1) laparoscopic surgery for GIST and gastrointestinal submucosal tumors; 2)multidisciplinary treatments for GIST, such as adjuvant therapy, neoadjuvant therapy, surgery during imatinib treatment, and surgery for focally imatinib-resistant GIST; and 3)the diagnosis and treatment of imatinib-resistant GIST.     

Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure

AimsTo assess the antitumour activity, safety, pharmacokinetics and pharmacodynamics of continuous daily sunitinib dosing in patients with imatinib-resistant/intolerant gastrointestinal stromal tumour (GIST) and to assess morning dosing versus evening dosing.Patients and methodsIn this open-label phase II study, patients were randomised to receive morning or evening dosing of sunitinib 37.5 mg/day. The primary end-point was clinical benefit rate (CBR; percent complete responses + partial responses [PRs] + stable disease [SD] ?24 weeks). Secondary end-points included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters and plasma biomarker levels.ResultsSixty of 61 planned patients received treatment (30 per dosing group); 26 completed the study. Overall, the CBR was 53% (95% exact CI, 40–66): eight patients (13%) achieved objective PRs; 24 (40%) achieved SD ?24 weeks. Median PFS was 34 weeks (95% CI, 24–49); median OS was 107 weeks (95% CI, 72 – not yet calculable). Most adverse events (AEs) were of grade 1 or 2 in severity, and were manageable through dose modification or standard interventions. No new AEs were apparent compared with the approved intermittent dosing schedule. Antitumour activity and safety were generally similar with morning and evening dosing. Continuous daily sunitinib dosing achieved and sustained effective drug concentrations without additional accumulation across cycles. Decreases from baseline in plasma levels of soluble KIT after 20 and 24 weeks of dosing correlated with longer OS.ConclusionFor patients with imatinib-resistant/intolerant GIST, continuous daily sunitinib dosing appears to be an active alternative dosing strategy with acceptable safety.     

Pharmacological management of gastrointestinal stromal tumours: an update on the role of sunitinib

The efficacy and tolerability of the receptor tyrosine kinase inhibitor, sunitinib malate, have been demonstrated in phase I–III clinical trials of patients with imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumours (GIST) as well as in a worldwide expanded-access study and in a continuous daily dosing (CDD) trial. Tumour genotype may have a significant influence on the activity of sunitinib in patients with imatinib-resistant GIST. Sunitinib activity was observed across different GIST genotypes and particularly in patients with wild-type and KIT exon 9 mutations (all relatively resistant to standard-dose imatinib) and in patients with secondary KIT exons 13 and 14 mutations. Adverse events with sunitinib were generally mild to moderate and easily managed by dose reduction, dose interruption or standard supportive measures. Treatment discontinuation can be avoided in most patients by close monitoring before and during treatment with appropriate adverse event management as necessary. The correlation between treatment exposure and clinical response is prompting the search for new approaches to treatment optimisation to ensure that patients derive maximum benefit from sunitinib therapy, including dose adjustments based on blood testing to ensure optimal drug exposure, and the use of the alternative CDD regimen to avoid treatment interruption.