吡咯替尼或来那替尼联合卡培他滨治疗HER-2阳性晚期乳腺癌疗效及安全性的Meta分析

目的:比较吡咯替尼或来那替尼联合卡培他滨(Pyrotinib/Neratinib+Capecitabine,P/N+C)与拉帕替尼联合卡培他滨(Lapatinib+Capecitabine,L+C)治疗HER-2阳性晚期乳腺癌的疗效性及安全性。方法:检索PubMed、Web of Science、Embase和Cochrane图书馆数据库,选自2005年01月01日截至2021年02月20日的潜在临床研究,合格的研究是前瞻性和注册的临床试验。对无病进展期（progression-free survival,PFS）、客观缓解率(objective response rate,ORR)及疾病控制率(disease control rate,DCR)具有95%置信区间(confidence interval,CI)的合并优势比和治疗相关不良事件的合并风险比进行Meta分析。结果:本次Meta分析包括3项随机对照试验,共有1 015例患者被纳入本研究。在P/N+C组,6个月PFS［OR=1.87,95%CI（1.44,2.43）,P＜0.000 01］、12个月PFS［OR=3.87,95%CI（1.95,7.70）,P=0.000 1］及ORR［OR=1.70,95%CI（1.10,2.64）,P=0.02］较L+C组延长;在常见的治疗相关的不良事件中,除P/N+C组的腹泻发生率较L+C组高［RR=3.10,95%CI（1.80,5.35）,P<0.000 1］以外,其余治疗相关不良事件均无显著差异。结论:本Meta分析表明,使用吡咯替尼或来那替尼联合卡培他滨治疗HER-2阳性晚期乳腺癌的疗效更好,并且是一种安全的治疗选择。     

辅助化疗联合拉帕替尼治疗HER-2阳性晚期或转移性乳腺癌的Meta分析

目的:应用Meta分析的方法系统评价联合拉帕替尼的辅助化疗治疗HER-2阳性晚期或转移性乳腺癌疗效的有效性和安全性.方法:计算机检索PubMed、Embase、Cochrane(2010年第2期)图书馆和CBM、CNKI、VIP、万方等数据库.收集HER-2阳性晚期或转移性乳腺癌患者联合拉帕替尼辅助化疗的随机和半随机对照试验,采用Stata 10.0软件对资料进行Meta分析.结果:共纳入4个研究,1028例患者.Meta分析结果显示,拉帕替尼联合辅助化疗与单纯辅助化疗相比,乳腺癌患者肿瘤的至疾病进展时间(TTP)显著性提高(HR=0.54,95%CI:0.44～0.66,P<0.001);肿瘤的无进展生存期(PFS)明显延长(HR=0.51,95%CI:0.34～0.76,P=0.001);总有效率(ORR)显著高于单纯化疗组(RR=1.69,95%CI:1.33～2.14,P<0.001);临床获益率(CBR)与单纯化疗组比较也较高(RR=1.63,95%CI:1.34～1.99,P<0.001).拉帕替尼联合辅助化疗与单纯辅助化疗组在腹泻(RR=2.07,95%CI:1.42～3.02,P<0.001)和皮疹(RR=2.31,95%CI:1.64～3.25,P=0.007)发生率差异有统计学意义.结论:与单纯辅助化疗相比较,联合拉帕替尼辅助化疗可以显著提高至TTP、PFS、ORR和CBR,同时也会显著的提高腹泻和皮疹的发生率.     

卡培他滨维持治疗晚期乳腺癌的临床观察

背景与目的：卡培他滨是晚期乳腺癌一线治疗方案用药,但在晚期乳腺癌的维持治疗中的研究较少。本文旨在探讨卡培他滨维持治疗晚期乳腺癌的疗效及不良反应。方法：将一线化疗后处于完全缓解(complete response,CR)、部分缓解(partial response,PR)或疾病稳定(stable disease,SD)的62例患者分为2组,卡培他滨治疗组(31例)患者予以单药口服卡培他滨维持治疗,对照组(31例)患者予以定期随访观察。每2个化疗周期后评价疗效。结果：卡培他滨治疗组中位疾病进展时间(time to progression,TTP)为12(2～24)个月,明显高于对照组的7(1～18)个月,且2组差异有统计学意义(P<0.05)。在亚组分析中,未绝经组、激素受体阳性组、HER-2阳性组、有内脏转移组、有肺转移组及既往未接受过卡培他滨化疗组的患者中,卡培他滨治疗组患者的TTP均显著高于对照组患者。卡培他滨治疗组总有效率(CR+PR)为19.4%(6/31),肿瘤控制率(CR+PR+SD)为74.2%(23/31)。主要不良反应为手足综合征及血液学不良反应,其次为胃肠道不良反应,但均可以耐受。卡培他滨治疗组的生活质量评分较对照组明显提高。结论：卡培他滨用于晚期乳腺癌一线治疗后的维持治疗可以延缓疾病进展,提高生活质量。     

阿帕替尼联合卡培他滨治疗晚期食管癌效果观察

目的观察阿帕替尼联合卡培他滨对晚期食管癌的疗效。方法选取2017年6月至2018年2月于江苏省泰兴市人民医院接受治疗的101例晚期食管癌患者,按随机数字表法分为对照组(50例)和观察组(51例),对照组给予卡培他滨联合放疗,观察组在对照组的基础上服用阿帕替尼。比较两组患者的疗效、不良反应及无进展生存(PFS)时间。结果观察组总有效率为90.2%(46/51),高于对照组的72.0%(36/50),差异有统计学意义(χ^2=5.473,P=0.019)。两组患者白细胞减少、中性粒细胞减少、血小板减少、贫血、蛋白尿、高血压发生情况比较,差异均无统计学意义(均P>0.05)。观察组中位PFS时间为18.49个月(95%CI 15.35~25.03个月),长于对照组的13.33个月(95%CI 10.36~18.24个月),差异有统计学意义(χ^2=5.995,P<0.01)。结论阿帕替尼联合卡培他滨治疗晚期食管癌效果确切,无明显不良反应发生,PFS时间延长。     

阿帕替尼联合卡培他滨对晚期转移性三阴性乳腺癌患者临床疗效、无进展生存期及不良反应的影响

目的 探究阿帕替尼联合卡培他滨对晚期转移性三阴性乳腺癌(TNBC)患者的临床疗效、无进展生存期及不良反应的影响.方法 将104例多线治疗失败的晚期TNBC患者按不同的治疗方法分为联合组和对照组,每组52例.联合组口服甲磺酸阿帕替尼和卡培他滨,对照组口服卡培他滨,观察两组患者的无进展生存期(PFS)、临床疗效及不良反应发生情况.结果 两组患者均无完全缓解(CR),联合组患者客观缓解率(ORR)为53.85％(28/52)、疾病控制率(DCR)为84.62％(44/52),均明显高于对照组的25.00％(13/52)、51.92％(27/52),差异均有统计学意义(χ2=8.993、12.828,P﹤0.01).两组患者各不良反应发生率比较,差异均无统计学意义(P﹥0.05).联合组患者的PFS为6.00个月(95％CI:4.922～7.085),明显长于对照组的4.00个月(95％CI:3.109～5.244),差异有统计学意义(χ2=8.358,P=0.004).结论 阿帕替尼联合卡培他滨治疗TNBC,可有效延长患者的PFS,疗效较好,且不良反应未明显增加,患者耐受性较好.     

SRT联合拉帕替尼治疗HER2阳性乳腺癌脑转移疗效及预后分析

目的 探讨立体定向放射治疗(Stereotactic radiotherapy,SRT)联合拉帕替尼治疗HER2阳性乳腺癌脑转移的疗效及预后。方法 回顾性分析91例HER2阳性乳腺癌脑转移患者接受拉帕替尼靶向治疗的同时接受全脑放疗或SRT的情况,其中42例患者接受SRT的同时进行拉帕替尼联合卡培他滨治疗(SRT组),另外49例患者采用全脑放疗同时进行拉帕替尼联合卡培他滨治疗(全脑放疗组)。评价其疗效和毒性,定期随访,并行多因素Cox回归分析其预后相关因素。结果 放疗结束后1月SRT组脑部病灶客观缓解率为92.86%(39/42),全脑放疗组客观缓解率为77.55%(38/49),SRT组优于全脑放疗组(χ²=4.070,P=0.044)。SRT组和全脑组12个月受照射肿瘤病灶无进展生存率分别为95.20%及83.10%, SRT组优于全脑放疗组(χ²=10.851,P=0.001)。 SRT组无颅内转移生存率与全脑放疗组无统计学差异(P＞0.05)。SRT组和全脑放疗组1年生存率分别为85.70%和69.40%,2年生存率分别为66.70%和55.10%,两组中位生存期分别为31.56个月和25.00个月,SRT组优于全脑放疗组(P=0.002)。多因素Cox回归分析结果表明无颅外转移(HR=0.527,95% CI:0.290~0.957,P=0.035),颅内病灶≤3个(HR=2.457,95% CI:1.223~4.933,P=0.012),放疗方式SRT(HR=1.746,95% CI:1.055~2.888,P=0.030)是HER2阳性乳腺癌脑转移放疗预后的独立保护因素。结论 SRT联合拉帕替尼在局部控制率以及生存率上优于全脑放疗联合拉帕替尼。颅内病灶个数少、无颅外转移灶和放疗方式是HER2阳性乳腺癌脑转移治疗的良好预后因素。     

曲妥珠单抗联合拉帕替尼及多西紫杉醇一线治疗HER-2阳性晚期乳腺癌的安全性和有效性

目的:观察曲妥珠单抗联合拉帕替尼及多西紫杉醇一线治疗HER-2阳性晚期乳腺癌的安全性和有效性。方法:这是一项前瞻、单臂、开放标签的单中心Ⅱ期临床研究(ChiCTR1800015814)。HER-2阳性晚期乳腺癌一线治疗给予曲妥珠单抗(6 mg/kg，首剂8 mg/kg)联合拉帕替尼(1 000 mg/d)及多西紫杉醇(75 mg/m2)，每3周重复。对非进展的患者继续用药直至疾病进展或毒性不可耐受，但最长用药时间不超过2年。主要研究终点是有效率，次要终点是PFS和OS。结果:自2016年9月至2019年5月共入组65例患者。本方案的剂量限制性毒性为腹泻，Ⅲ-Ⅳ度腹泻发生率为24.6%。总体有效率为69.2%(CR 3.1%，PR 66.1%)，激素受体阴性患者有效率明显优于激素受体阳性患者(76.7% vs 57.1%，P＜0.01)。中位随访31个月，PFS为16.4个月(95%CI:13.4~19.6个月)。尚未达到中位OS时间。Log-rank检验显示是否内脏转移、是否多器官转移对PFS的影响具有统计学意义(P＜0.01和P=0.022)。结论:曲妥珠单抗联合拉帕替尼及多西紫杉醇毒性可耐受，疗效较好，作为HER-2阳性晚期乳腺癌一线治疗新的治疗策略，值得进一步研究。     

哺乳动物雷帕霉素靶蛋白抑制剂用于多重靶向治疗耐药的HER-2阳性晚期乳腺癌一例

在HER-2阳性晚期乳腺癌的临床治疗中,抗HER-2靶向药物曲妥珠单克隆抗体（赫赛汀）及拉帕替尼的应用显著改善了患者的无进展生存期（progression—freesurvival,PFS）和0S[1],然而,有些患者在接受靶向治疗过程中先后出现曲妥珠单克隆抗体及拉帕替尼治疗耐药,     

曲妥珠单抗治疗失败的HER-2阳性乳腺癌患者不同后续治疗方案的疗效及影响因素分析

目的:观察人表皮生长因子受体2（human epidermal growth factor receptor-2,HER-2）阳性乳腺癌患者曲妥珠单抗治疗失败后不同后续治疗方案的疗效,分析影响因素。方法:回顾性分析2014年1月至2016年12月在我院肿瘤科治疗的曲妥珠单抗治疗失败的94例HER-2阳性晚期乳腺癌患者,根据其后续治疗方案不同将其分为A组（接受单纯化疗）、B组（接受曲妥珠单抗+化疗）和C组（接受拉帕替尼+化疗）;比较三组患者治疗效果,并分析可能影响抗HER-2治疗效果的相关因素。结果:94例患者均完成随访,中位随访时间22.3个月。三组患者中位无进展生存期（median progression free survival,mPFS）分别为3个月、4.5个月及6个月,差异有统计学意义（P<0.000 1）;C组PFS较A组及B组均明显延长,B组PFS较A组明显延长。A、B、C三组客观有效率（objective response rate,ORR）分别为8.7%、29.7%、38.2%,三组的临床获益率（clinical benefit rate,CBR）分别为21.7%、54.1%、64.7%,以上差异均有统计学意义（P<0.05）。对可能影响PFS的单因素进行分析,拉帕替尼、一线疗程（曲妥珠单抗）获益时间≥6个月、无内脏转移是PFS的影响因素;而拉帕替尼、一线疗程（曲妥珠单抗）获益时间≥6个月是PFS的独立影响因素。结论:对于曲妥珠单抗治疗失败的HER-2阳性晚期乳腺癌患者,后续治疗方案中含抗HER-2靶向药物可改善患者预后。     

人表皮生长因子受体2阳性晚期乳腺癌靶向治疗耐药与预后关系的真实世界研究

目的探讨抗人表皮生长因子受体2(HER-2)原发耐药与继发耐药对HER-2阳性晚期乳腺癌患者预后的影响。方法选取1998—2018年于中国医学科学院肿瘤医院接受治疗的HER-2阳性晚期乳腺癌患者, 分析其新辅助或辅助及晚期三线化疗的治疗情况。抗HER-2靶向治疗药物包括曲妥珠单抗、帕妥珠单抗、T-DM1、RC48-ADC、拉帕替尼、吡咯替尼、艾力替尼、西帕替尼、塞拉替尼。基于患者对抗HER-2治疗获益的持续时间, 将患者分为原发抗HER-2耐药(原发耐药)组和继发抗HER-2耐药(继发耐药)组。以总生存时间(OS)为主要研究终点, 生存分析采用Kaplan-Meier法。结果全组284例患者发生复发转移时的中位年龄为48岁, 激素受体阳性155例(54.6%), 阴性129例(45.4%);绝经前128例(45.1%), 绝经后156例(54.9%)。初次确诊复发转移时美国东部肿瘤协作组(ECOG)功能状态(PS)评分0～1分277例(97.5%), ECOG PS评分≥2分7例(2.5%)。原发耐药组103例(36.3%), 继发耐药组181例(63.7%), 两组患者中位OS分别为...     

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases �C the UK experience

Background:

The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab.

Methods:

Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented.

Results:

Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6–24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15–27%) and median TTP was 22 weeks (95% CI: 17–27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9–39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15–28).

Conclusions:

Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.     

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BackgroundLapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.Patients and methodsDNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher’s exact test, Kaplan–Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.ResultsThere were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).ConclusionOur findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.     

FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2

On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2-overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab. One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3+ or 2+ with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function. Patients received either lapatinib (1,250 mg once daily on days 1-21) plus capecitabine (1,000 mg/m(2) every 12 hours on days 1-14) every 21 days or capecitabine alone (1,250 mg/m(2) every 12 hours on days 1-14) every 21 days. The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. After TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled). The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p = .00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7% (lapatinib plus capecitabine) versus 13.9% (capecitabine alone). Survival data were not mature. Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. Grade 3 or 4 adverse reactions that occurred with a frequency of >5% in patients on the combination arm were diarrhea (13%) and palmar-plantar erythrodysesthesia (12%). There was a 2% incidence of reversible decreased left ventricular function in the combination arm.     

曲妥珠单抗联合紫杉醇脂质体和卡培他滨治疗HER-2阳性复发转移性乳腺癌

目的：评估曲妥珠单抗（trastuzumab,H）与紫杉醇脂质体（paclitaxel liposome,P）、卡培他滨（capecit-abine,X）的联合方案HPX方案治疗人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）阳性复发转移性乳腺癌的疗效与安全性。方法筛选HER-2阳性复发转移性乳腺癌患者32例,给予HPX方案治疗：曲妥珠单抗首次8 mg／kg,后6 mg／kg维持,d1;紫杉醇脂质体175 mg／m2,d1;卡培他滨825 mg／m2,2次／d,d1－14,21天为1周期。结果32例患者中位无进展生存时间（progression-free survival,PFS）为12．7月（95％CI：5．7－19.7月）,客观缓解率（objective response rate,ORR）为53．2％,临床获益率（clinical benefit rate,CBR）为84．5％。一线治疗患者的PFS达15．3月（95％ CI：2．5－28．1月）,ORR达68．4％,CBR达84．2％。Ⅲ～Ⅳ级不良反应主要为血液学毒性,包括中性粒细胞减少（46．9％）、白细胞减少（37．5％）、血小板减少（6．3％）,Ⅲ～Ⅳ级非血液学不良反应主要为手足综合征（9．4％）和腹泻（3．1％）。结论曲妥珠单抗联合紫杉醇脂质体和卡培他滨是治疗HER-2阳性复发转移性乳腺癌的有效治疗方案,且安全性良好。     

Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea

ABSTRACT: Purpose: To evaluate efficacy in patients with brain metastasis (BM) on entry into the lapatinib expanded access program (LEAP). METHODS: LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m2 daily in two divided doses, days 1-14, every 21 days and lapatinib 1250 mg once daily. RESULTS: Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression-free survival (PFS) was 18.7 weeks in patients with BM and 19.4 weeks without BM (P=0.88). In patients with BM, brain response was synchronized with systemic responses (P=0.0001). Overall survival (OS) was 48.9 weeks in patients with BM and 64.6 weeks without BM (P=0.23). Multivariable analysis found hormone receptor positivity (P=0.003) and clinical benefit rate (CBR) of combined systemic and brain disease (P<0.0001) significantly associated with prolonged brain PFS, and CBR of combined systemic and brain disease (P=0.03) and longer trastuzumab use (P=0.047) associated with prolonged OS in patients with BM; prior capecitabine did not affect PFS or OS in patients with BM. CONCLUSION: Lapatinib plus capecitabine is equally effective in patients with or without BM.     

Ki-67 index as a prognostic factor of subsequent lapatinib-based therapy in HER2-positive metastatic breast cancer with resistance to trastuzumab

Prognostic factor analysis has been conducted to determine whether the parameters of clinical data and biomarkers would predict differential progression-free survival (PFS) or overall survival (OS) from lapatinib-based therapy in patients with primary or acquired resistance to trastuzumab. Treatment with lapatinib plus capecitabine for HER2-positive metastatic breast cancer (MBC) with primary or acquired resistance to trastuzumab was analyzed retrospectively. Tumor biomarkers, which came from the biopsies before the starting of lapatinib therapy, were evaluated by immunohistochemistry (IHC). Prognostic factors related to PFS or OS of the lapatinib therapy were assessed by univariate and multivariate analysis. Ki-67 index and liver metastases were the significant prognostic factors for predicting PFS of subsequent lapatinib therapy in the univariate analysis and the multivariate analysis. The risk for disease progression in patients who had a Ki-67 index < 40% was 59% less than that in patients had Ki-67 ≥ 40 (HR = 0.41, 95% CI, 0.23–0.74, P = 0.003). TTP of prior trastuzumab therapy, liver metastases, and the number of metastatic sites were three independent prognostic factors of subsequent lapatinib therapy. Ki-67 index was the significant prognostic factors for predicting PFS of the subsequent second line targeted therapy in patients with trastuzumab resistance.