Abstract
目的
评价真实世界中口服吡咯替尼治疗表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阳性转移性乳腺癌的疗效和毒副反应.
方法
回顾性分析72例接受以口服吡咯替尼为治疗基础的HER2阳性转移性乳腺癌患者.
结果
72例HER2阳性转移性乳腺癌患者中69例(95.8%)在复发转移阶段和/或(新)辅助治疗阶段曾行抗HER2靶向治疗;61例(84.7%)在复发转移阶段接受过抗HER2靶向治疗药物,包括曲妥珠单抗56例(77.8%),拉帕替尼36例(50.0%),T-DM1 4例(5.6%).72例患者中接受吡咯替尼联合化疗(±曲妥珠单抗)62例(86.1%),吡咯替尼联合内分泌治疗(±曲妥珠单抗)6例(8.3%),吡咯替尼(±曲妥珠单抗)4例(5.6%).72例患者均可评价疗效,其中完全缓解1例(1.4%),部分缓解18例(25.0%),疾病稳定41例(56.9%),疾病进展12例(16.7%).客观缓解率(完全缓解+部分缓解)为26.4%,中位无进展生存期(progression free survival, PFS)为7.6个月(95%CI: 5.5~9.7个月).36例曾接受过拉帕替尼治疗的患者中,吡咯替尼治疗的中位PFS为7.9个月(95%CI: 4.1~11.7个月), 15例脑转移患者中,吡咯替尼治疗的中位PFS为6.0个月(95%CI: 2.2~9.8个月).吡咯替尼相关的主要毒副反应为腹泻,共57例(79.2%),1~2级者48例(66.7%),3级者9例(12.5%).
结论
以吡咯替尼为基础的方案能够有效治疗HER2阳性转移性乳腺癌,包括拉帕替尼治疗失败及脑转移的患者,不良反应可耐受.
Keywords: 吡咯替尼, 受体, 表皮生长因子, 乳腺肿瘤, 曲妥珠单抗, 拉帕替尼
Abstract
Objective
Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase Ⅱ and phase Ⅲ randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world.
Methods
We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated.
Results
Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (±trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg.
Objective
response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3.
Conclusion
Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.
Keywords: Pyrotinib, Receptor, epidermal growth factor, Breast neoplasms, Trastuzumab, Lapatinib
表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)阳性乳腺癌患者约占乳腺癌总体人数的15%~30%[1,2],肿瘤侵袭性强,患者预后差.随着抗HER2靶向治疗药物(如曲妥珠单抗,帕妥珠单抗,拉帕替尼,T-DM1等)的不断出现和广泛应用,HER2阳性转移性乳腺癌患者的生存期显著延长[3].虽然如此,仍有许多患者在治疗过程中出现上述药物耐药,因此仍需更多的新型药物以不断改善治疗效果,使患者获得更佳的生存机会.
马来酸吡咯替尼是我国自主研发的一种小分子,不可逆的酪氨酸激酶抑制剂,它作用于三个靶点,在细胞内的酪氨酸激酶区,可以与HER1,HER2和HER4的胞内激酶区ATP结合位点共价结合,抑制自身磷酸化,从而阻断下游信号通路的激活,抑制肿瘤细胞生长[4,5].随机对照的Ⅱ期及Ⅲ期临床研究显示,吡咯替尼联合卡培他滨治疗可以显著延长HER2阳性转移性乳腺癌的无进展生存期[6,7],适用于治疗HER2阳性,既往未接受或接受过曲妥珠单抗的复发或转移性乳腺癌患者.吡咯替尼自2018年8月在中国上市时间仅1年余,真实世界中对吡咯替尼的临床应用还少有报道,本研究对实际工作中吡咯替尼治疗的72例患者进行了回顾性分析,旨在探讨吡咯替尼在真实世界中治疗HER2阳性转移性乳腺癌的疗效及安全性.
1. 资料与方法
1.1. 患者纳入标准
本研究的患者纳入标准为:(1)经组织病理学证实的术后复发转移或确诊时无法手术的Ⅳ期HER2阳性乳腺癌患者,HER2阳性乳腺癌的定义为原发灶或转移灶组织标本免疫组织化学HER2为3+或荧光原位杂交技术检测(fluorescence in situ hybridization, FISH)为+;(2)患者年龄为18~80岁;(3)按照实体肿瘤的疗效评价标准(response evaluation criteria in solid tumors,RECIST 1.1),至少有1个可测量的病灶;(4)美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)体能状态评分≤2;(5)预计生存期≥3个月;(6)重要脏器功能基本正常,化疗前血常规以及肝肾功能检查基本正常,无治疗禁忌证.
1.2. 临床资料
收集来自5个医院2018年8月至2019年9月经吡咯替尼治疗的HER2阳性转移性乳腺癌患者72例,其中北京大学肿瘤医院61例,北京大学第一医院4例,北京大学第三医院4例,中国人民解放军总医院2例,中日友好医院1例.患者中位年龄55岁(范围32~79岁).所有患者均经组织病理学证实为乳腺癌,且均经免疫组织化学和/或FISH检测确定为HER2阳性乳腺癌.
激素受体(hormone receptor, HR)阳性定义为雌激素受体(estrogen receptor, ER)和/或孕激素受体(progesterone receptor, PR)阳性.激素受体阴性定义为ER阴性且PR阴性.本组患者中,ER阴性且PR阴性者为39例(54.2%),ER和/或PR阳性者为33例(45.8%).80.6%的患者存在内脏转移,最常见的内脏转移部位包括肝31例(43.1%),肺30例(41.7%), 脑15例(20.8%),具体见表1.
1.
72例患者基本人口学和疾病特征
Baseline demographic and disease characteristics of 72 patients
| Items | Data |
| *, (neo) adjuvant trastuzumab; HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; PR, progesterone receptor. | |
| Age | |
| Median/years | 55 |
| Range/years | 32-79 |
| <65 years, n (%) | 64 (88.9) |
| ≥65 years, n (%) | 8 (11.1) |
| Histologic type, n (%) | |
| Invasive ductal | 70 (97.2) |
| Others | 2 (2.8) |
| Hormone receptor status, n (%) | |
| Negative ER and PR | 39 (54.2) |
| Positive ER and/or positive PR | 33 (45.8) |
| Stage at first diagnosis of breast cancer, n (%) | |
| Ⅰ-Ⅲ | 59 (81.9) |
| Ⅳ | 13 (18.1) |
| Sites of metastases, n (%) | |
| Visceral | 58 (80.6) |
| Liver | 31 (43.1) |
| Lung | 30 (41.7) |
| Brain | 15 (20.8) |
| Nonvisceral | 14 (19.4) |
| Previous anti-HER2 treatment, n (%) | |
| Yes | 69 (95.8) |
| (Neo) adjuvant setting* | 31 (43.1) |
| Metastatic setting | 61 (84.7) |
| No | 3 (4.2) |
| Prior anti-HER2 therapy for metastases disease, n (%) | |
| Trastuzumab | 56 (77.8) |
| Lapatinib | 36 (50.0) |
| T-DM1 | 4 (5.6) |
| No | 11 (15.3) |
| Primary resistant to trastuzumab therapy, n (%) | |
| Yes | 26 (36.1) |
| No | 46 (63.9) |
| Previous lines of chemotherapy in metastatic setting | |
| Median, n | 2 |
| 0, n (%) | 7 (9.7) |
| 1, n (%) | 19 (26.4) |
| 2, n (%) | 11 (15.3) |
| ≥3, n (%) | 35 (48.6) |
95.8%的患者在复发转移阶段和/或(新)辅助治疗阶段曾行抗HER2靶向治疗,61例(84.7%)患者在复发转移阶段接受过抗HER2靶向治疗药物,包括曲妥珠单抗56例(77.8%),拉帕替尼36例(50.0%),T-DM1 4例(5.6%).原发性曲妥珠单抗耐药是指转移性乳腺癌经曲妥珠单抗治疗3个月内出现疾病进展(progressive disease,PD),或第1次影像学疗效评价即出现PD,早期乳腺癌术后辅助曲妥珠单抗治疗过程中出现复发转移,或曲妥珠单抗治疗结束后12个月内出现复发转移[8].本组患者中26例(36.1%)存在原发性曲妥珠单抗耐药.
1.3. 治疗方法
口服马来酸吡咯替尼片(商品名:艾瑞妮,江苏恒瑞医药股份有限公司),规格为160 mg和80 mg.联合化疗者每治疗2个周期(6周)即进行疗效评价,单药治疗,联合内分泌治疗,联合其他抗HER2靶向治疗药物者每8~12周进行疗效评价,治疗直至出现PD或无法耐受治疗.
1.4. 疗效及毒副反应判定
所有可测量病灶均有治疗前的基线测量,定期进行影像学检查和测量.按照RECIST 1.1标准:完全缓解(complete response,CR)为所有目标病灶消失;部分缓解(partial response,PR)为基线病灶长径总和缩小≥30%;PD为基线病灶长径总和增加超过20%,最小绝对值升高5 mm或出现新病灶;疾病稳定(stable disease, SD)为基线病灶长径总和有缩小但未达PR或有增加但未达PD.客观缓解率=CR+PR,疾病控制率=CR+PR+SD,临床获益率=CR+PR+SD≥6个月,无进展生存期(progression free survival,PFS)定义为开始治疗至第1次发生PD或任何原因死亡的时间间隔.不良反应按美国国立癌症研究所不良反应事件通用术语标准(National Cancer Institue-Common Terminology Criteria for Adverse Events,NCI-CTC 4.0)判定,标准分为0~4级.
1.5. 随访
截至2019年11月,40例患者结束吡咯替尼治疗并观察到PFS,32例患者目前继续吡咯替尼治疗.
1.6. 统计学分析
应用SPSS 15.0分析软件,患者临床特征采用描述性分析进行评价,具体分类用构成比表示,采用Kaplan-Meier法绘制生存曲线并计算中位生存时间的95%CI.
2. 结果
2.1. 吡咯替尼治疗情况
初始剂量:65例(90.3%)患者初始治疗剂量为400 mg,7例(9.7%)为320 mg.具体方案如下:(1)吡咯替尼联合化疗(±曲妥珠单抗)62例(86.1%), 方案包括:卡培他滨40例,长春瑞滨(口服)12例,依托泊苷(口服)4例,吉西他滨2例,紫杉醇1例,紫杉醇(白蛋白结合型)1例,曲妥珠单抗+吉西他滨1例,曲妥珠单抗+紫杉醇(白蛋白结合型)1例;(2)吡咯替尼联合内分泌治疗(±曲妥珠单抗)6例(8.3%), 方案包括:阿那曲唑2例,氟维司群1例,曲妥珠单抗+来曲唑1例,曲妥珠单抗+氟维司群1例,曲妥珠单抗+戈舍瑞林+氟维司群1例;(3)吡咯替尼(±曲妥珠单抗)4例(5.6%),方案包括:吡咯替尼单药3例,联合曲妥珠单抗双靶向治疗1例.
2.2. 疗效
72例患者均可评价疗效,其中CR 1例(1.4%),PR 18例(25.0%),SD 41例(56.9%),PD 12例(16.7%).客观缓解率(CR+PR)为26.4%,临床获益率(CR+PR+SD≥6月)为48.6%,疾病控制率(CR+PR+SD)为83.3%(表2).整体的PFS为7.6个月(95%CI: 5.5~9.7个月,图1).
2.
近期疗效亚组分析
Subgroup analysis of short term response
| Agents | Total, n (%) | Response, n (%) | ORR, n (%) | DCR, n (%) | |||
| CR | PR | SD | PD | ||||
| CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate. | |||||||
| Total | 72 (100.0) | 1 (1.4) | 18 (25.0) | 41 (56.9) | 12 (16.7) | 19 (26.4) | 60 (83.3) |
| Pyrotinib+chemotherapy (±trastuzumab) | |||||||
| Pyrotinib+capecitabine | 40 (55.6) | 1 (2.5) | 13 (32.5) | 20 (50.0) | 6 (15.0) | 14 (35.0) | 34 (85.0) |
| Pyrotinib+vinorelbine (oral) | 12 (16.7) | 0 (0) | 0 (0) | 9 (75.0) | 3 (25.0) | 0 (0) | 9 (75.0) |
| Pyrotinib+etoposide (oral) | 4 (5.6) | 0 (0) | 1 (25.0) | 2 (50.0) | 1 (25.0) | 1 (25.0) | 3 (75.0) |
| Pyrotinib+gemcitabine | 2 (2.8) | 0 (0) | 0 (0) | 2 (100.0) | 0 (0) | 0 (0) | 2 (100.0) |
| Pyrotinib+paclitaxel | 1 (1.4) | 0 (0) | 0 (0) | 1 (100.0) | 0 (0) | 0 (0) | 1 (100.0) |
| Pyrotinib+albumin-bound paclitaxel | 1 (1.4) | 0 (0) | 0 (0) | 1 (100.0) | 0 (0) | 0 (0) | 1 (100.0) |
| Pyrotinib+trastuzumab+gemcitabine | 1 (1.4) | 0 (0) | 1 (100.0) | 0 (0) | 0 (0) | 1 (100.0) | 1 (100.0) |
| Pyrotinib+trastuzumab+albumin-bound paclitaxel | 1 (1.4) | 0 (0) | 0 (0) | 0 (0) | 1 (100.0) | 0 (0) | 0 (0) |
| Pyrotinib+endocrine therapy (±trastuzumab) | |||||||
| Pyrotinib+endocrine therapy | 3 (4.2) | 0 (0) | 1 (33.3) | 2 (66.7) | 0 (0) | 1 (33.3) | 3 (100.0) |
| Pyrotinib+trastuzumab+endocrine therapy | 3 (4.2) | 0 (0) | 2 (66.7) | 1 (33.3) | 0 (0) | 2 (66.7) | 3 (100.0) |
| Pyrotinib (±trastuzumab) | |||||||
| Pyrotinib alone | 3 (4.2) | 0 (0) | 0 (0) | 2 (66.7) | 1 (33.3) | 0 (0) | 2 (66.7) |
| Pyrotinib+trastuzumab | 1 (1.4) | 0 (0) | 0 (0) | 1 (100.0) | 0 (0) | 0 (0) | 1 (100.0) |
1.
72例患者无进展生存期
Progression free survival (PFS) of 72 patients
26例曲妥珠单抗原发耐药患者中,14例(53.8%)在1~2线治疗中选择了吡咯替尼治疗,而46例曲妥珠单抗非原发耐药患者中,仅12例(26.1%)在1~2线治疗中应用吡咯替尼.在整体人群中比较曲妥珠单抗原发耐药和非原发耐药,吡咯替尼治疗的中位PFS差异无统计学意义(7.9个月 vs. 7.2个月,P=0.685).
36例(50.0%)曾接受过拉帕替尼治疗的患者中,吡咯替尼治疗的客观缓解率(CR+PR)为22.2%,临床获益率(CR+PR+SD≥6月)为41.7%,疾病控制率(CR+PR+SD)为77.8%,中位PFS为7.9个月(95%CI: 4.1~11.7个月,图2),与未接受过拉帕替尼治疗患者的7.2个月(95%CI:4.7~9.7个月)相似(P=0.657).
2.
36例曾接受过拉帕替尼治疗患者的无进展生存期
Progression free survival (PFS) of 36 patients with prior lapatinib therapy
15例脑转移患者在复发转移阶段均经过拉帕替尼治疗,14例(93.3%)经过曲妥珠单抗治疗,治疗方案包括:(1)吡咯替尼联合化疗(±曲妥珠单抗)12例(80.0%),其中卡培他滨5例,长春瑞滨(口服)4例,吉西他滨1例,紫杉醇(白蛋白结合型)1例,曲妥珠单抗+吉西他滨1例;(2)吡咯替尼联合内分泌治疗(+曲妥珠单抗)1例(6.7%),具体为曲妥珠单抗+戈舍瑞林+氟维司群;(3)吡咯替尼(±曲妥珠单抗)2例(13.3%),包括吡咯替尼单药1例,联合曲妥珠单抗双靶向治疗1例.吡咯替尼治疗的中位PFS为6.0个月(95%CI:2.2~9.8个月,图3).
3.
15例脑转移患者的无进展生存期
Progression free survival (PFS) of 15 patients with brain metastasis
2.3. 毒副反应与剂量调整
吡咯替尼相关的主要毒副反应为腹泻,共57例(79.2%),其中1~2级者48例(66.7%),3级者9例(12.5%),无4级腹泻发生.血液学毒性考虑主要与化疗药物相关.65例初始剂量为400 mg的患者中,14例(21.5%)因腹泻进行了降低剂量的调整(表3,4).
3.
72例患者治疗相关不良反应
Treatment related toxicities of 72 patients
| Toxicity | All grades, n (%) | Grade, n (%) | ||||
| 1 | 2 | 3 | 4 | |||
| ALT, glutamic pyruvic transaminase; AST, glutamic oxaloacetic transaminase; TBIL, total bilirubin. | ||||||
| Diarrhea | 57 (79.2) | 26 (36.1) | 22 (30.6) | 9 (12.5) | 0 (0) | |
| Neutropenia | 16 (22.2) | 11 (15.3) | 4 (5.6) | 1 (1.4) | 0 (0) | |
| Anemia | 9 (12.5) | 4 (5.6) | 5 (6.9) | 0 (0) | 0 (0) | |
| Thrombocytopenia | 2 (2.8) | 0 (0) | 2 (2.8) | 0 (0) | 0 (0) | |
| Hand-foot syndrome | 5 (6.9) | 2 (2.8) | 0 (0) | 3 (4.2) | 0 (0) | |
| Rash | 2 (2.8) | 0 (0) | 2 (2.8) | 0 (0) | 0 (0) | |
| Fatigue | 2 (2.8) | 1 (1.4) | 1 (1.4) | 0 (0) | 0 (0) | |
| Increased ALT/AST | 6 (8.3) | 5 (6.9) | 1 (1.4) | 0 (0) | 0 (0) | |
| Increased TBIL | 7 (9.7) | 7 (9.7) | 0 (0) | 0 (0) | 0 (0) | |
4.
72例患者吡咯替尼的剂量调整
Dose adjustments of pyrotinib in 72 patients
| Starting dose | Total, n (%) | Dose adjustments |
| 400 mg | 65 (90.3) | Reduction to 320 mg (n=11) |
| Reduction to 240 mg (n=2) | ||
| Reduction to 160 mg (n=1) | ||
| 320 mg | 7 (9.7) | Increase to 400 mg (n=1) |
| Reduction to 160 mg (n=1) |
3. 讨论
HER2阳性转移性乳腺癌患者预后差,生存期短,在抗HER2靶向治疗药物使用之前,患者的5年生存率仅有13.2%[9],随着抗HER2靶向治疗药物曲妥珠单抗[10,11,12],拉帕替尼[13,14,15],帕妥珠单抗[16],T-DM1[17]等的广泛应用,患者的中位生存期延长至43.47~52.96个月[3].临床实践中,HER2阳性转移性乳腺癌的一线治疗方案通常为抗体类药物曲妥珠单抗±帕妥珠单抗联合化疗或内分泌治疗,而一线治疗进展后或是多线抗HER2治疗进展后的后续治疗选择,目前仍是治疗的难点.
与传统抗体类药物曲妥珠单抗相比,吡咯替尼有机制上的优势.曲妥珠单抗主要作用在HER2-HER2同源二聚体,对配体诱导的HER2异源二聚体信号通路的阻断作用很弱,而吡咯替尼可以全面阻断HER家族同/异源二聚体下游通路,同时,由于作用机制的不同,对于曲妥珠单抗耐药的患者,吡咯替尼仍可能有效.吡咯替尼的Ⅱ期随机,对照临床研究共纳入128例患者,评估吡咯替尼联合卡培他滨方案对比拉帕替尼联合卡培他滨方案治疗HER2阳性转移性乳腺癌的有效性和安全性,结果显示,吡咯替尼组对比拉帕替尼组可以显著提高患者的客观缓解率(78.5% vs. 57.1%,P=0.01)和中位PFS(18.1个月 vs. 7.0个月,P<0.001)[6].目前另一项设计相似的Ⅲ期临床研究(NCT03080805)正在进行,其旨在进一步验证吡咯替尼联合卡培他滨治疗既往曲妥珠单抗治疗失败患者的疗效.PHENIX也是一项Ⅲ期临床研究,评价吡咯替尼联合卡培他滨用于既往接受过曲妥珠单抗和紫杉类药物治疗的HER2阳性晚期乳腺癌,279例患者以2 ∶1比例随机分为吡咯替尼联合卡培他滨组和安慰剂联合卡培他滨组,结果显示,吡咯替尼组中位PFS显著延长(11.1个月 vs. 4.1个月,P<0.001)[7].
本研究纳入的患者95.8%在复发转移阶段和/或(新)辅助治疗阶段曾行以曲妥珠单抗为主的抗HER2靶向治疗,结果显示中位PFS为7.6个月(95%CI: 5.5~9.7个月), 低于Ⅱ~Ⅲ期临床研究中吡咯替尼的治疗结果,考虑与纳入患者的既往治疗情况有关,在Ⅱ期研究中只允许患者在复发转移后进行0~2线治疗,且仅53.8%的患者在辅助治疗阶段和/或转移阶段曾接受过曲妥珠单抗治疗[6],而在PHENIX研究中,91.2%的患者既往仅接受过1~2线治疗[7].本研究中,48.6%的患者既往曾行≥3线治疗,且80.6%的患者有内脏转移,43.1%有肝转移.本研究显示,经多线治疗,对于肿瘤负荷较重的患者吡咯替尼治疗仍能获益,且对曲妥珠单抗是否原发耐药并不影响疗效(7.9个月 vs. 7.2个月,P=0.685).
拉帕替尼和吡咯替尼均是小分子酪氨酸激酶抑制剂,拉帕替尼是可逆性抑制HER1,HER2,而吡咯替尼同时抑制HER1,HER2和HER4三个靶点,并具有共轭双键结构,可以与ATP结合位点永久结合,作用不可逆,疗效更强[4,5].既往关于T-DM1[17]和吡咯替尼[6,7]的随机对照研究中均未纳入曾接受过拉帕替尼治疗的患者,因此拉帕替尼治疗失败患者的后续治疗选择尚无循证医学证据.本研究中36例患者曾接受过拉帕替尼治疗,吡咯替尼治疗的客观缓解率(CR+PR)为22.2%,中位PFS为7.9个月,与未接受过拉帕替尼治疗患者的7.2个月相似(P=0.657),提示吡咯替尼可能对曾接受过拉帕替尼治疗的患者仍然有效.
HER2阳性转移性乳腺癌中,30%~50%的患者存在脑转移[18].美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)针对HER2阳性晚期乳腺癌脑转移患者给出了治疗推荐[19,20],根据脑转移的病灶大小,数目,预后等因素选择个体化的局部治疗手段(手术,立体定向放疗,全脑放疗等),并联合全身系统性治疗,如抗HER2靶向治疗,化疗,内分泌治疗等.PHENIX研究入组了31例脑转移患者,吡咯替尼联合卡培他滨组的中位PFS为6.9个月[7],高于拉帕替尼联合卡培他滨(5.5个月)[21]和T-DM1[22]相关研究中报道的数据.本研究中包括15例脑转移患者,均经过拉帕替尼治疗,14例(93.3%)经过曲妥珠单抗治疗,吡咯替尼治疗的中位PFS仍能达到6.0个月.
吡咯替尼最常见的不良反应是腹泻,单药治疗的发生率是44.7%[5],联合卡培他滨治疗的发生率为96.9%~98.4%[15,16],但3级腹泻的发生率在单药治疗组仅为13.2%[5],联合治疗组为15.4%~30.8%[15,16],因此,在部分吡咯替尼联合化疗的临床研究中可以预防性使用洛哌丁胺治疗腹泻.本研究中,吡咯替尼相关腹泻的发生率为79.2%,3级腹泻的发生率为12.5%,不良反应可控.
在真实世界的临床实践中,吡咯替尼可用于既往未接受或接受过曲妥珠单抗的复发或转移性乳腺癌患者,疗效好,不良反应可控制,吡咯替尼作为小分子酪氨酸激酶抑制剂治疗HER2阳性乳腺癌脑转移患者存在一定优势.
References
- 1.Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–182. doi: 10.1126/science.3798106. [DOI] [PubMed] [Google Scholar]
- 2.Xu B, Hu X, Zheng H, et al. Outcomes of re-treatment with first-line trastuzumab plus a taxane in HER2 positive metastatic breast cancer patients after (neo) adjuvant trastuzumab: A prospective multicenter study. Oncotarget. 2016;7(31):50643–50655. doi: 10.18632/oncotarget.9331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cobleigh M, Yardley D, Brufsky AM, et al. Baseline characteristics, treatment patterns, and outcomes in patients with HER2-positive metastatic breast cancer by hormone receptor status from SystHERs. Clin Cancer Res. 2020;26(5):1105–1113. doi: 10.1158/1078-0432.CCR-19-2350. [DOI] [PubMed] [Google Scholar]
- 4.Ma F, Li Q, Chen S, et al. Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2017;35(27):3105–3112. doi: 10.1200/JCO.2016.69.6179. [DOI] [PubMed] [Google Scholar]
- 5.Li Q, Guan X, Chen S, et al. Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: a phase Ⅰ clinical trial. Clin Cancer Res. 2019;25(17):5212–5220. doi: 10.1158/1078-0432.CCR-18-4173. [DOI] [PubMed] [Google Scholar]
- 6.Ma F, Ouyang Q, Li W, et al. Pyrotinib or lapatinib combined with capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase Ⅱ study. J Clin Oncol. 2019;37(29):2610–2619. doi: 10.1200/JCO.19.00108. [DOI] [PubMed] [Google Scholar]
- 7.Jiang ZF, Yan M, Hu XC, et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: A randomized phase Ⅲ study. J Clin Oncol. 2019;37(15 suppl):1001. doi: 10.1200/JCO.19.00108. [DOI] [PubMed] [Google Scholar]
- 8.Wong H, Leung R, Kwong A, et al. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2 + metastatic breast cancer . Oncologist. 2011;16(11):1535–1546. doi: 10.1634/theoncologist.2011-0165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–98. doi: 10.1200/JCO.2008.19.9844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792. doi: 10.1056/NEJM200103153441101. [DOI] [PubMed] [Google Scholar]
- 11.Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110(5):965–972. doi: 10.1002/cncr.22885. [DOI] [PubMed] [Google Scholar]
- 12.Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase Ⅲ study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpres-sing metastatic breast cancer. J Clin Oncol. 2006;24(18):2786–2792. doi: 10.1200/JCO.2005.04.1764. [DOI] [PubMed] [Google Scholar]
- 13.Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capeci-tabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733–2743. doi: 10.1056/NEJMoa064320. [DOI] [PubMed] [Google Scholar]
- 14.Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase Ⅲ randomized trial. Oncologist. 2010;15(9):924–934. doi: 10.1634/theoncologist.2009-0181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Xu BH, Jiang ZF, Chua D, et al. Lapatinib plus capecitabine in treating HER2-positive advanced breast cancer: efficacy, safety, and biomarker results from Chinese patients. Chin J Cancer. 2011;30(5):327–335. doi: 10.5732/cjc.010.10507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Baselga J, Cortés J, Kim SB. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109–119. doi: 10.1056/NEJMoa1113216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–1791. doi: 10.1056/NEJMoa1209124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Leyland-Jones B. Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol. 2009;27(31):5278–5286. doi: 10.1200/JCO.2008.19.8481. [DOI] [PubMed] [Google Scholar]
- 19.Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(19):2100–2108. doi: 10.1200/JCO.2013.54.0955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: ASCO clinical practice guideline update. J Clin Oncol. 2018;36(27):2804–2807. doi: 10.1200/JCO.2018.79.2713. [DOI] [PubMed] [Google Scholar]
- 21.Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64–71. doi: 10.1016/S1470-2045(12)70432-1. [DOI] [PubMed] [Google Scholar]
- 22.Montemurro F, Ellis P, Delaloge S, et al. Safety and efficacy of trastuzumab emtansine(>T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study. Cancer Res. 2017;77(4 Suppl):P1-12-10. [Google Scholar]