真实世界吡咯替尼治疗HER2阳性转移性乳腺癌的疗效及安全性

doi:10.19723/j.issn.1671-167X.2020.02.010

摘要/Abstract

摘要：

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.

关键词: 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. Objectiveresponse 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.

Key words: Pyrotinib, Receptor, epidermal growth factor, Breast neoplasms, Trastuzumab, Lapatinib

中图分类号:

R737.9

宋国红,李惠平,邸立军,严颖,姜晗昉,徐玲,万冬桂,李瑛,王墨培,肖宇,张如艳,冉然,王环. 真实世界吡咯替尼治疗HER2阳性转移性乳腺癌的疗效及安全性[J]. 北京大学学报（医学版）, 2020, 52(2): 254-260.

Guo-hong SONG,Hui-ping LI,Li-jun DI,Ying YAN,Han-fang JIANG,Ling XU,Dong-gui WAN,Ying LI,Mo-pei WANG,Yu XIAO,Ru-yan ZHANG,Ran RAN,Huan WANG. Efficacy and safety of oral pyrotinib in HER2 positive metastatic breast cancer: real-world practice[J]. Journal of Peking University (Health Sciences), 2020, 52(2): 254-260.

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参考文献 22

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Items	Data
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)

Agents	Total, n (%)	Response, n (%)				ORR, n (%)	DCR, n (%)
Agents	Total, n (%)	CR	PR	SD	PD	ORR, n (%)	DCR, n (%)
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)

Toxicity	All grades, n (%)	Grade, n (%)
Toxicity	All grades, n (%)	1	2	3	4
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)

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)