对于HER2阳性晚期乳腺癌，标准治疗方案为HER2靶向治疗联合化疗，但是并非任何患者都适合化疗。对于雌激素受体和HER2双阳性晚期乳腺癌，可以选择HER2靶向治疗联合内分泌治疗，虽然毒性较低，但是疗效较差。HER2靶向治疗联合内分泌治疗加入细胞周期蛋白依赖性蛋白激酶CDK4和CDK6抑制剂，或可增强抗肿瘤疗效的持久性，已被证实可以为雌激素受体阳性HER2阳性晚期乳腺癌后线治疗提供免化疗替代方案，但是对前线治疗的作用尚不明确。2022年3月7日，复旦大学附属肿瘤医院胡夕春和张剑等学者发表单中心一期临床研究LORDSHIPS初步证实，中国原创CDK4/6抑制剂达尔西利＋HER2抑制剂吡咯替尼＋芳香化酶抑制剂来曲唑全口服方案一线或二线治疗双阳性晚期乳腺癌的耐受性和安全性良好，确认客观缓解率66.7%，中位无进展生存11.3个月，为二期临床研究PLEASURABLE奠定了基础。该二期研究由胡夕春教授和张剑教授牵头开展。
2025年7月31日，美国《公共科学图书馆》医学分册在线发表复旦大学附属肿瘤医院张剑①✉️、孟艳春①、王碧芸、王磊苹、曹君、陶中华、李婷、胡欣和胡夕春✉️、湖北省肿瘤医院吴新红和郑红梅、哈尔滨医科大学附属肿瘤医院胡晶、刘炜和孙立春、南昌市人民医院陈文艳、汪云和彭蔷、南通大学附属医院倪苏婕、牡丹江市肿瘤医院于政岩和王松、恒瑞医药王建飞和吴一佳等学者的多中心二期临床研究PLEASURABLE报告，进一步探索达尔西利＋吡咯替尼＋内分泌治疗一线或二线治疗双阳性晚期乳腺癌患者的有效性和安全性。
PLEASURABLE (NCT03772353): Pyrotinib, Dalpiciclib(SHR6390) and Endocrine Therapy in Subjects With Dual-receptor Positive(ER+/HER2+) Advanced Breast Cancer: a Multi-center Phase Ib/II Study
该多中心单组二期临床研究2019年8月1日至2022年11月28日在中国6个中心入组雌激素受体阳性HER2阳性晚期乳腺癌患者51例，给予达尔西利（每28天前21天每天1次口服125毫克）和吡咯替尼（每天1次口服320毫克）联合医生选择的内分泌治疗（来曲唑或氟维司群）。主要终点为客观缓解率，次要终点包括无进展生存、缓解持续期、疾病控制率、临床获益率、安全性、血浆药物代谢动力学和生物标志物分析。对改良意向治疗人群（基线后肿瘤评定至少一次）分析有效性。对全部至少治疗一次患者评定安全性。
结果，其中48例可评价（年龄29岁至74岁，中位52.5岁）、31例（64.6%）既往经HER2靶向治疗、37例（77.1%）既往经内分泌治疗、30例（62.5%）和18例（37.5%）患者分别接受本研究治疗作为乳腺癌一线和二线HER2靶向治疗。
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中位随访：27.3个月（四分位：24.8～30.5）
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研究者确认客观缓解率：70.2%（95%置信区间：55.1～82.7）
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疾病控制率：100%（95%置信区间：92.5～100）
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临床获益率：87.2%（95%置信区间：74.3～95.2）
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无进展生存：中位22.0个月（95%置信区间：16.6～26.6）
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缓解持续期：中位22.3个月（95%置信区间：16.4～26.9）
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未观察到新的安全问题，未发生治疗相关死亡，仅1例（2.1%）出现1级脱发，未见间质性肺疾病。3级或4级治疗相关不良事件发生率分别为68.8%和12.5%，主要是骨髓抑制。
药物代谢动力学分析表明，达尔西利或吡咯替尼治疗期间未出现明显药物蓄积。值得注意的是，最初两个周期内检测到3例患者BRCA突变（2例）或镓68同位素HER2摄取增加（2例）。
由于探索性分析的患者队列和样本量有限，应谨慎解读本研究结果。
因此，该研究结果表明，非静脉免化疗的达尔西利＋吡咯替尼＋内分泌治疗联合方案对雌激素受体阳性HER2阳性晚期乳腺癌一线治疗有抗肿瘤活性且安全性可控，支持进一步评价将其作为潜在替代方案的有效性。
PLoS Med. 2025 Jul 31;22(7):e1004669. IF: 9.9
Dalpiciclib combined with pyrotinib and endocrine therapy in women with ER-positive, HER2-positive advanced breast cancer: A prospective, multicenter, single-arm, phase 2 trial.
Zhang J, Meng Y, Wang B, Wu X, Zheng H, Hu J, Liu W, Chen W, Wang L, Cao J, Tao Z, Li T, Ni S, Yu Z, Sun L, Wang Y, Peng Q, Wang S, Hu X, Wang J, Wu Y, Hu X.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Hubei Cancer Hospital, Wuhan, China; The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China; Nanchang People’s Hospital, Nanchang, China; Affiliated Hospital of Nantong University, Nantong, China; Tumour Hospital of Mudanjiang City, Mudanjiang, China; Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China.
BACKGROUND: Combination of HER2-targeted therapy and endocrine therapy offers a more tolerable alternative to HER2-targeted chemotherapy regimens for estrogen receptor (ER)-positive, HER2-positive advanced breast cancer (ABC), but with compromised efficacy. The addition of cyclin-dependent kinase 4/6 (CDK4/6) inhibition may enhance the durability of anti-tumor responses, offering a potential chemotherapy-sparing alternative, although its role in the frontline setting remains uncertain. We performed a multicenter, single-arm, phase 2 clinical trial (PLEASURABLE) to assess the activity and safety of combining dalpiciclib with pyrotinib and endocrine therapy in patients receiving first- or second-line treatment for ER-positive and HER2-positive ABC.
METHODS AND FINDINGS: We enrolled patients with ER-positive and HER2-positive ABC between August 1, 2019, and November 28, 2022 in this prospective, investigator-initiated trial conducted at six centers in China. Patients received dalpiciclib (125 mg once daily, on days 1-21 of each 28-day cycle) and pyrotinib (320 mg once daily) plus endocrine therapy determined by the physician’s choice (letrozole or fulvestrant). The primary endpoint was the objective response rate (ORR), while secondary endpoints included progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), safety, plasma pharmacokinetics (PK), and biomarker analysis. Efficacy was analyzed in the modified intention-to-treat population, comprising patients with at least one post-baseline tumor assessment. Safety was assessed in all patients who received at least one dose. A total of 51 patients were screened, and 48 were evaluable (median age was 52.5 years [range, 29-74]); 31 (64.6%) had prior HER2-target therapy, and 37 (77.1%) had received prior endocrine therapy. Thirty (62.5%) and 18 (37.5%) patients received the study treatment as first- and second-line HER2-targeted treatment for ABC, respectively. As of the data cutoff on December 11, 2024, six patients were lost to follow-up, and the median follow-up was 27.3 months (interquartile range, 24.8-30.5). The investigator confirmed ORR was 70.2% (95% CI [55.1, 82.7]), with a DCR of 100% (95% CI [92.5, 100]) and a CBR of 87.2% (95% CI [74.3, 95.2]). The median PFS was 22.0 months (95% CI [16.6, 26.6]), and the median DOR was 22.3 months (95% CI [16.4, 26.9]). No new safety signals were observed, and no treatment-related deaths occurred with only one (2.1%) grade 1 alopecia and no interstitial lung disease. Grade 3 or 4 treatment-related adverse events occurred in 68.8% and 12.5% of patients, respectively, mostly myelosuppression. PK analysis showed no major drug accumulation for dalpiciclib or pyrotinib over the treatment period. Of interest, no objective response was observed in three patients with detected BRCA mutations (n = 2) or increased 68Ga-HER2 affibody uptake over the initial two cycles (n = 2). The findings of this study should be interpreted with caution due to the limited patient cohort and sample size in exploratory analyses.
CONCLUSIONS: The non-intravenous, chemotherapy-sparing combination of dalpiciclib, pyrotinib, and endocrine therapy demonstrated anti-tumor activity with a manageable safety profile in the frontline treatment of ER-positive, HER2-positive ABC, supporting its further evaluation as a potential alternative.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03772353
DOI: 10.1371/journal.pmed.1004669
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