【原】多靶点新药首战早期三阴性乳腺癌

　　安罗替尼是中国生物制药旗下正大天晴原研的新型酪氨酸激酶抑制剂，能够靶向至少4大类10种靶点，包括血管内皮生长因子受体（VEGFR1、VEGFR2、VEGFR3）、血小板衍生生长因子受体（PDGFRα、PDGFRβ）、成纤维细胞生长因子受体（FGFR1、FGFR2、FGFR3、FGFR4）和肥大/干细胞生长因子受体（c-Kit），对肿瘤血管生成和肿瘤生长具有广谱抑制作用，已被证明对HER2阴性晚期乳腺癌有效，但是对三阴性早期乳腺癌的疗效尚不明确。

　　2024年4月11日，英国《柳叶刀》旗下《临床医学》在线发表中国人民解放军陆军军医大学第一附属医院（西南医院）梁燕①、刘静①、葛佳①、史绮韵①、章国智、万安弟、罗韬、田浩、范林军、王姝姝、陈莉、唐鹏、姜军✉、卞修武院士✉、张毅✉、齐晓伟✉和正大天晴朱凯等学者的neoALTAL研究报告，首次探讨了安罗替尼加入早期三阴性乳腺癌术前新辅助化疗的有效性和安全性。

neoALTAL (ChiCTR2100043027): A prospective, single-arm, single-center clinical study of the efficacy and safety of anlotinib combined with taxanes and lobaplatin in the neoadjuvant treatment of triple-negative breast cancer

　　该单中心单组II/III期临床研究于2021年1月至2022年8月入组临床II或III期三阴性乳腺癌术前患者45例，给予5个周期安罗替尼（每3周第1～14天口服12毫克）联合6个周期多西他赛或白蛋白紫杉醇＋洛铂，随后进行手术。主要终点为病理完全缓解，预设90%置信区间下限大于历史对照值44%即为成功。次要终点包括乳腺病理完全缓解、腋窝病理完全缓解、残癌负荷、客观缓解率、无病生存、总生存和安全性。探索性终点是根据复旦大学附属肿瘤医院三阴性乳腺癌免疫组织化学分型（复旦分型）和患者肿瘤组织和血液标本425基因组大规模并行测序的疗效生物学标志物。

　　结果，全部患者均接受至少一次研究方案治疗并接受手术，患者中位年龄48.5岁（标准差8.7），71%为淋巴结阳性，20%为III期。

　　根据意向治疗分析：

• 病理完全缓解率：57.8%（90%置信区间：44.5%～70.3%）
• 残癌负荷≤I级：86.7%（95%置信区间：73.2%～94.9%）
• 乳腺病理完全缓解率：64.4%（95%置信区间：48.8%～78.1%）
• 腋窝病理完全缓解率：71.9%（95%置信区间：53.4%～86.3%）

　　短期随访未见复发或转移。

　　根据复旦分型，病理完全缓解率：

• 免疫调节亚型：68.8%
• 基底样免疫抑制亚型：58.3%
• 管腔雄激素受体亚型：33.3%

　　根据425基因组大规模并行测序，病理完全缓解率：

• MYC扩增型：77%
• MYC野生型：50%
• gBRCA突变型：78%
• gBRCA野生型：53%

　　中位随访14.9个月（95%置信区间：13.5～16.3个月），新辅助治疗期间未见疾病进展或死亡，术后随访期间未见死亡事件发生。

　　治疗期间3或4级不良事件发生率：

• 全部：64%
• 中性粒细胞减少：38%
• 白细胞减少：27%
• 血小板减少：25%
• 贫血：13%
• 高血压：13%

　　因此，该研究结果首次证实，对于临床II或III期三阴性乳腺癌术前患者，安罗替尼加入新辅助化疗的抗肿瘤活性令人鼓舞、毒性可控，故有必要进一步开展多中心大样本随机对照临床研究长期随访进行验证。

相关链接

• 安罗替尼联合紫杉洛铂新辅助治疗三阴性乳腺癌的单臂单中心二期临床研究：疗效、安全性和生物标志物分析

• ESMO中国之声丨齐晓伟教授：安罗替尼联合紫杉烷类及洛铂新辅助治疗mTNBC的neoALTAL研究疗效、安全性结果更新

• SABCS中国之声丨齐晓伟教授：安罗替尼联合紫杉烷类及洛铂新辅助治疗TNBC的单臂、单中心、Ⅱ期临床研究（neoALTAL）

• ASCO中国之声丨齐晓伟教授：安罗替尼联合紫杉烷类及洛铂新辅助治疗三阴性乳腺癌的有效性、安全性和生物标志物分析结果

EClinicalMedicine. 2024 Apr 11;71:102585. IF: 15.1

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial.

Yan Liang, Jing Liu, Jia Ge, Qiyun Shi, Guozhi Zhang, Andi Wan, Tao Luo, Hao Tian, Linjun Fan, Shushu Wang, Li Chen, Peng Tang, Kai Zhu, Jun Jiang, Xiuwu Bian, Yi Zhang, Xiaowei Qi.

Southwest Hospital, Army Medical University, Chongqing, China; The Eighth Medical Center of Chinese PLA General Hospital, Beijing, China; Chia Tai Tianqing Pharmaceutical Group Co., Ltd. L., Nanjing, Jiangsu, China.

BACKGROUND: Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC.

METHODS: Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12 mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027).

FINDINGS: From Jan 2021 to Aug 2022, 48 patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45 patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N = 45), Grade 3 or 4 treatment emergent adverse events occurred in 29 patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively.

INTERPRETATION: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC.

FUNDING: Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

KEYWORDS: Anlotinib, Anti-tumor angiogenesis, Triple-negative breast cancer, Neoadjuvant chemotherapy

DOI: 10.1016/j.eclinm.2024.102585

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