早期三阴性乳腺癌新辅助治疗新星

　　三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗基本无效，过去药物治疗主要依靠化疗。戈沙妥珠单抗由滋养层细胞表面抗原TROP2单克隆抗体沙妥珠单抗与7～8个化疗药物戈维替康通过可水解链接分子缀合而成，已被证实对晚期三阴性乳腺癌疗效显著。那么，戈沙妥珠单抗对早期三阴性乳腺癌疗效如何？

　　2023年12月12日，欧洲肿瘤内科学会《肿瘤学年鉴》在线发表美国哈佛大学医学院旗下五大医疗教学研究机构麻省总医院癌症中心、达纳法伯癌症研究院、贝斯以色列（和新英格兰）女执事医疗中心、布莱根（医院）和（波士顿）妇女医院、路德维希（癌症研究）中心联合发起的NeoSTAR研究报告，首次探讨了早期三阴性乳腺癌术前单用戈沙妥珠单抗新辅助治疗的有效性和安全性。

NeoSTAR (NCT04230109): Sacituzumab Govitecan In TNBC (A Phase 2 Study of Response-guided Neoadjuvant Sacituzumab Govitecan in Patients With Localized Triple-Negative Breast Cancer)

　　该多中心非对照二期临床研究于2020年7月至2021年8月入组早期三阴性乳腺癌术前患者50例（中位年龄：48.5岁，临床分期：I期13例、II期26例、III期11例）接受戈沙妥珠单抗新辅助治疗4个周期，随后由治疗医师根据戈沙妥珠单抗疗效自行决定直接手术或追加新辅助化疗。主要目标为戈沙妥珠单抗治疗后乳房和淋巴结病理完全缓解率（yp T0 / is N0）。次要目标包括总体缓解率、安全性、无事件生存、疗效预测生物指标。

　　结果，49例（98%）完成4个周期戈沙妥珠单抗，其中15例病理完全缓解，病理完全缓解率为30%（95%置信区间：18%～45%）。

　　全部50例患者，其中32例完全或部分缓解，总体缓解率为64%（95%置信区间：77%～98%）。

　　疗效预测生物指标分析：

• Ki-67指数：显著（P=0.007）
• 肿瘤浸润淋巴细胞：显著（P=0.002）
• 基线TROP2表达：不显著（P=0.440）

　　不良事件发生率：恶心82%、疲劳76%、脱发76%、中性粒细胞减少44%、皮疹48%。

　　中位随访18.9个月（95%置信区间：16.3～21.9）期间，全部患者的2年无事件生存率达95%，其中15例病理完全缓解患者的2年无事件生存率达100%。

　　因此，该研究结果首次证实早期三阴性乳腺癌术前单用戈沙妥珠单抗新辅助治疗的有效性和可行性，大约三分之二患者有效，30%的患者不需追加化疗已经达到病理完全缓解，其疗效可指导治疗升级或降级，Ki-67和肿瘤浸润淋巴细胞可预测戈沙妥珠单抗的病理完全缓解，而TROP2表达则否，故有必要进一步研究戈沙妥珠单抗的最佳疗程以及新辅助治疗联合策略，包括免疫治疗。

Ann Oncol. 2023 Dec 12. IF: 50.5

Response-guided neoadjuvant sacituzumab govitecan for localized triple negative breast cancer: results from the NeoSTAR trial.

Spring LM, Tolaney SM, Fell G, Bossuyt V, Abelman RO, Wu B, Maheswaran S, Trippa L, Comander A, Mulvey T, McLaughlin S, Ryan P, Ryan L, Abraham E, Rosenstock A, Garrido-Castro AC, Lynce F, Moy B, Isakoff SJ, Tung N, Mittendorf EA, Ellisen LW, Bardia A.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Ludwig Center, Harvard Medical School, Boston, MA.

HIGHLIGHTS

• Neoadjuvant treatment with sacituzumab govitecan for localized TNBC is safe and feasible

• Approximately 2/3 of patients responded to neoadjuvant SG alone, and 30% achieved pCR without additional chemotherapy.

• Higher Ki-67 and TILs were predictive of pCR to SG, while TROP2 expression was not.

BACKGROUND: Sacituzumab govitecan (SG), a novel antibody-drug conjugate targeting Trop2, is approved for pre-treated metastatic triple negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results

PATIENTS AND METHODS: Participants with early-stage TNBC received NA SG for 4 cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician.

RESULTS: From July 2020-August 2021, 50 participants were enrolled (median age = 48.5; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed 4 cycles of SG. Overall, the pCR rate with SG alone was 30% (n= 15, 95% CI 18%, 45%). The ORR per RECIST V1.1 after SG alone was 64% (n= 32/50, 95% CI 77%, 98%). Higher Ki-67 and tumor infiltrating lymphocytes (TILs) were predictive of pCR to SG (p = 0.007 for Ki-67; 0.002 for TILs), while baseline TROP2 expression was not (p = 0.440). Common AEs were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3, 21.9), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (N = 15), the 2-year EFS was 100%.

CONCLUSION: In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed.

KEYWORDS: ADC; sacituzumab govitecan; neoadjuvant; triple-negative breast cancer; TROP2

DOI: 10.1016/j.annonc.2023.11.018