University of Pittsburgh Medical Center, Hillman Cancer Center/Magee Women's Hospital, Pittsburgh, PA, USA.
Oncology Biomarkers Development, Genentech, Inc, South San Francisco, CA, USA.
J Natl Cancer Inst. 2021 Aug 2;113(8):1005-1016. doi: 10.1093/jnci/djab004.
Understanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer.
Patients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations.
PD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.
Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.
了解肿瘤免疫微环境和 BRCA1/2 相关 DNA 修复缺陷对免疫检查点抑制剂临床活性的影响，可能有助于优化转移性三阴性乳腺癌患者和治疗选择。在这项来自 III 期 IMpassion130 试验的子研究中，评估了免疫生物标志物和 BRCA1/2 改变与atezolizumab 和 nab-紫杉醇（A+nP）对比安慰剂和 nP 治疗不可切除（P+nP）局部晚期或转移性三阴性乳腺癌的临床获益的相关性。
患者按 1:1 随机分配至 nab-紫杉醇 100mg/m2（28 天周期的第 1、8 和 15 天）和 atezolizumab 840mg 每 2 周一次，或安慰剂，直至进展或毒性。无进展生存期和总生存期基于免疫细胞（IC）和肿瘤细胞上的程序性死亡配体 1（PD-L1）表达、肿瘤内 CD8、基质肿瘤浸润淋巴细胞和 BRCA1/2 突变进行评估。
原发性或转移性肿瘤组织中 PD-L1 IC+与 A+nP 的无进展生存期和总生存期获益相关。PD-L1 IC+低（26.9%；902 例患者中的 243 例）和高（13.9%；902 例患者中的 125 例）人群的结局得到改善，且结果相当。肿瘤内 CD8 和基质肿瘤浸润淋巴细胞阳性（sTIL+）与 PD-L1 IC+状态相关；仅在 CD8+和 sTIL+且 PD-L1 IC+的患者中，A+nP 对比 P+nP 观察到改善的结局。BRCA1/2 突变（发生于 14.5%[612 例患者中的 89 例]）与 PD-L1 IC 状态无关，且 PD-L1 IC+患者无论 BRCA1/2 突变状态如何，均可从 A+nP 中获益。
尽管 A+nP 在肿瘤免疫微环境更丰富的患者中更有效，但临床获益仅见于 PD-L1 IC+的患者。
