National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, China.
Signal Transduct Target Ther. 2023 Nov 17;8(1):429. doi: 10.1038/s41392-023-01672-5.
In our phase Ib trial (ClinialTrials.gov Identifier: NCT03855358), benmelstobart (TQB2450), a novel humanized IgG1 antibody against PD-L1, plus antiangiogenic multikinase inhibitor, anlotinib, demonstrated promising antitumor activities in pretreated triple negative breast cancer (TNBC) patients. We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes. Targeted next generation sequencing (NGS) was undertaken toward circulating tumor DNA (ctDNA) collected from peripheral blood samples prior to the start of treatment and after disease progression. A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed. The most frequent mutations were TP53 (72%), MLL3 (28%), and PIK3CA (17%). At a blood-based tumor mutational burden (bTMB) cutoff of 6.7 mutations per megabase, patients with low bTMB showed better response to anlotinib plus TQB2450 (50% vs. 7%, P = 0.015) and gained greater PFS benefits (7.3 vs. 4.1 months, P = 0.012) than those with high bTMB. At a maximum somatic allele frequency (MSAF) cutoff of 10%, a low MSAF indicated a better objective response (43% vs. 20%) as well as a significantly longer median PFS (7.9 vs. 2.7 months, P < 0.001). Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450 (70% vs. 11%, P < 0.001) and a significantly longer median PFS (11.0 vs. 2.9 months, P < 0.001) than patients with other scenarios. Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.
在我们的 Ib 期临床试验（临床试验.gov 标识符：NCT03855358）中，新型人源化 IgG1 抗 PD-L1 抗体 benmelstobart（TQB2450）联合抗血管生成多激酶抑制剂安罗替尼，在预处理的三阴性乳腺癌（TNBC）患者中显示出有希望的抗肿瘤活性。我们进行了探索性的基因组生物标志物分析，以探索与治疗反应和生存结果的关联。在治疗开始前和疾病进展后，从外周血样本中采集循环肿瘤 DNA（ctDNA）进行靶向下一代测序（NGS）。共有 31 名患者接受了靶向 NGS 分析，29 名患者的功能驱动突变进行了分析。最常见的突变是 TP53（72%）、MLL3（28%）和 PIK3CA（17%）。在血液肿瘤突变负担（bTMB）截断值为 6.7 个突变/兆碱基时，低 bTMB 的患者对安罗替尼联合 TQB2450 的反应更好（50%比 7%，P=0.015），并且获得了更大的 PFS 获益（7.3 比 4.1 个月，P=0.012）。在最大体细胞等位基因频率（MSAF）截断值为 10%时，低 MSAF 表明更好的客观缓解（43%比 20%），以及显著更长的中位 PFS（7.9 比 2.7 个月，P<0.001）。低 MSAF 和低 bTMB 的患者对安罗替尼联合 TQB2450 的客观缓解率显著更高（70%比 11%，P<0.001），中位 PFS 显著更长（11.0 比 2.9 个月，P<0.001），优于其他患者。我们的研究结果支持未来的研究和验证 MSAF 和联合 bTMB-MSAF 分类作为晚期 TNBC 患者免疫检查点抑制剂治疗方案的预测生物标志物。
