PO.CL01.08 · 临床研究
靶向治疗在通过液体活检被归类为TMB-高的癌症中的影响:来自Gustave Roussy分子肿瘤委员会的见解
Impact of targeted therapies in cancers classified as TMB-high by liquid biopsy: Insights from the Gustave Roussy molecular tumor board
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景:
肿瘤突变负荷(TMB)已成为免疫治疗反应的生物标志物,但其对靶向治疗的预测价值仍不确定。在基因组不稳定的肿瘤中,高TMB可能反映的是乘客突变而非驱动事件,可能限制靶向药物的疗效。
方法:
我们回顾性分析了接受基于血浆的综合基因组分析(STING master protocol,Foundation Medicine)且TMB ≥ 16 mut/Mb的晚期实体瘤成年患者。所有病例均由Gustave Roussy分子肿瘤委员会审查,以指导早期临床试验、II-III期研究或经MTB验证的超说明书靶向治疗的方向。根据整合的分子和临床证据,并借助IntOGen和DriverDB等参考数据库的支持,将改变分类为驱动或非驱动。
结果:
纳入56例患者(平均年龄61.6岁;71%为男性)。最常见的肿瘤类型为肺(41%)、结直肠(11%)和膀胱(11%)。脑(20%)、骨(38%)和肝(5%)转移常见;72%有≥2个转移部位。中位血浆TMB为20 mut/Mb(范围16-1,450)。患者既往接受了中位3线治疗(范围1-6)。最常见的改变涉及KRAS(21%)、MET(11%)和ERBB2(11%)。靶向治疗包括小分子抑制剂(41%)、TKI(27%)、ADC(14%)、双特异性抗体(5%)和PROTAC(5%)。总体而言,13例患者(23%)达到部分缓解(PR),21例(38%)为疾病稳定(SD),客观缓解率(ORR)为23%,疾病控制率(DCR)为61%。在驱动病例中(n=43),观察到12例PR和17例SD,而在非驱动病例中(n=13)为1例PR和4例SD。中位PFS为3.7个月(95% CI 2.8-4.8)。前一线治疗的PFS为5.6个月(95% CI 4.0-11.0)。PFS比值>1/3(表示与前一治疗线相比具有临床获益)在63.3%的可评估患者(31/49)中实现。存在驱动改变与改善的PFS相关(HR 0.43;95% CI 0.22-0.82;p = 0.011)。TMB与PFS之间未发现相关性(Spearman ρ = 0.10;p = 0.45),不同TMB组间(<20、20-50、≥50 mut/Mb)也未见差异。
结论:
只有具有真正驱动改变的患者才从靶向治疗中获益,与TMB水平无关。高TMB反映的是基因组不稳定性而非治疗敏感性,凸显了分子甄别在指导精准肿瘤学决策中的重要性。与TMB-低病例的比较分析正在进行中,以完善TMB在靶向治疗反应中作为预测因素与混杂因素的角色。
查看英文原文 English abstract
Background:
Tumor mutational burden (TMB) has emerged as a biomarker for immunotherapy response, but its predictive value for targeted therapies remains uncertain. In genomically unstable tumors, high TMB may reflect passenger rather than driver events, potentially limiting the efficacy of targeted agents.
Methods:
We retrospectively analyzed adult patients with advanced solid tumors who underwent plasma-based comprehensive genomic profiling (STING master protocol, Foundation Medicine) and had a TMB ≥ 16 mut/Mb. All cases were reviewed by the Gustave Roussy Molecular Tumor Board for orientation toward early-phase trials, phase II-III studies, or MTB-validated off-label targeted therapies. Alterations were classified as driver or non-driver based on integrated molecular and clinical evidence, supported by reference databases such as IntOGen and DriverDB.
Results:
Fifty-six patients were included (mean age 61.6 y; 71% male). The most frequent tumor types were lung (41%), colorectal (11%), and bladder (11%). Brain (20%), bone (38%), and liver (5%) metastases were common; 72% had ≥ 2 metastatic sites. Median plasma TMB was 20 mut/Mb (range, 16-1,450). Patients had received a median 3 prior lines (range 1-6). The most frequent alterations involved KRAS (21%), MET (11%), and ERBB2 (11%). Targeted therapies included small-molecule inhibitors (41%), TKIs (27%), ADCs (14%), bispecific antibodies (5%), and PROTACs (5%). Overall, 13 patients (23%) achieved partial response (PR) and 21 (38%) stable disease (SD), resulting in an overall response rate (ORR) of 23% and a disease control rate (DCR) of 61%. Among driver cases (n=43), 12 PR and 17 SD were observed vs 1 PR and 4 SD in non-driver cases (n=13). Median PFS was 3.7 months (95% CI 2.8-4.8). The prior-line PFS was 5.6 months (95% CI 4.0-11.0). A PFS ratio >1/3, indicating clinical benefit compared with the previous treatment line, was achieved in 63.3% of evaluable patients (31/49). Presence of a driver alteration was associated with improved PFS (HR 0.43; 95% CI, 0.22-0.82; p = 0.011). No correlation was found between TMB and PFS (Spearman ρ = 0.10; p = 0.45), and no difference was seen across TMB groups (<20, 20-50, ≥50 mut/Mb).
Conclusions:
Only patients with bona fide driver alterations derived benefit from targeted therapy, irrespective of TMB level. High TMB reflects genomic instability rather than therapeutic sensitivity, underscoring the importance of molecular curation to guide precision oncology decisions. Comparative analyses with TMB-low cases are ongoing to refine the predictive versus confounding role of TMB in targeted therapy response.
利益披露 Disclosure
A. Mouren, None.