循环肿瘤DNA早期预测非小细胞肺癌免疫治疗的疗效

早期血浆循环肿瘤DNA (ctDNA)变化预测非小细胞肺癌(NSCLC)对一线pembrolizumab +/-化疗的反应。

有研究提示血浆中ctDNA脱落可预测肺癌的预后，血浆中ctDNA水平的变化与全身治疗的反应可能相关。研究探索早期检测ctDNA水平的变化能否预测一线帕博利珠单抗（Pembrolizumab）（加或者不加化疗）的疗效，希望通过NGS对血浆ctDNA进行系列评估，在影像评估之前发现NSCLC对免疫治疗的反应。

研究通过使用增强标记-扩增子测序(eTAm-Seq)对36个基因的热点和编码区(InVisionFirst-Lung)进行NGS分析，在开始治疗前和开始治疗后连续收集患者的血浆。ctDNA等位基因组分(allele fractions，AF)的变化与治疗反应相关。

结果显示38例患者中，9例(23.7%)基线时未检测到ctDNA（看来阴性也不少）, 29例检测到ctDNA改变。29例患者中有19例(65.5%)采用博利珠单抗单药治疗，10例(34.5%)采用联合化疗。首次ctDNA评估的中位时间为21天。与治疗前相比，首次抽血时最大AF降低的患者对联合化疗的反应率明显高于AF升高的患者(64.5% vs 7.7%， P, 0.01)。早期AF下降患者的中位PFS (mPFS)和中位OS (mOS)明显长于AF升高患者的中位PFS: 13.7 vs 3.4个月，HR:0.20, P, 0.01;mOS: 32.8 vs 14.7个月，HR:0.06, P,0.01)。在第一次治疗中抽血的AF变化中值分数与疗效有关。在9例基线未检出ctDNA的患者中，2例在8周内出现cfDNA的患者出现进展性疾病。在其他7例中，ctDNA仍然未被检测到。

研究初步提示在晚期非小细胞肺癌患者中，在影像学改变之前的ctDNA快速降低与临床获益相关。这些结果提示ctDNA作为免疫治疗反应或耐药性的早期药效学生物标志物的潜在作用。

3518 Poster Discussion Session; Displayed in Poster Session (Board #248),

Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session,

Early plasma circulating tumor DNA (ctDNA) changes to predict response to first-line pembrolizumab +/- chemotherapy in non-small cell lung cancer (NSCLC). 

First Author: Biagio Ricciuti, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA

Background: ctDNA shedding into plasma can be prognostic in lung cancer, and changes in plasma ctDNA levels correlate with response to systemic therapy. However, is unknown whether early detection of ctDNA levels change predicts response to firstline pembrolizumab +/- chemotherapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing would enable early detection of response to immunotherapy in NSCLC prior to radiological assessment. 

Methods: Patients (pts) with advanced NSCLC who received first-line treatment with pembrolizumab +/- platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from pts prior to starting therapy and serially after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing (eTAm-Seq) of hotspots and coding regions from36 genes (InVisionFirst-Lung). ctDNA allele fractions (AF) change was correlated with treatment responses. 

Results: Among 38 ptswho received first-line pembrolizumab +/- platinum/pemetrexed, 9 (23.7%) had no ctDNA detected at baseline while 29 had alterations detected. Pembrolizumab was administered as monotherapy in 19 of the 29 pts (65.5%) and in combination with chemotherapy in 10 (34.5%). The median time to the first ctDNA assessment was 21 days (IQR:21-24). Pts who had a decrease in the max AF at the first blood drawn compared to pre-treatment AF had a significantly higher response rate to treatment with pembrolizumab +/- platinum doublet chemotherapy than those with an AF increase (64.5% vs 7.7%, P , 0.01). The median PFS (mPFS) and median OS (mOS) were significantly longer among pts with early AF decrease compared to those with an AF increase mPFS: 13.7 vs 3.4 months, HR:0.20, P , 0.01; mOS: 32.8 vs 14.7 months, HR:0.06, P,0.01). The median change in allele fraction at the first ontreatment blood draw was -90%(range: -100 to +65), -71%(range: -100 to +100) and +35% (range: +17 to +100) in pts with subsequent radiological response (N = 11), stable disease (N = 11) and progressive disease (N = 7), respectively (P , 0.01). Among the 9 cases with no detected ctDNA at baseline, 2 pts with emergence of cfDNA within 8 weeks developed progressive disease. In the other 7 cases, ctDNA remained undetected. 

Conclusions: In pts with advanced NSCLC, rapid decreases in ctDNAprior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies. 

ASCO 2020摘要 

Cancer Prevention, Risk Reduction, and Genetics

Developmental Therapeutics—Immunotherapy

Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Lung Cancer— Other Thoracic Cancers

Lung Cancer—Non-Small Cell Metastatic

Symptoms and Survivorship