PO.BCS01.11 · 生物信息与计算
标志性ctDNA分子反应作为肺癌免疫治疗结局早期指标的临床效用
Clinical utility of landmark ctDNA molecular response as an early indicator of immunotherapy outcomes in lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：循环肿瘤DNA（ctDNA）分析作为晚期非小细胞肺癌（NSCLC）免疫治疗反应的早期指标具有信息价值，然而ctDNA分子反应的临床作用仍需进一步验证。
方法：作为一项前瞻性临床方案（NCT05995821）的一部分，我们对109名接受抗PD-(L)1单药或联合化疗的晚期/转移性NSCLC患者进行了ctDNA（n=328）和配对白细胞DNA（WBC；n=109）的521固定基因面板靶向二代测序（Elio Plasma Complete）。在解析变异细胞来源后，标志性分子反应（mR）定义为在治疗开始后3-9周内ctDNA不可检测。对于一部分患者（n=34），进行了基线肿瘤的全外显子组测序，并用于对ctDNA检测和治疗反应评估进行基准测试。
结果：在2,818个血浆变异中，23%与克隆性造血相关，这混淆了对驱动基因与临床结局关联的解释以及分子反应的评估。实施不依赖肿瘤的WBC DNA指导方法增加了可评估病例数，同时保持了标志性ctDNA分子反应的总体准确性。治疗前ctDNA负荷（而非血液肿瘤突变负荷）可预测生存。总体而言，77名患者可评估标志性分子反应；其中29名患者（38%）取得了mR。标志性分子反应评估使所有病例都可评估，具有高度特异性（92%），并且与从基线清除或ctDNA降低相比取得了更高的敏感性（66%对59%）。在预测6个月时的标志性无进展生存期（PFS）（持久临床获益，DCB）方面，与仅血浆方法（敏感性=14.3%，特异性=100%）或肿瘤指导方法（敏感性=78.6%，特异性=71.4%）相比，不依赖肿瘤的WBC指导方法在敏感性（71.4%）和特异性（100%）之间取得了平衡。在接受免疫治疗（p=2.5e-05）和化学免疫治疗（p=0.02）后取得DCB的患者中，观察到标志性ctDNA mR显著富集。标志性mR组的患者与分子进展者相比取得了更长的PFS（p=1.6e-06）和总生存期（p=2.5e-05）。在考虑临床协变量、治疗线数和基线ctDNA水平后，标志性分子反应与生存之间的关联仍然显著（PFS和OS，P<0.001）。
结论：我们的研究结果表明，治疗后3-9周的标志性ctDNA分子反应为监测免疫治疗临床结局提供了一种实时且准确的方法。尽管目前尚未获得监管用途的验证，这些发现证明了ctDNA作为临床试验早期终点的潜在效用。
查看英文原文 English abstract
Background: Circulating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC), however the clinical role of ctDNA molecular response requires further validation.
Methods: As part of a prospective clinical protocol (NCT05995821), we performed ctDNA (n=328) and matched white blood cell DNA (WBC; n=109) targeted 521 fixed gene panel next-generation sequencing (Elio Plasma Complete) from 109 patients with advanced/metastatic NSCLC who received anti-PD-(L)1 as monotherapy or in combination with chemotherapy. Following variant cellular origin resolution, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation. For a subset of patients (n=34), whole-exome sequencing of baseline tumors was performed and used in benchmarking ctDNA detection and therapy response assessment.
Results: Among 2,818 plasma variants, 23% were clonal haematopoiesis-related, which confounded the interpretation of driver gene associations with clinical outcomes and assessment of molecular responses. Implementing a tumor-naïve WBC DNA-informed approach increased the number of evaluable cases while maintaining the overall accuracy of landmark ctDNA molecular responses. Pre-treatment ctDNA burden but not blood tumor mutation burden, predicted survival. Overall, 77 patients were evaluable for landmark molecular response assessment; of these, 29 patients (38%) attained a mR. Landmark evaluation of molecular response enabled evaluation of all cases, was highly specific (92%), and achieved a higher sensitivity (66%) compared to clearance or ctDNA reduction from baseline (sensitivity 59%). In predicting landmark progression-free survival (PFS) at 6 months (durable clinical benefit, DCB), the tumor-agnostic WBC-informed approach strikes a balance between sensitivity (71.4%) and specificity (100%) compared to plasma-only (sensitivity=14.3%, specificity=100%) or tumor-informed (sensitivity=78.6%, specificity=71.4%) approaches. A significant enrichment in landmark ctDNA mR was noted among patients with DCB with immunotherapy (p=2.5e-05) and chemo-immunotherapy (p=0.02). Patients in the landmark mR group attained longer PFS (p=1.6e-06) and overall survival (p=2.5e-05) compared to those with molecular progression. The association between landmark molecular response and survival remained significant (PFS and OS, P < 0.001) after accounting for clinical covariates, line of therapy, and baseline ctDNA levels.
Conclusions: Our findings indicate that landmark ctDNA molecular response at 3-9 weeks on treatment provides a real-time and accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential utility of ctDNA as an early endpoint in clinical trials.
利益披露 Disclosure
J. Wehr, None..
N. Niknafs, None.
L. Sivapalan,
ANGLE Employment.
A. Balan, None..
G. Pereira, None..
S. Hosseini-Nami, None..
I. Beadles, None.
A. Pabani,
BMS ).
ACF Pharmaceuticals ).
Canadian Agency for Drugs and Technologies in Health Other, Personal Fees.
AstraZeneca Other, Personal Fees.
F. Hoffman-La Roche AG Other, Personal Fees.
Merck & Co inc Other, Personal Fees.
Pfizer Other, Personal Fees.
K. Marrone,
AstraZeneca Other, Consultant,Honoraria.
Amgen Other, Consultant.
Puma Biotechnology Other, Consultant.
Jannsen Other, Consultant.
Mirati Therapeutics ), Other, Consultant.
Daiichi Sankyo/Lilly Other, Consultant.
Bristol Myers Squibb ).
Q. K. Li, None.
J. C. Murray,
AstraZeneca Other, Consultant.
Johnson & Johnson Other, Consultant.
NIH/NCI ).
Merck ).
CDC ).
Maryland Cigarette Restitution Fund ).
Curio Science Other, Honoraria.
Caris Life Sciences Other, Honoraria.
ION Oncology Practice Network Other, Honoraria.
Nebraska Oncology Society Other, Honoraria.
PRIME Other, Honoraria.
iTeos Therapeytics Other, Advisory board.
Doximity Stock Option.
M. Sausen,
LabCorp Employment, Stock.
B. Chesnick,
Delfi Diagnostics, Inc. Employment, Stock.
L. Rinaldi,
Delfi Diagnostics, Inc. Employment, Stock.
C. L. Hann,
AstraZeneca ), Other, Consultant.
Daiichi Sankyo Europe GmbH ), Other, Consultant.
Genentech Other, Consultant.
Amgen ).
S. C. Scott,
AstraZeneca ), Other, Consultant.
Johnson & Johnson ), Other, Consultant.
Black Diamond ).
Nuvalent ).
EMD Serono Other, Consultant.
Daiichi Sankyo Other, Consultant.
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J. Feliciano,
Astra Zeneca ), Other, Consultant.
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Pfizer ).
Bristol-Myers Squibb ).
Regeneron Other, Consultant.
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Janssen Other, Consultant.
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V. K. Lam,
Anheart Therapeutics Other, Consultant.
Takeda Other, Consultant.
Seattle Genetics ), Other, Consultant.
Bristol Myers Squibb ), Other, Consultant.
AstraZeneca ), Other, Consultant.
Guardant Health Other, Consultant.
GlaxoSmithKline ).
Merck ).
Lovance Biotherapeutics Other, Consultant.
B. Levy,
AstraZenca Other, Personal Fees.
Novartis Other, Personal Fees.
Eli Lilly Other, Personal Fees.
Genentech Other, Personal Fees.
Pfizer Other, Personal Fees.
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AstraZeneca ), Other, Consultant.
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Regeneron ), Other, Consultant.
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J. R. Brahmer,
AstraZeneca ), Other, Consultant.
Bristol Myers Squibb ).
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Summit Therapeutics Other, Consultant.
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Genmab Other, Data Safety and Monitoring Board.
V. Anagnostou,
Astra Zeneca g., Board of Directors, non-salaried role), ).
Bristol-Myers Squibb ).
Personal Genome Diagnostics/Labcorp ).
Delfi Diagnostics ).
Neogenomics g., Board of Directors, non-salaried role).
Foundation Medicine Other, Honoraria.
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Roche Other, Honoraria.
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