Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma
Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma
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DOI：
10.1093/annonc/mdx026
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发表时间：
2017-05-01
影响因子：
50.5
通讯作者：
Rizos, H.
中科院分区：
文献类型：
--
作者：
Lee, J. H.;Long, G. V.;Rizos, H.
背景：程序性死亡1（PD 1）抑制剂现在是转移性黑色素瘤医学管理的基础。本研究旨在确定循环肿瘤DNA（ctDNA）是否提供有用的早期反应和预后信息。患者和方法：我们评估了治疗前和治疗早期ctDNA与单独使用PD 1抑制剂或与伊匹单抗联合治疗的黑色素瘤患者的结果之间的关系。在基线时，在40/76例患者（53%）中检测到ctDNA，并与分期、LDH水平、疾病体积和ECOG表现相关。A组（基线时未检测到ctDNA）、B组（基线时ctDNA升高，但在治疗12周内未检测到）和C组（基线时ctDNA升高，但在治疗期间保持升高）的RECIST应答率分别为72%（26/36）、77%（17/22）和6%（1/18）。A组和B组未达到中位PFS，C组为2.7个月[风险比（HR）0.09; A组与C组相比P < 0.001，B组与C组相比0.16; P < 0.001]。A组和B组未达到中位OS，C组为9.2个月（HR 0.02; A组与C组P < 0.001，B组与C组0.14; P < 0.001）。在校正LDH、体能状态、肿瘤分期和疾病体积后的多变量分析中，与C组相关的不良结局指标仍具有显著性。在单独的验证队列中证实了ctDNA对缓解的预测价值（n = 29，P < 0.01）。接受PD 1抑制剂治疗的转移性黑色素瘤患者中ctDNA的纵向评估是肿瘤反应、PFS和OS的准确预测因子。治疗中ctDNA持续升高的患者预后不良，并且这可以指导后续治疗的组合和顺序。
Background: Programmed death 1 (PD1) inhibitors are now a foundation of medical management of metastatic melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information.Patients and methods: We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab.Results: ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [ hazard ratio (HR) 0.09; P < 0.001 for group A versus C, and 0.16; P < 0.001 for group B versus C]. The median OS was not reached for groups A and B and was 9.2 months for group C (HR 0.02; P < 0.001 for group A versus C and 0.14; P < 0.001 for group B versus C). The poor outcome measures associated with group C remained significant in multivariate analysis adjusted for LDH, performance status, tumour stage and disease volume. The predictive value for ctDNA for response was confirmed in a separate validation cohort (n = 29, P < 0.01).Conclusion: Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.