Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney.
Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney.
Ann Oncol. 2017 May 1;28(5):1130-1136. doi: 10.1093/annonc/mdx026.
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.
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.
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).
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.
程序性死亡受体 1（PD1）抑制剂现已成为转移性黑色素瘤医学治疗的基础。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。
我们评估了单独使用 PD1 抑制剂或联合使用 ipilimumab 治疗的黑色素瘤患者治疗前和早期治疗 ctDNA 与结果之间的关系。
40/76 名患者（53%）基线时可检测到 ctDNA，与分期、LDH 水平、疾病体积和 ECOG 表现相关。在 A 组（基线时 ctDNA 不可检测）中，RECIST 反应率为 72%（26/36），B 组（基线时 ctDNA 升高但治疗 12 周内不可检测）为 77%（17/22），C 组（基线时 ctDNA 升高且治疗期间持续升高）为 6%（1/18）。A 组和 B 组的中位 PFS 未达到，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 组的中位 OS 未达到，C 组为 9.2 个月（HR 0.02；A 组与 C 组相比，P<0.001，B 组与 C 组相比，0.14；P<0.001）。多变量分析调整 LDH、表现状态、肿瘤分期和疾病体积后，与 C 组相关的不良预后因素仍有显著意义。在单独的验证队列（n=29）中，ctDNA 对反应的预测价值得到证实（P<0.01）。
在接受 PD1 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 的准确预测指标。在治疗过程中 ctDNA 持续升高的患者预后不良，这可能指导后续治疗的联合和序贯。
