为了确定能够可靠预测转移性黑色素瘤免疫治疗长期结果的生物标志物,我们调查了[18F]FDGPET/CT的预后作用,在基线和抗PD-1治疗过程中的早期进行。
25例IV期黑色素瘤患者,计划用PD-1抑制剂治疗,参加了这项研究(pembrolizumab,n=8名患者;纳武单抗,n=4例患者;nivolumab/ipilimumab,13名患者)。[18F]FDGPET/CT在治疗开始之前(基线PET/CT)和PD-1阻断给药的最初两个周期(临时PET/CT)之后进行。在施用四个周期的治疗后,17名患者还进行了第三次PET/CT扫描。在应用欧洲癌症研究和治疗组织(EORTC)1999标准和免疫疗法PET反应评估标准(PERCIMT)后,通过PET/CT评估患者的反应。对治疗的反应分为4类:完全代谢反应(CMR),部分代谢反应(PMR),稳定代谢性疾病(SMD),和进行性代谢性疾病(PMD)。患者被进一步分为两组:那些显示代谢益处(MB),包括SMD患者,PMR,和CMR,和那些没有MB(无MB),包括PMD患者。此外,记录了提示放射学免疫相关不良事件(irAEs)的[18F]FDG摄取模式.无进展生存期(PFS)的测量从中期PET/CT的日期,直到疾病进展或任何原因死亡。
中期PET/CT的中位随访时间为24.2个月(19.3-41.7个月)。根据EORTC标准,14例患者显示MB(1例CMR,6PMR,和7SMD),11例患者显示无MB(PMD)。分别,PERCIMT标准的应用显示19例患者患有MB(1CMR,6PMR,和12SMD),其中6例无MB(PMD)。关于PFS,根据EORTC标准(p=0.088),在中期PET/CT上,MB和非MB患者之间没有观察到显著差异.相反,根据PERCIMT标准,MB患者的PFS显著长于无MB患者(p=0.045).放射学irAE的出现(n=11例患者)与显著的生存获益无关。关于还接受第三次PET/CT的子队列,14/17患者(82%)显示一致的反应,3/17(18%)在中期和晚期PET/CT之间的反应评估不匹配。
应用最近提出的PERCIMT标准后,基于PET/CT的转移性黑色素瘤对PD-1阻断的反应与PFS显着相关。这突出了[18F]FDGPET/CT对于抗PD-1药物反应的早期分层的潜在能力,一项可能具有重大临床和财务影响的发现。需要包括更多患者在内的进一步研究来验证这些结果。
In an attempt to identify biomarkers that can reliably predict long-term outcomes to immunotherapy in metastatic melanoma, we investigated the prognostic role of [18F]FDG PET/CT, performed at baseline and early during the course of anti-PD-1 treatment.
Twenty-five patients with stage IV melanoma, scheduled for treatment with PD-1 inhibitors, were enrolled in the study (pembrolizumab, n = 8 patients; nivolumab, n = 4 patients; nivolumab/ipilimumab, 13 patients). [18F]FDG PET/CT was performed before the start of treatment (baseline PET/CT) and after the initial two cycles of PD-1 blockade administration (interim PET/CT). Seventeen patients underwent also a third PET/CT scan after administration of four cycles of treatment. Evaluation of patients\' response by means of PET/CT was performed after application of the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria and the PET Response Evaluation Criteria for IMmunoTherapy (PERCIMT). Response to treatment was classified into 4 categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Patients were further grouped into two groups: those demonstrating metabolic benefit (MB), including patients with SMD, PMR, and CMR, and those demonstrating no MB (no-MB), including patients with PMD. Moreover, patterns of [18F]FDG uptake suggestive of radiologic immune-related adverse events (irAEs) were documented. Progression-free survival (PFS) was measured from the date of interim PET/CT until disease progression or death from any cause.
Median follow-up from interim PET/CT was 24.2 months (19.3-41.7 months). According to the EORTC criteria, 14 patients showed MB (1 CMR, 6 PMR, and 7 SMD), while 11 patients showed no-MB (PMD). Respectively, the application of the PERCIMT criteria revealed that 19 patients had MB (1 CMR, 6 PMR, and 12 SMD), and 6 of them had no-MB (PMD). With regard to PFS, no significant difference was observed between patients with MB and no-MB on interim PET/CT according to the EORTC criteria (p = 0.088). In contrary, according to the PERCIMT criteria, patients demonstrating MB had a significantly longer PFS than those showing no-MB (p = 0.045). The emergence of radiologic irAEs (n = 11 patients) was not associated with a significant survival benefit. Regarding the sub-cohort undergoing also a third PET/CT, 14/17 patients (82%) showed concordant responses and 3/17 (18%) had a mismatch of response assessment between interim and late PET/CT.
PET/CT-based response of metastatic melanoma to PD-1 blockade after application of the recently proposed PERCIMT criteria is significantly correlated with PFS. This highlights the potential ability of [18F]FDG PET/CT for early stratification of response to anti-PD-1 agents, a finding with possible significant clinical and financial implications. Further studies including larger numbers of patients are necessary to validate these results.