MERMAID-1：MRD+完全切除非小细胞肺癌辅助度伐利尤单抗+化疗

Phase III Study to Determine the Efficacy of Durvalumab in Combination With Chemotherapy in Completely Resected Stage II-III Non-small Cell Lung Cancer (NSCLC) - Full Text View - ClinicalTrials.gov

MERMAID-1: A Phase III Study of Adjuvant Durvalumab plus Chemotherapy in Resected NSCLC Patients with MRD+ Post-Surgery
S.Peters，D.Spigel，M.Ahn，，C.Swanton

Introduction
30% of non-small-cell lung cancer (NSCLC) patients present with surgically resectable disease at diagnosis. To reduce disease recurrence, adjuvant chemotherapy is standard of care (SoC) for patients with completely (R0) resected stage II/III NSCLC. However, 5-year disease-free survival (DFS) rates remain low (∼40%), with a 5-year absolute benefit of only 5.4% derived from chemotherapy (Pignon et al. JCO 2008;26:3552-9). Determining who will benefit from adjuvant chemotherapy remains challenging. Identifying minimal residual disease (MRD) through detection of circulating tumour (ct) DNA post-surgery could predict early disease recurrence. Durvalumab is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. In the phase III PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression following radical platinum-based concurrent chemoradiotherapy, durvalumab improved progression-free survival (PFS) and overall survival (OS), demonstrating its efficacy in situations of residual disease. Further, initial data from POSEIDON showed durvalumab plus chemotherapy prolongs PFS versus chemotherapy in first line treatment of metastatic NSCLC. In the adjuvant setting (i.e. following complete tumour resection), this regimen could provide additional DFS benefit versus chemotherapy alone. MRD assessment could facilitate earlier, more selective adjuvant therapy for MRD+ patients, allowing for treatment intensification for this potentially biologically distinct disease, while minimising overtreatment of MRD– patients. MERMAID-1 will investigate the efficacy and safety of adjuvant durvalumab + SoC chemotherapy versus placebo + SoC chemotherapy in patients with completely resected stage II/III NSCLC, to assess the benefits of adjuvant therapy in patients with MRD+ status.

Methods
MERMAID-1 (NCT04385368) is a phase III, parallel-arm, placebo-controlled, double-blind, multicentre study, conducted across 16 countries. Patients aged ≥18 years with histologically confirmed EGFR-/ALK- Wild-type, stage II/III NSCLC will enter the first screening period; a personalised MRD panel will be created. Before randomisation, and following assessment of MRD status post-surgery, patients will be further screened for full eligibility (no evidence of disease recurrence, WHO/ECOG performance status 0/1). Patients who have received prior adjuvant therapy or durvalumab, and those with mixed small cell and NSCLC histology or evidence of post-operative disease recurrence are ineligible. MRD status will be determined via ctDNA analysis of plasma samples, collected 3–4 weeks post-surgery, and based on personalised panels (comprised of ≤50 tumour-specific DNA variants) created by whole exome sequencing analysis of the patient’s resected tumour tissue. Approximately 332 patients will be randomised 1:1 (stratified by disease stage, MRD status, and PD-L1 expression) to durvalumab (1500 mg, intravenously) or placebo, plus concurrent SoC chemotherapy, once every three weeks (Q3W) for 12 weeks. Patients will continue with durvalumab monotherapy/placebo Q4W thereafter, until Week 48 or disease recurrence, whichever occurs first. Following a baseline radiological scan prior to randomisation, patients will be assessed Q12W until disease recurrence (per RECIST v1.1). The primary endpoint is DFS in the MRD+ analysis set (investigator-assessed). Secondary endpoints include DFS in the full analysis set (FAS; investigator-assessed); DFS in the MRD+ analysis set and FAS (blinded independent central review); OS in the MRD+ analysis set and FAS; and safety and tolerability, and patient-reported outcomes.


MERMAID-1（NCT04385368）3 期临床试验正在评估完整手术切除后的II~III期NSCLC患者的MRD与PFS情况。完整手术切除后的II~III期NSCLC患者将接受血浆采集以进行MRD状态的检测（MRD状态将通过血浆样本的ctDNA分析来确定，在手术后3-4周收集，并基于由患者切除的肿瘤组织的全外显子组测序分析创建个性化的MRD panel（由≤50个肿瘤特异性DNA变体组成），即使用的是ArcherDX的PCM），然后，将患者按1：1的比例随机接受度伐利尤单抗（durvalumab）/安慰剂+化疗治疗，首要研究终点是MRD+患者的PFS，MRD状态做为分层因素。

Charles Swanton医学博士表示表示：“MERMAID-1是一项新的随机试验，使用ctDNA来确定手术后具有高复发风险的患者，这些患者可能受益于免疫治疗的干预。我们希望通过加强对最有可能复发的患者的治疗，同时避免术后进行额外的化疗，为患者带来更好的结局。”


ArcherDX的个体化癌症监测（PCM）技术旨在检测早期癌症患者手术后的MRD，该技术获得了美国食品和药物管理局（FDA）授予突破性设备资格认定（Breakthrough Device Designation）。