德国癌症研究中心Alwin Krämer团队比较了未知原发性癌症患者疾病控制后综合基因组分析（CGP）指导治疗与化疗对预后的影响。2024年7月31日出版的《柳叶刀》杂志发表了这项成果。

当接受标准的基于铂的化疗时，患有未知原发性癌症不良亚群（CUP）的患者预后不良。综合基因组分析（CGP）指导的一线治疗是否可以改善预后尚不清楚。CUPISCO试验旨在提供一种分子指导的治疗策略，以改善新诊断、预后不佳、非鳞状CUP患者的预后，且优于标准的铂类化疗。该研究旨在比较分子导向治疗（MGT）与标准铂类化疗在这些患者中的疗效和安全性。这是为了确定将CGP纳入初步诊断检查是否会比目前的护理标准带来更好的预后。研究组在此报告初步分析。

CUPISCO是一项临床2期、前瞻性、随机、开放标签、活性对照、多中心试验，在美国以外34个国家的159个地点进行。中心资格审查确认疾病（可接受的组织学包括腺癌和低分化癌）且东部肿瘤合作组表现状态为0或1的患者，经CGP评估，在三个周期的标准一线铂类化疗后达到疾病控制，通过区块分层随机程序以3:1的比例随机分配到MGT或继续化疗至少三个周期。主要终点是研究者评估的意向治疗人群的无进展生存期。

2018年7月10日至2022年12月9日，1505名筛查患者中有636名（42%）被纳入研究。治疗中位随访时间为24.1个月（IQR 11.6–35.6）。438名在诱导化疗后达到疾病控制的患者中，436名被随机分配：326名（75%）进入MGT组，110名（25%）进入化疗组。MGT组意向治疗人群的中位无进展生存期为6.1个月（95%CI 4.7-6.5），而化疗组为4.4个月（4.1-5.6）（风险比为0.72[95%CI 0.56-0.92]；p=0.0079）。与化疗组相比，MGT组每100患者-年的相关不良事件发生率通常相似或更低。

研究结果表明，在先前未经治疗、预后不佳、非鳞状CUP的患者中，在诱导化疗后达到疾病控制，CGP和随后的MGT导致的无进展生存期比标准铂类化疗更长。基于这些结果，研究组建议对CUP不佳的患者在初步诊断时进行CGP。

附：英文原文

Title: Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study

Author: Alwin Krmer, Tilmann Bochtler, Chantal Pauli, Kai-Keen Shiu, Natalie Cook, Juliana Janoski de Menezes, Roberto A Pazo-Cid, Ferran Losa, Debbie GJ Robbrecht, Jií Tomáek, Cagatay Arslan, Mustafa zgürolu, Michael Stahl, Frédéric Bigot, Sun Young Kim, Yoichi Naito, Antoine Italiano, Nasséra Chalabi, Gonzalo Durán-Pacheco, Chantal Michaud, Jeremy Scarato, Marlene Thomas, Jeffrey S Ross, Holger Moch, Linda Mileshkin

Issue&Volume: 2024-07-31

Abstract:

Background

Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis.

Methods

CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing.

Findings

From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6–35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7–6·5) in the MGT group versus 4·4 months (4·1–5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56–0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy.

Interpretation

In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP.

DOI: 10.1016/S0140-6736(24)00814-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00814-6/abstract