A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial

IF 10 1区 医学 Q1 ONCOLOGY
Francesca Sarno, Jair Tenorio, Sofia Perea, Laura Medina, Roberto Pazo-Cid, Ignacio Juez, Rocio Garcia-Carbonero, Jaime Feliu, Carmen Guillen-Ponce, Pedro P. Lopez-Casas, Carmen Guerra, Yolanda Duran, Jose Francisco López-Acosta, Carolina Alonso, Estrella Esquivel, Ana Dopazo, Dipikaa Akshinthala, Senthil K. Muthuswamy, Pablo Lapunzina, Bruno Bockorny, Manuel Hidalgo
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Abstract

Purpose: Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC. Methods: Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician’s discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS). Results: 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months. Conclusions: Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.
综合基因组学和阿凡达模型用于胰腺癌个性化治疗的 III 期随机试验:AVATAR 试验
目的:胰腺腺癌(PDAC)的治疗方案有限。我们比较了综合精准医疗与传统治疗对 PDAC 的疗效。方法:晚期 PDAC III 期试验晚期 PDAC III 期试验,患者被随机(1:2)分配到由医生决定的常规治疗(A 组)或精准医疗(B 组)。被随机分配到B组的受试者接受肿瘤活检,进行全外显子组测序(WES),并生成阿凡达小鼠模型和患者衍生的器官组织,进行表型药物筛选,最终治疗方案由分子肿瘤委员会推荐。主要目标是中位总生存期(OS)。研究结果B组80.3%(65/81)的患者进行了WES检查,21.5%(14/65)的患者检测到了潜在的可操作突变。16/81(19.8%)名患者建立了实验模型。实验组的 39 例患者接受了二线治疗,但只有 4 例(10.2%)接受了个性化治疗,35 例因临床病情迅速恶化、研究结果迟迟未出或缺乏可作用靶点而无法接受匹配治疗。常规组和实验组的中位生存期分别为8.7个月和8.6个月(P=0.849),中位无进展生存期分别为3.8个月和4.3个月(P=0.563)。值得注意的是,接受个性化治疗的四名患者的中位生存期为 19.3 个月。结论对大多数 PDAC 患者实施个体化治疗具有挑战性,这限制了对意向治疗分析的解释。接受匹配治疗的亚组患者的生存率有所提高。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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