Zauderer Marjorie G, Jegede Opeyemi, Jackman David M, Zwiebel James A, Gray Robert J, Wang Victoria, McShane Lisa M, Rubinstein Larry V, Patton David R, Williams P Mickey, Hamilton Stanley R, Takebe Naoko, Huang Raymond, Carrillo Jose A, Brenner Andrew J, Tricoli James V, Conley Barbara A, Arteaga Carlos L, Harris Lyndsay N, O'Dwyer Peter J, Chen Alice P, Flaherty Keith T
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY and Westchester Medical Center and New York Medical College, Valhalla, NY.
Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA.
JCO Precis Oncol. 2024 Dec;8:e2400327. doi: 10.1200/PO.24.00327. Epub 2024 Dec 18.
The NCI-MATCH trial assigned patients with solid tumors, lymphomas, or multiple myeloma to targeted therapies on the basis of identified genetic alterations from tumor biopsies. In preclinical models, ()-inactivated tumors display sensitivity to focal adhesion kinase (FAK) inhibition. The EAY131-U subprotocol evaluated the efficacy of defactinib, a FAK inhibitor, in patients with -altered tumors.
Patients whose tumors harbored an inactivating mutation on next-generation sequencing were assigned to subprotocol U. Defactinib 400 mg was given orally twice a day until progression or intolerable toxicity. The primary end point was objective response rate (ORR), secondary end points included toxicity, progression-free survival (PFS), and 6-month PFS.
Of 5,548 patients with sufficient tissue for genomic analysis, 57 patients were found to have alterations. Thirty-five patients ultimately enrolled and 33 were treated, with one not having central confirmation and two ineligible for outcome analysis. All patients had received previous treatment, with 52% having received three or more previous lines of therapy. The most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%), with 27% of patients having grade 3 toxicities. Median follow-up was 35.9 months with an ORR of 3% from one partial response in a patient with choroid meningioma. Among the 12 patients (40%) with a best response of stable disease, eight demonstrated some tumor shrinkage. Median PFS was 1.9 months, and six patients achieved a PFS >5.5 months. No correlation was identified between clinical outcomes and tumor histology or specific genotype.
This protocol did not meet its prespecified primary end point. Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting loss.
NCI-MATCH试验根据肿瘤活检中确定的基因改变，将实体瘤、淋巴瘤或多发性骨髓瘤患者分配至靶向治疗组。在临床前模型中，（）失活的肿瘤对粘着斑激酶（FAK）抑制敏感。EA Y131-U子方案评估了FAK抑制剂地法替尼对（）改变的肿瘤患者的疗效。
肿瘤在下一代测序中存在失活突变的患者被分配至子方案U组。口服地法替尼400mg，每日两次，直至病情进展或出现无法耐受的毒性。主要终点为客观缓解率（ORR），次要终点包括毒性、无进展生存期（PFS）和6个月PFS。
在5548例有足够组织进行基因组分析的患者中，57例被发现存在（）改变。最终35例患者入组，33例接受治疗，其中1例未得到中心确认，2例不符合疗效分析条件。所有患者均接受过先前治疗，52%的患者接受过三线或更多线的先前治疗。最常见的治疗相关毒性为疲劳（36%）、恶心（33%）和高胆红素血症（27%），27%的患者出现3级毒性。中位随访时间为35.9个月，脉络丛脑膜瘤患者中有1例部分缓解，ORR为3%。在12例最佳疗效为疾病稳定的患者（40%）中，8例出现了一定程度的肿瘤缩小。中位PFS为1.9个月，6例患者的PFS>5.5个月。未发现临床结局与肿瘤组织学或特定（）基因型之间存在相关性。
该方案未达到预先设定的主要终点。在这组先前接受过治疗且存在（）缺失的实体瘤患者中，地法替尼单药治疗的临床活性有限。
