Phase Ib/II study of safety and efficacy of EZH2 inhibitor, tazemetostat, and PD-1 blockade for treatment of advanced non-small cell lung cancer

背景：检查点阻断免疫疗法已成为治疗艾滋病的重要手段 治疗晚期肺癌患者。然而，提高治疗水平仍是临床上尚未满足的需要。 结果，考虑到只有一小部分患者受益于免疫治疗的事实。据我们所知， 更多关于反应和耐药的机制，目前正在进行大量的临床试验来测试 联合治疗以提高疗效。多梳抑制酶的酶组分EZH2 根据研究表明，复杂的(PRC)2成为肺癌患者的可行靶点 在联合治疗的小鼠模型中，其过度表达和肿瘤控制改善的预后， 特别是通过检查站封锁免疫疗法。此外，第一种口服EZH2抑制剂，他赛托斯特，是 FDA于2020年初批准用于晚期上皮样肉瘤患者。因此，我们建议测试 他赛托斯特联合培溴利珠治疗退伍军人晚期非小细胞肺癌 细胞肺癌(NSCLC)。 假设：EZH2抑制剂tazemTostat能够使癌细胞对检查点做出反应 封锁免疫疗法。 目标：主要目标：他珠单抗和培溴利珠单抗联合应用的安全性和有效性 从一线或二线治疗进展的晚期非小细胞肺癌患者的治疗 客观有效率采用RECIST V1.1评定。次要目标：疾病控制率、进展 自由存活率、一年存活率和反应持续时间。 具体目标：目标1.对EZH2的安全性和有效性进行开放标签单臂Ib/II期研究 抑制剂他赛托斯特和PD-1阻滞剂pembrolizumab用于治疗晚期非小细胞肺癌患者。 目的2.进行探索性分析，以确定相关的临床或分子标记(生物标记) 对这种联合疗法的反应和抵抗力。 研究设计：目的1.利用3+3标准剂量递增策略确定推荐的II期剂量 用3个剂量水平，400,600和800毫克，每天两次，结合平坦剂量，200毫克 静脉注射培溴利珠单抗。对于第二阶段，我们的目标是招募总共54名使用Simon Optimum的患者 采用两阶段设计进行疗效检验。 目的2.生物标志物及相关研究。使用肿瘤检测主要生物标志物H3K27me3和PD-L1 活组织检查。肿瘤的突变负荷、新抗原和细胞外DNA(CtDNA)的动力学将使用肿瘤进行测试。 活检和连续采血以及免疫监测(通过Flow/CyTOF，NanoString，免疫表型 和多重免疫荧光)。 与军事健康相关：改善对多种晚期癌症的治疗对 退伍军人的健康。许多退伍军人在被诊断为癌症时有很大的发病率 这限制了他们的治疗选择。免疫疗法通常耐受性良好，并有很大的潜力 持久的反应，然而，好处仅限于部分患者(和退伍军人)。因此，它是 采用合理的组合策略，提高免疫治疗的疗效势在必行。新兴 有证据表明，EZH2在肺癌生物学和治疗耐药中发挥重要作用。此外， 第一个口服EZH2抑制剂在临床上可用。因此，拟议的试验具有很大的发展潜力。 老年晚期肺癌患者的有效治疗及副作用可控 从一线或二线治疗进展。

Background: Checkpoint blockade immunotherapy has become an essential therapeutic armamentarium for treating patients with advanced lung cancer. However, it is an unmet clinical need to improve the therapeutic outcome, given the fact that only a subset of patients are benefitting from immunotherapy. As we understand more about the mechanisms of response and resistance, numerous clinical trials are now underway to test combination therapy to improve the responses. EZH2, an enzymatic component of Polycomb Repressive Complex (PRC) 2 emerged as a viable target for patients with lung cancer based on the studies showing poor prognosis with its overexpression and improved tumor control in the mouse models in combination therapy, particularly with checkpoint blockade immunotherapy. In addition, a first oral EZH2 inhibitor, tazemetostat, was approved by FDA in early 2020 for patients with advanced epithelioid sarcoma. Therefore, we propose to test the combination treatment with tazemetostat and pembrolizumab for Veteran patients with advanced non-small cell lung cancer (NSCLC). Hypothesis: EZH2 inhibitor, tazemetostat, is able to re-sensitize cancer cells responding to checkpoint blockade immunotherapy. Objectives: Primary objectives: Safety and efficacy of the tazemtostat and pembrolizumab combination treatment for patients with advanced NSCLC who progressed from the front or 2nd line of therapy measured by Objective Response Rate assessed by RECIST v1.1. Secondary objectives: Disease control rate, progression free survival, one-year survival rate and duration of response. Specific aims: Aim 1. Perform an open label single arm phase Ib/II study of safety and efficacy of the EZH2 inhibitor, tazemetostat, and PD-1 blockade, pembrolizumab, for treatment of patients with advanced NSCLC. Aim 2. Perform exploratory analyses to identify correlative clinical or molecular markers (biomarkers) of response and resistance to this combination therapy. Study design: Aim 1. Utilize 3+3 standard dose escalation strategy to determine recommended phase II dose with 3 dose levels, 400, 600 and 800 mg twice daily of tazemetostat combined with flat dose, 200 mg of intravenous pembrolizumab. For phase II, we are aiming to enroll a total of 54 patients using Simon Optimum Two Stage design to test the efficacy. Aim 2. Biomarker and correlative studies. Primary biomarkers to be tested, H3K27me3 and PD-L1 using tumor biopsies. Tumor mutational burden, neoantigen and cell free DNA (ctDNA) dynamics will be tested using tumor biopsies and serial blood draw along with immune monitoring (immunophenotype via flow/CyTOF, NanoString and multiplex immunofluorescence). Relevant to Military health: Improving treatment of many types of advanced cancers is critically important to the health of Veterans. Many Veterans suffer from significant morbidity when they are diagnosed with cancer that limits their therapeutic options. Immunotherapy is generally well tolerated and has a significant potential for durable response, however, the benefit is limited to a subset of patients (and Veterans). Therefore, it is imperative to improve therapeutic efficacy of immunotherapy using rational combinatorial strategies. Emerging evidence indicates the important role of EZH2 in lung cancer biology and therapeutic resistance. Moreover, the first oral EZH2 inhibitor is available in clinics. Hence, the proposed trial has a great potential to develop effective treatment with manageable side effects for Veteran patients with advanced lung cancer who progressed from the first or 2nd line of therapy.