A randomized phase II study of erlotinib with or without the anti-IGF-1R monoclon

描述(申请人提供)：肺癌是全球癌症死亡的主要原因。在美国，每年有近20万名男性和女性被诊断出患有肺癌，其中约80%将死于这种疾病。需要更有效、更耐受性更好的治疗方案。组织学上，大约85%的肺癌是非小细胞肺癌(NSCLC)。针对表皮生长因子受体(EGFR)的新疗法最近显示出对晚期NSCLC患者的显著生存益处，尽管只有相对较小比例的患者表现出客观反应。基于回顾分析，已经表明，EGFR基因拷贝数和EGFR和ras突变可以有效地区分对EGFR抑制反应更多/更少的患者。目前正在进行多项前瞻性试验，以证实这些是预选因素。临床前研究表明，EGFR通路与胰岛素样生长因子-1受体(IGF-1R)通路有广泛的串扰，IGF-1R可能在EGFR靶向药物，如厄洛替尼的耐药机制中发挥重要作用。IMC-A12是一种完全人源的IgG1/？针对IGF-1R的单抗。这项授权假设，IGF-1R阻滞剂与IMC-A12以及抗EGFR治疗与erlotinib联合使用将在非小细胞肺癌患者中显示出比任何一种药物单独使用更大的活性，并且联合抑制可能逆转抗EGFR治疗的耐药机制。这项资助还假设，与EGFR和IGF-1R途径相关的生物标记物，如基因拷贝数，可以预测那些最有可能从联合中受益的人。这笔赠款的目标是完成厄洛替尼与IMC-A12联合或不与IMC-A12联合治疗晚期非小细胞肺癌患者的随机II期临床研究，以确认联合用药在临床上是可耐受的，并评估联合用药是否会证明在目标人群中与单用厄洛替尼相比，联合用药的抗肿瘤效果更好。将收集血液样本和存档的肿瘤样本，用于分析临床受益/治疗耐药的可疑生物标志物。将从患者那里收集更多的血液样本，以探索IMC-A12和埃洛替尼之间的药物-药物药代动力学相互作用，以及遗传种系对与临床活性、毒性和埃洛替尼暴露相关的结果的影响。公共卫生相关性：肺癌是全球癌症死亡的主要原因，自20世纪50年代中期以来，它一直是美国男性和女性最常见的恶性肿瘤死亡原因。尽管最近针对可能导致肺癌的关键分子的靶向治疗的进展改善了一些患者的前景，但治疗耐药性仍然是一个主要问题。该项目是在患者中进行的临床试验，将测试两种新型靶向药物的合理组合，以克服肺癌的部分治疗耐药性(新药针对的是EGFR和IGF-1R分子通路之间进行的通信)，并着手探索可能预测未来将从这种组合中获得最大好处的因素。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death worldwide. In the USA, nearly 200,000 men and women are diagnosed with lung cancer every year and approximately 80% of them will die from the disease. More effective, and better tolerated, treatment regimens are needed. Histologically, approximately 85% of lung cancers are non-small cell lung cancer (NSCLC). Novel therapies targeting the epidermal growth factor receptor (EGFR) have recently shown a significant survival benefit in patients with advanced NSCLC, although only a relatively small percentage of patients manifest objective responses. Based on retrospective analyses it has already been shown that EGFR gene copy number and EGFR and ras mutations can usefully differentiate patients that are more/less likely to respond to EGFR inhibition. Multiple prospective trials are now in progress to verify these as pre-selection factors. Pre-clinically, the EGFR pathway has been shown to have extensive crosstalk with the insulin-like growth factor-1 receptor (IGF-1R) pathway and IGF-1R may play an important role in resistance mechanisms to EGFR-targeted agents, such as erlotinib. IMC-A12 is a fully human IgG1/? monoclonal antibody directed against the IGF-1R. This grant hypothesizes that the combination of IGF-1R blockade with IMC-A12 and anti-EGFR therapy with erlotinib will demonstrate greater activity in NSCLC patients than either agent alone and that combined inhibition may reverse mechanisms of resistance to anti-EGFR therapy. This grant also hypothesizes that biomarkers, such as gene copy number, that relate to both the EGFR and IGF-1R pathways may predict those most likely to benefit from the combination. The goal of this grant is to complete a randomized phase II clinical study of erlotinib with or without IMC-A12 in patients with advanced NSCLC, to confirm that the combination will be clinically tolerable and to assess whether the combination will demonstrate evidence of improved anti-tumor effects compared to erlotinib alone in the target population. Blood specimens and archived tumor specimens will be collected for analysis of suspected biomarkers of clinical benefit/treatment resistance. Additional blood specimens from the patients will be collected to explore aspects of drug-drug pharmacokinetic interactions between IMC-A12 and erlotinib, and inherited germline effects on outcomes relating to clinical activity, toxicity and erlotinib exposures. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death worldwide, and it has been the most common cause of death from malignancy in the USA in men since the mid-1950s and in women since the mid-1980s. Although recent advances in targeting treatment to key molecules that may drive lung cancer have improved the outlook for some patients, treatment resistance remains a major problem. This project is a clinical trial in patients and will test a rational combination of two novel targeted agents to overcome some of this treatment resistance in lung cancer (the new drugs target the communication that goes on between the EGFR and IGF-1R molecular pathways) and sets out to explore the factors that may predict those who will gain the most benefit from this combination in the future.