Oh Yun, Herbst Roy S, Burris Howard, Cleverly Ann, Musib Luna, Lahn Michael, Bepler Gerold
Anderson Cancer Center, Houston, TX, USA.
J Clin Oncol. 2008 Mar 1;26(7):1135-41. doi: 10.1200/JCO.2007.14.3685.
Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non-small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.
Patients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status <or= 2, and <or= two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.
Fifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS >or= 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade <or= 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).
Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for >or= 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.
恩杂鲁胺是一种口服丝氨酸/苏氨酸激酶抑制剂，可抑制蛋白激酶C（PKC）和蛋白激酶B/AKT转化（AKT）信号传导，诱导肿瘤细胞凋亡，并抑制增殖和血管生成。PKC和AKT活性增加与非小细胞肺癌（NSCLC）的不良预后相关。开展这项恩杂鲁胺的II期试验以确定晚期转移性NSCLC患者6个月无进展生存期（PFS）率。
转移性（IV期和湿性IIIB期）NSCLC患者，东部肿瘤协作组体能状态≤2，且既往接受过≤两种全身治疗方案（包括一种或多种铂类化疗方案），接受500mg恩杂鲁胺每日一次给药。
入组55例患者（55%为男性患者，45%为女性患者；中位年龄63岁；范围44至82岁；78%的患者为IV期疾病）。腺癌是最常见的诊断类型（65%）。既往治疗包括放疗（73%）和表皮生长因子抑制剂（29%）。中位PFS为1.8个月（95%CI，1.7至1.9）。6个月PFS率为13%（95%CI，3.9%至21.5%）。中位总生存期（OS）为8.4个月（95%CI，6.0至13.6个月）。12个月OS率为44%（95%CI，30.5%至57.3%）。19例患者（35%）病情稳定。未观察到客观缓解。7例患者（13%）PFS≥6个月，其中3例持续超过10个月。最常见的毒性反应为疲劳（≤3级；n = 17）。3级或更严重的毒性反应为疲劳（n = 2）、血栓栓塞（n = 1）、共济失调（n = 1）和贫血（n = 1）。2例患者因药物相关的疲劳和头晕而停药。5例患者在研究期间死亡（与药物无关）。
虽然未达到20%PFS率的主要终点，但13%的患者PFS≥6个月。鉴于耐受性和生存数据，有必要在NSCLC中评估恩杂鲁胺与细胞毒性药物联合使用的情况。
