Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer
Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer
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DOI：
10.1200/jco.2001.19.10.2626
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发表时间：
2001-05-15
影响因子：
45.3
通讯作者：
Hong, WK
中科院分区：
文献类型：
--
作者：
Khuri, FR;Rigas, JR;Hong, WK
目的：贝沙罗汀（Targretin; Ligand Pharmaceuticals，Inc，San Diego，CA）是类视色素-X-受体（RXR）-选择性类视色素，在鳞状细胞癌中具有临床前抗肿瘤活性。在这项I/II期试验中，我们联合贝沙罗汀、顺铂和长春瑞滨治疗非小细胞肺癌（NSCLC）患者。患者和方法：43例IIIB期NSCLC伴胸腔积液或IV期NSCLC且未接受既往治疗的患者接受了贝沙罗汀联合顺铂治疗（100 mg/m2）和长春瑞滨（30 mg/m2和15 mg/m2交替剂量）。在I期部分，从顺铂-长春瑞滨方案开始前1周开始，3名患者的队列中贝沙罗汀的日剂量从150 mg/m2递增至600 mg/m2。一旦确定贝沙罗汀的最大耐受剂量（MTD），研究进入II期部分。反应率是主要终点;中位生存时间和1年生存率是次要终点paints.Results：在I期部分，贝沙罗汀的每日MTD确定为400 mg/m2。43例患者中有8例表现出主要反应。II期部分的28例患者中有7例（25%）对治疗有反应。II期部分的中位生存时间为14个月; 28例患者中有9例（32%）在至少2年的随访时仍然存活。1年和预计3年生存率分别为61%和30%。最常见的3级和4级不良事件是高血糖、白细胞减少、恶心、呕吐、肺炎、呼吸困难、贫血和虚弱。发生率大于5%的3级和4级实验室检查异常为血红蛋白水平和WBC、中性粒细胞绝对计数和淋巴细胞绝对计数降低以及凝血酶原时间、肌酐和淀粉酶水平升高。在2例胰腺炎病例中，1例需要住院治疗，2例均与甘油三酯水平升高相关。有1例继发于肾功能不全的死亡，与贝沙罗汀治疗无关。结论：在晚期NSCLC患者中，贝沙罗汀联合顺铂和长春瑞滨产生了可接受的II期缓解率（25%），并与好于预期的生存率相关（14个月中位生存时间; 61%的I年生存率，32%的2年生存率和30%的3年生存率）。该方案应在更大规模的临床试验中进行研究。
Purpose: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell rung cancer (NSCLC).Patients and Methods: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and hold received no prior therapy received bexarotene in combination with cisplatin (100 mg/m(2)) and vinorelbine (alternating doses of 30 mg/m(2) and 15 mg/m(2)). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m(2) to 600 mg/m(2), beginning 1 week before the start of the cisplatin-vinorelbine regimen, Once the maximum-tolerated dose (MTD) of bexarotene wars determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end paints.Results: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treat\ment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment,Conclusion: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% I-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.