肺癌疫苗仅对部分NSCLC患者有生存益处

阿姆斯特丹——欧洲多学科癌症会议上公布的Ⅲ期STOP研究结果显示，试验性肺癌疫苗belagenpumatucel-L(Lucanix)仅可延长部分非小细胞肺癌(NSCLC)患者的总生存。


Guiseppe Giaccone医生

这项随机、双盲、安慰剂对照研究由华盛顿乔治敦大学Lombardi综合癌症中心的临床研究副主任Giuseppe Giaccone医生及其同事在8个国家进行，为期46个月，共入组532例含铂化疗6个周期后疾病稳定的晚期NSCLC患者。490例为ⅢB/Ⅳ期，42例为ⅢA期。研究目的是探讨成功一线化疗后，接种belagenpumatucel-L疫苗是否可预防进展。主要终点为一线含铂化疗后的总生存。研究期间，疫苗为18个月皮内注射接种，随后再注射2次，每次之间间隔3个月。每剂含2.5×10⁷个细胞。

总体而言，疫苗接种组的缓解率较低，为2.6%。仅有1例(0.4%)完全缓解和6例(2.2%)部分缓解。无进展生存(PFS)与总生存无关，在一些亚组患者中观察到PFS改善的趋势，但无统计学显著性。

在2年时间内，疫苗组和安慰剂组的中位总生存分别为20.3个月和17.8个月[危险比(HR) 0.54； P=0.0595)。然而，有迹象表明，如果在停止一线化疗12周内接种疫苗，则可改善总生存。在停止化疗12周内接种疫苗的169例患者中，总生存为20.7个月，而在停止化疗12周后才接种疫苗的149例患者中，总生存为13.3个月(HR 0.77；P=0.0092)。

最常见的副作用是注射部位反应(1~2级)，见于疫苗组260例和安慰剂组62例患者。非预期反应包括腹痛、便秘、食欲下降、鼻咽炎和非心源性胸痛，疫苗组发生所有这些非预期反应的人数高于安慰剂组。发生5起严重不良事件，其中3起见于疫苗组患者，仅1起(过敏反应)可能由疫苗本身引起。

该研究由NovaRx公司资助。Giaccone医生声明无经济利益冲突，但其他研究者是NovaRx公司员工。

专家点评：新数据支持进一步评估疫苗

苏黎世大学的Rolf Stahel医生表示，该研究的总生存分析应在发生354起事件后进行，但实际上在仅发生253起事件后就进行了，这可影响研究的统计学效度。此外，所进行的各种亚组分析和对照组较低的总生存估计值可对结果产生影响。

完成一线化疗12周内接受随机化的ⅢB/Ⅳ期患者似乎具有生存优势，并且放疗前接种的患者可能也有获益。这些探索性数据表明有必要进一步评估疫苗。

Stahel医生未披露其是否与疫苗生产商有关。

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By: SARA FREEMAN, Oncology Practice

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.
 
Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 107 cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.

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Data support further vaccine assessment

The overall survival analysis in this study was due to be performed after 354 events had occurred. Instead, the analysis was done after only 253 events, which would affect the statistical power of the trial. In addition, the variety of subgroup analyses undertaken and the low estimate of overall survival in the control arm would have an influence on the outcome.

There did appear to be a survival advantage in stage IIIB/IV patients randomized within 12 weeks of completion of the frontline chemotherapy and perhaps a benefit in those who had received prior radiation therapy. These exploratory data warrant further assessment of the vaccine.

Dr. Rolf Stahel is with the University of Zurich. He was the discussant of the presentation at the meeting. Dr. Stahel made no disclosures as to his relationship with the company that makes the vaccine.