替莫唑胺胶丸联合放疗治疗恶性脑胶质瘤的疗效观察
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.
机构信息
Robert H.I. Andtbacka, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Frances Collichio, University of North Carolina Medical Center, Chapel Hill, NC; Thomas Amatruda, Minnesota Oncology, Fridley, MN; Neil Senzer, Mary Crowley Cancer Research Center, Dallas; Merrick Ross, University of Texas MD Anderson Cancer Center, Houston, TX; Jason Chesney, University of Louisville, Louisville, KY; Keith A. Delman, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; Lynn E. Spitler, Northern California Melanoma Center, San Francisco; Gregory A. Daniels, University of California San Diego Medical Center, Moores Cancer Center, La Jolla; Yining Ye, Bin Yao, Ai Li, Ari Vander Walde, and Jennifer Gansert, Amgen, Thousand Oaks, CA; Igor Puzanov, Vanderbilt University, Nashville, TN; Sanjiv S. Agarwala, St Luke's University Hospital and Health Network, Bethlehem, and Temple University School of Medicine, Philadelphia, PA; Mohammed Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA; Lee Cranmer, University of Arizona, Tucson, AZ; Brendan Curti, Earle A. Chiles Research Institute, Portland, OR; Karl Lewis, University of Colorado Cancer Center, Aurora, CO; Troy Guthrie, Baptist Cancer Institute, Jacksonville; Jonathan S. Zager, Moffitt Cancer Center, Tampa, FL; Gerald P. Linette, Washington University School of Medicine, St Louis, MO; Kevin Harrington, Institute of Cancer Research, Royal Marsden Hospital, London; Mark R. Middleton, National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom; Wilson H. Miller Jr, McGill University, Montreal, Quebec, Canada; and Susan Doleman and Robert S. Coffin, Amgen, Woburn, MA.
出版信息
J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Epub 2015 May 26.
PURPOSE
Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial.
PATIENTS AND METHODS
Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate.
RESULTS
Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred.
CONCLUSION
T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.
目的
替莫唑胺拉帕肽（T-VEC）是一种单纯疱疹病毒 1 衍生的溶瘤免疫疗法，旨在选择性地在肿瘤内复制并产生粒细胞巨噬细胞集落刺激因子（GM-CSF），以增强全身抗肿瘤免疫反应。T-VEC 与 GM-CSF 进行了比较，在随机开放标签 III 期试验中，对不可切除的 IIIB 至 IV 期黑色素瘤患者进行了比较。
患者和方法
患者可注射不可切除的黑色素瘤，按 2:1 的比例随机分配至瘤内 T-VEC 或皮下 GM-CSF。主要终点是独立评估的持久缓解率（DRR；持续≥6 个月的客观缓解）。关键次要终点包括总生存（OS）和总缓解率。
结果
在 436 例随机分配的患者中，T-VEC 的 DRR 明显高于 GM-CSF（16.3%；95%CI，12.1%至 20.5%；比值比，8.9；P<.001）。T-VEC 组的总缓解率也较高（26.4%；95%CI，21.4%至 31.5%比 5.7%；95%CI，1.9%至 9.5%）。T-VEC 的中位 OS 为 23.3 个月（95%CI，19.5 至 29.6 个月），GM-CSF 为 18.9 个月（95%CI，16.0 至 23.7 个月）（风险比，0.79；95%CI，0.62 至 1.00；P=0.051）。T-VEC 的疗效在 IIIB、IIIC 或 IVM1a 期疾病患者和初治疾病患者中最为明显。T-VEC 最常见的不良反应（AE）是疲劳、寒战和发热。T-VEC 治疗患者中唯一发生≥2%的 3 级或 4 级 AE 是蜂窝织炎（2.1%）。没有致命的与治疗相关的 AE 发生。
结论
T-VEC 是首个在 III 期临床试验中证明对黑色素瘤有治疗益处的溶瘤免疫疗法。T-VEC 耐受性良好，DRR（P<.001）和中位 OS（P=0.051）更长，特别是在未经治疗的患者或 IIIB、IIIC 或 IVM1a 期疾病患者。T-VEC 代表了一种治疗转移性黑色素瘤的新型潜在疗法。
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