度伐利尤单抗联合卡介苗（BCG）或外照射放疗用于卡介苗无反应性非肌层浸润性膀胱癌患者的1期试验：印第安纳癌症研究网络GU16 - 243 ADAPT - 膀胱研究。
A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.
作者信息
Hahn Noah M, O'Donnell Michael A, Efstathiou Jason A, Zahurak Marianna, Rosner Gary L, Smith Jeff, Kates Max R, Bivalacqua Trinity J, Tran Phuoc T, Song Daniel Y, Baras Alex S, Matoso Andres, Choi Woonyoung, Smith Kellie N, Pardoll Drew M, Marchionni Luigi, McGuire Bridget, Grace Phelan Mary, Johnson Burles A, O'Neal Tanya, McConkey David J, Rose Tracy L, Bjurlin Marc, Lim Emerson A, Drake Charles G, McKiernan James M, Deutsch Israel, Anderson Christopher B, Lamm Donald L, Geynisman Daniel M, Plimack Elizabeth R, Hallman Mark A, Horwitz Eric M, Al-Saleem Essel, Chen David Y T, Greenberg Richard E, Kutikov Alexander, Guo Gordon, Masterson Timothy A, Adra Nabil, Kaimakliotis Hristos Z
机构信息
Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.
University of Iowa Carver College of Medicine, Iowa City, IA, USA.
出版信息
Eur Urol. 2023 Jun;83(6):486-494. doi: 10.1016/j.eururo.2023.01.017. Epub 2023 Jan 28.
BACKGROUND
Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients.
OBJECTIVE
To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT).
DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites.
INTERVENTION
Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates.
RESULTS AND LIMITATIONS
Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients.
CONCLUSIONS
D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches.
PATIENT SUMMARY
Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.
背景
对于卡介苗（BCG）无反应的非肌层浸润性膀胱癌（NMIBC）患者而言，新型治疗方法和试验设计仍然是重中之重。
目的
评估度伐利尤单抗（D）、度伐利尤单抗联合卡介苗（D + BCG）以及度伐利尤单抗联合体外束放射治疗（D + EBRT）的抗程序性死亡受体1配体（PD-L1）导向治疗的安全性和初步疗效。
设计、地点和参与者：在社区和学术机构开展了一项多中心1期试验。
干预措施
患者每3周静脉注射1120 mg的D，共8个周期。D + BCG组患者还需每周接受一次全剂量膀胱内卡介苗灌注，持续6周，并建议进行卡介苗维持治疗。D + EBRT组患者仅在第1周期接受同步体外束放射治疗（6 Gy×3）。
结局测量和统计分析
在治疗后3个月和6个月进行膀胱镜检查和尿液细胞学检查，6个月评估时需要进行膀胱活检。每种治疗方案的推荐2期剂量（RP2D）为主要终点。次要终点包括毒性特征和完全缓解（CR）率。
结果和局限性
28例患者分别接受了D组（n = 3）、D + BCG组（n = 13）和D + EBRT组（n = 12）的治疗。全剂量D、全剂量卡介苗和6 Gy×3被确定为RP2D。1例患者（4%）发生了3级剂量限制性毒性事件，即自身免疫性肝炎。3个月时，所有患者的CR率为64%，D组、D + BCG组和D + EBRT组的CR率分别为33%、85%和50%。所有患者的12个月CR率为46%，D + BCG组和D + EBRT组分别为73%和33%。
结论
对于卡介苗无反应的NMIBC患者，D联合膀胱内卡介苗或体外束放射治疗被证明是可行且安全的。令人鼓舞的初步疗效证明进一步研究联合治疗方法是合理的。
患者总结
度伐利尤单抗联合治疗可以安全地应用于非肌层浸润性膀胱癌患者，目标是提高持久缓解率。
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