Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer.,JAMA Oncology

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Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer.
JAMA Oncology ( IF 22.5 ) Pub Date : 2019-11-27 , DOI: 10.1001/jamaoncol.2019.3857
Jyoti S Mayadev ₁ , Danielle Enserro ₂ , Yvonne G Lin ₃ , Diane M Da Silva ₃ , Heather A Lankes ₄ , Carol Aghajanian ₅ , Sharad Ghamande ₆ , Kathleen N Moore ₇ , Vanessa A Kennedy ₈ , Paula M Fracasso ₉ , Russell J Schilder ₁₀

Affiliation

Department of Radiation Medicine and Applied Sciences, University of California, San Diego, Medical Center, La Jolla.
NRG Oncology, Clinical Trial Development Division, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles.
Biopathology Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Augusta University Medical Center, Augusta, Georgia.
Department of Obstetrics and Gynecology, Oklahoma University Health Science Center, Oklahoma City.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Davis Comprehensive Cancer Center, Sacramento.
Department of Medicine, UVA Cancer Center, University of Virginia, Charlottesville.
Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.

Importance Despite standard chemoradiotherapy (CRT), most women with lymph node (LN)-positive cervical cancer experience disease recurrence. Immunotherapy is being investigated in the up-front treatment setting. Objectives To assess the safety of sequential immunotherapy after CRT and to investigate human papillomavirus (HPV) genotype and HLA allele status on survival and programmed cell death 1 (PD-1) expression before and after CRT and sequential immunotherapy. Design, Setting, and Participants This prospective phase 1 trial conducted in 29 Gynecology Oncology Cooperative Group member institutions enrolled participants from December 18, 2012, to August 31, 2016, with a 14.8-month median follow-up and translational end points. Thirty-four women with International Federation of Gynecology and Obstetrics stage IB2 to IVA cervical cancer with positive pelvic LNs, para-aortic LNs, or both were enrolled; 13 did not receive ipilimumab and were excluded from the analysis. Data were analyzed from January 21 to April 4, 2018. Interventions Treatment consisted of 6 weekly doses of cisplatin, 40 mg/m2, concurrent with radiotherapy. After completion of chemotherapy, sequential ipilimumab was given every 21 days for 4 doses. Two dosage levels of ipilimumab, 3 mg/kg and 10 mg/kg, were studied to identify the maximum tolerated dose. Main Outcomes and Measures The primary end point was safety, and the secondary end points were overall survival and progression-free survival. Exploratory end points included HPV genotype, HLA allele status, and PD-1 expression measured in peripheral blood. Results The median age of the 32 participants included in the intent-to-treat analysis was 50 (range, 26-61) years, and 22 patients (69%) were white. Of the 21 patients who received ipilimumab, all had positive pelvic LN, and 6 (29%) had positive para-aortic LNs. All patients completed CRT, and of the 21 patients who received at least 2 cycles of ipilimumab, 18 (86%) completed 4 cycles of ipilimumab, and 3 (14%) completed 2 cycles. The maximum tolerated dose was 10 mg/kg. Two of the 21 patients (9.5%) who received ipilimumab had self-limiting grade 3 toxic effects (lipase increase; dermatitis). The 12-month overall survival was 90%, and progression-free survival was 81%. Human papillomavirus genotype and HLA subtype were not associated with progression-free survival or overall survival. T cells expressing PD-1 increased after CRT, and levels were sustained with ipilimumab. Conclusions and Relevance This study's findings suggest that the use of immunotherapy after CRT for curative-intent treatment of patients with cervical cancer is tolerable and effective. The results indicated that PD-1 was upregulated after CRT and sustained with sequential ipilimumab therapy. These immune findings may help guide future therapies to harness the activated T-cell phenotype in patients with node-positive cervical cancer.

中文翻译：

放化疗后序贯伊匹单抗对淋巴结阳性宫颈癌患者的根治性治疗。

重要性尽管有标准的放化疗 (CRT)，但大多数淋巴结 (LN) 阳性宫颈癌的女性都会出现疾病复发。免疫疗法正在前期治疗环境中进行研究。目的评估 CRT 后序贯免疫治疗的安全性，并研究 CRT 和序贯免疫治疗前后人乳头瘤病毒 (HPV) 基因型和 HLA 等位基因状态对生存和程序性细胞死亡 1 (PD-1) 表达的影响。设计、设置和参与者这项前瞻性 1 期试验于 2012 年 12 月 18 日至 2016 年 8 月 31 日在 29 家妇科肿瘤合作组成员机构中进行，招募参与者，中位随访时间为 14.8 个月，转化终点为 14.8 个月。纳入了 34 名国际妇产科联合会 IB2 至 IVA 宫颈癌且盆腔淋巴结阳性、主动脉旁淋巴结阳性或两者兼有的女性；13 名未接受易普利姆玛治疗并被排除在分析之外。数据分析时间为 2018 年 1 月 21 日至 4 月 4 日。干预治疗包括每周 6 剂 40 mg/m2 顺铂，同时进行放疗。化疗完成后，每 21 天连续给予 ipilimumab 4 剂。研究了易普利姆玛的两个剂量水平，3 mg/kg 和 10 mg/kg，以确定最大耐受剂量。主要结局指标主要终点是安全性，次要终点是总生存期和无进展生存期。探索性终点包括 HPV 基因型、HLA 等位基因状态、和在外周血中测量的 PD-1 表达。结果意向治疗分析中纳入的 32 名参与者的中位年龄为 50（范围，26-61）岁，其中 22 名患者（69%）为白人。在接受易普利姆玛治疗的 21 名患者中，所有患者的盆腔 LN 均呈阳性，6 名（29%）的主动脉旁 LN 呈阳性。所有患者都完成了 CRT，在接受至少 2 个周期的易普利姆玛治疗的 21 名患者中，18 名（86%）完成了 4 个周期的易普利姆玛治疗，3 名（14%）完成了 2 个周期。最大耐受剂量为 10 mg/kg。接受易普利姆玛治疗的 21 名患者中有 2 名 (9.5%) 具有自限性 3 级毒性作用（脂肪酶增加；皮炎）。12个月总生存率为90%，无进展生存率为81%。人乳头瘤病毒基因型和 HLA 亚型与无进展生存期或总生存期无关。CRT 后表达 PD-1 的 T 细胞增加，而 ipilimumab 维持水平。结论和相关性本研究的结果表明，在 CRT 后使用免疫疗法对宫颈癌患者进行根治性治疗是可耐受且有效的。结果表明，PD-1 在 CRT 后上调，并在连续 ipilimumab 治疗后持续。这些免疫发现可能有助于指导未来的治疗，以利用淋巴结阳性宫颈癌患者的活化 T 细胞表型。结果表明，PD-1 在 CRT 后上调，并在连续 ipilimumab 治疗后持续。这些免疫发现可能有助于指导未来的治疗，以利用淋巴结阳性宫颈癌患者的活化 T 细胞表型。结果表明，PD-1 在 CRT 后上调，并在连续 ipilimumab 治疗后持续。这些免疫发现可能有助于指导未来的治疗，以利用淋巴结阳性宫颈癌患者的活化 T 细胞表型。

更新日期：2020-01-09

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