Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer
Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer
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DOI：
10.1001/jamaoncol.2019.3857
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发表时间：
2020-01-01
期刊：
影响因子：
28.4
通讯作者：
Schilder, Russell J.
中科院分区：
文献类型：
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作者：
Mayadev, Jyoti S.;Enserro, Danielle;Schilder, Russell J.
淋巴结阳性宫颈癌放化疗后的免疫治疗是否可以耐受？在这项多机构的1期临床试验中，21例淋巴结阳性宫颈癌患者接受了放化疗，随后伊匹单抗治疗，最大耐受剂量为10mg /kg。2例患者出现自限性3级毒性作用。本研究结果提示，淋巴结阳性宫颈癌患者放化疗后抗细胞毒性t淋巴细胞抗原4治疗是可耐受的。尽管标准的放化疗（CRT），大多数淋巴结（LN）阳性的宫颈癌妇女经历疾病复发。免疫疗法正在进行前期治疗的研究。目的评价序贯免疫治疗CRT后的安全性，探讨人乳头瘤病毒（HPV）基因型和HLA等位基因对CRT和序贯免疫治疗前后患者存活和程序性细胞死亡1 （PD-1）表达的影响。该前瞻性一期试验于2012年12月18日至2016年8月31日在29家妇科肿瘤学合作组织成员机构中进行，中位随访时间为14.8个月，随访终点为转化终点。34名国际妇产联合会IB2至IVA期宫颈癌患者，盆腔、主动脉旁或两者均有阳性ln；13例未接受伊匹单抗治疗，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。治疗包括每周6次顺铂剂量，40mg /m(2)，同时进行放疗。化疗完成后，依匹单抗序贯治疗每21天一次，共4次。研究了ipilimumab的两个剂量水平，3mg /kg和10mg /kg，以确定最大耐受剂量。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等位基因状态和外周血中PD-1的表达。纳入意向治疗分析的32名参与者的中位年龄为50岁（范围26-61岁），22名患者（69%）为白人。在接受ipilimumab治疗的21例患者中，所有患者盆腔LN阳性，6例（29%）主动脉旁LN阳性。所有患者均完成了CRT治疗，在接受至少2个周期伊匹单抗治疗的21例患者中，18例（86%）完成了4个周期伊匹单抗治疗，3例（14%）完成了2个周期伊匹单抗治疗。最大耐受剂量为10 mg/kg。接受ipilimumab治疗的21例患者中有2例（9.5%）出现自限性3级毒性作用（脂肪酶升高；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，伊匹单抗维持水平。结论和意义本研究的结果表明，在CRT后使用免疫疗法治疗宫颈癌患者的治愈意图治疗是可容忍的和有效的。结果表明，PD-1在CRT后上调，并在序贯伊匹单抗治疗下持续。这些免疫发现可能有助于指导未来的治疗方法，以利用淋巴结阳性宫颈癌患者的活化t细胞表型。这项多机构的1期临床试验评估了淋巴结阳性宫颈癌患者在完成放化疗后增加一个疗程的免疫治疗的安全性和耐受性。
Question Is immunotherapy after chemoradiotherapy in node-positive cervical cancer tolerable? Findings In this multi-institutional phase 1 trial, 21 patients with node-positive cervical cancer received chemoradiotherapy followed by ipilimumab therapy at a maximum tolerated dose of 10 mg/kg. Two patients experienced self-limiting grade 3 toxic effects. Meaning This study's findings suggest that treatment with anti-cytotoxic T-lymphocyte antigen 4 after chemoradiotherapy is tolerable for patients with node-positive cervical cancer.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/m(2), 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.This multi-institutional phase 1 clinical trial assesses the safety and tolerability of adding a course of immunotherapy after completion of chemoradiotherapy in patients with node-positive cervical cancer.