Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial
Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial
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DOI：
10.1001/jamaoncol.2020.0750
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发表时间：
2020-06-01
期刊：
影响因子：
28.4
通讯作者：
Engert, Andreas
中科院分区：
文献类型：
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作者：
Broeckelmann, Paul J.;Goergen, Helen;Engert, Andreas
问题：纳武利尤单抗与多柔比星、长春碱和达卡巴嗪（N-AVD）联合或序贯治疗作为早期不良典型霍奇金淋巴瘤的一线治疗的疗效如何？在这项由制药商申办的2期随机临床试验中，包括109例成人患者，在2个周期的N-AVD（87%）或4剂纳武单抗（51%）治疗后观察到非常高的中期完全缓解率。在4个周期的N-AVD和30-戈伊的受累部位放疗结束后，两组的疗效指标，如完全缓解率、1年无进展生存率和1年总生存率均为极好。Nivolumab为基础的一线治疗在早期不良典型霍奇金淋巴瘤患者中非常有效，值得进一步研究。这项2期随机临床试验评估了Nivolumab与多柔比星、长春碱和达卡巴嗪（AVD）联合和序贯治疗早期不良霍奇金淋巴瘤患者的疗效。重要性在早期不良典型霍奇金淋巴瘤（cHL）中，常规疗法引起高治愈率，但也引起相关的急性和长期毒性作用。Nivolumab在复发性/难治性cHL中耐受性良好且高度有效，但尚未在早期cHL的一线治疗中进行充分研究。NIVAHL试验评估了nivolumab在这种情况下的作用，目的是开发一种高效但可耐受的全身治疗，以最终减轻cHL存活患者的发病率。2017年4月至2018年10月期间开放。试验在德国的35个试验中心进行，从学术中心到私人办公室。合格性定义为年龄18至60岁，经专家病理学审查证实的cHL，根据德国霍奇金研究组标准（I至II期，有风险因素）的早期不利疾病，以及无严重伴随疾病或器官功能障碍。干预系统治疗，按照随机分配（1：1），以4个周期的纳武单抗和多柔比星、长春碱和达卡巴嗪（N-AVD）的伴随治疗或以标准剂量的4个剂量的纳武单抗、2个周期的N-AVD和2个周期的AVD的序贯治疗，随后是30-戈伊的受累部位放疗。主要结果和测量研究治疗后的完全缓解（CR）率，旨在排除CR率为80%或更低，通过双侧95%CI为每个治疗group.Results纳入本研究的109例患者中，65（59.6%）是女性，中位（范围）年龄为27（18 - 60）岁。在2个周期的N-AVD或4剂纳武利尤单抗单药治疗后的中期分期中，54/54（100%）和49/51（96%）例符合缓解条件的患者分别实现了客观缓解，47（87%）和26（51%）例患者分别实现了CR。在符合主要终点分析条件的101例患者中，51例接受伴随治疗的患者中有46例（90%; 95% CI，79%-97%）和50例接受序贯治疗的患者中有47例（94%; 95% CI，84%-99%）在研究治疗后达到CR。中位随访时间为13个月，接受伴随治疗的患者12个月无进展生存率为100%，接受序贯治疗的患者为98%（95%CI，95%-100%）。尽管在伴随治疗组中勉强错过了疗效基准，但在4剂纳武利尤单抗单药治疗后，出色的12个月无进展生存期和意外的高CR率值得进一步评估这种方法在早期cHL患者的一线治疗中的作用。
Question What is the efficacy of concomitant or sequential nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) as first-line treatment for early-stage unfavorable classic Hodgkin lymphoma? Findings In this investigator-sponsored phase 2 randomized clinical trial including 109 adult patients, very high interim complete remission rates were observed after treatment with 2 cycles of N-AVD (87%) or 4 doses of nivolumab (51%). After end of treatment with 4 cycles of N-AVD and 30-Gy involved-site radiotherapy, efficacy measures, such as complete remission rates, 1-year progression-free survival, and 1-year overall survival were excellent in both groups. Meaning Nivolumab-based first-line treatment is highly effective in patients with early-stage unfavorable classic Hodgkin lymphoma and warrants further investigation.This phase 2 randomized clinical trial assesses the efficacy of concomitant and sequential treatment with nivolumab and doxorubicin, vinblastine, and dacarbazine (AVD) for patients with early-stage unfavorable Hodgkin lymphoma.IMPORTANCE In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL.OBJECTIVE To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL.DESIGN, SETTING, AND PARTICIPANTS This was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible.INTERVENTIONS Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. Main Outcomes and Measures Complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group.RESULTS Of 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy.CONCLUSIONS AND RELEVANCE Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL.