目的:多种常见癌症受益于免疫治疗;然而,对罕见肿瘤的疗效知之甚少。我们报告了罕见肿瘤中NCI/SWOGS1609双重抗CTLA-4和抗PD-1阻断的肾上腺皮质癌队列的结果。
方法:前瞻性,ipilimumab联合nivolumab的2期临床试验由SWOG早期治疗学和罕见癌症委员会针对超过1,000个国家临床试验网络站点的多个罕见肿瘤队列进行.
方法:登记了21例符合条件的患者。中位年龄为53岁(范围26-69);16(76%)为女性。
方法:伊匹单抗每6周静脉注射1mg/kg,纳武单抗每2周静脉注射240mg,直至疾病进展,症状恶化,任何原因的治疗延迟>56天,不可接受的或与免疫相关的毒性,无法将泼尼松降低至每天<10mg,或根据患者要求。
方法:主要终点是总缓解率(ORR)(RECISTV.1.1)。次要终点包括临床获益率(CBR)(包括疾病稳定(SD)>6个月),无进展生存期(PFS),总生存期(OS),和毒性。免疫相关结果包括免疫ORR(iORR),免疫CBR(iCBR),免疫PFS(iPFS)。采用两阶段设计,假设:null=5%替代=30%,n=6在第一阶段,16max,单侧α=13%。
结果:先前治疗线的中位数为2(范围:1-9)。21例患者中有3例获得确认的部分缓解(PR)(ORR=14%)。此外,一名患者有未经证实的公关;一名,稳定疾病(SD)>6个月;一,免疫相关RECIST(IRECIST)PR(iPR);一名患者达到iSD>6个月:临床获益率(反应或SD>6个月)=5/21(24%),iORR=4/21(19%),iCBR=7/21(33%)。6个月PFS为24%;6个月iPFS,33%。iRECIST临床获益患者(N=7)的PFS分别为57、52、18、15、13、7和7个月。6个月OS为76%;OS中位数,是15.8个月。最常见的毒性是疲劳(62%)和皮疹(38%),最常见的3/4级免疫相关不良事件是肝功能障碍(9.5%)和肾上腺功能不全(9.5%).治疗相关的不良事件导致4例患者停止治疗(21%)。没有发生5级不良事件。
结论:Ipilimumab联合nivolumab在难治性转移性肾上腺皮质癌中具有活性,达到研究的主要终点,iORR为19%,iCBR为33%(包括SD/iSD>6个月),PFS/iPFS最长为52个月和57个月。
背景:NCT02834013(7月15日注册,2016;https://clinicaltrials.gov/ct2/show/NCT02834013)。
OBJECTIVE: Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors.
METHODS: A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites.
METHODS: 21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women.
METHODS: Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10 mg daily, or per patient request.
METHODS: The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%.
RESULTS: The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events.
CONCLUSIONS: Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months.
BACKGROUND: NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).