背景:修饰的多西他赛,顺铂,和氟尿嘧啶(mDCF)方案已显示出疗效和安全性作为一线治疗晚期肛门鳞状细胞癌,使其成为标准方案。程序性细胞死亡蛋白1及其配体抑制剂,比如pembrolizumab,Nivolumab,retifanlimab,阿维鲁单抗,和阿妥珠单抗,在化疗难以治疗的晚期肛门鳞状细胞癌中,作为单一疗法已显示出一定的抗肿瘤活性。这项2期研究评估了mDCF和阿特珠单抗的组合作为晚期肛门鳞状细胞癌的一线治疗。
方法:在这个随机的,开放标签,非比较性,第二阶段研究,来自21个中心的参与者(学术,私人,以及法国各地的社区医院和癌症研究中心),转移性,或不可切除的局部晚期复发性肛门鳞状细胞癌,18岁或以上,并且东部肿瘤协作组的表现状态为0或1,被随机分配(2:1)接受阿妥珠单抗(每2周一次静脉注射800mg,直至1年)加mDCF(8个周期,即40mg/m2多西他赛和40mg/m2顺铂,第1天,每天1200mg/m2氟尿嘧啶,持续2天,每2周静脉注射;A组)或单独使用mDCF(B组)。使用最小化技术集中进行随机化,并按年龄(<65岁vs≥65岁)和疾病状态分层。主要终点是A组改良意向治疗人群中研究者评估的12个月无进展生存期(零假设为35%,替代假设为50%)。该试验已在ClinicalTrials.gov注册,NCT03519295,并对新参与者关闭。
结果:在2018年7月3日至2020年8月19日之间招募了97名可评估参与者(A组64名,B组33名)。中位随访时间为26·5个月(95%CI24·8-28·4)。参与者的平均年龄为64·1岁(IQR56·2-71·6),71名(73%)为女性。A组的12个月无进展生存率为45%(90%CI35-55),B组的12个月无进展生存率为43%(29-58)。A组12个月无进展生存率为70%(95%CI47-100),B组为40%(19-85)(交互作用p=0.051)。在A组39名(61%)和B组14名(42%)参与者中观察到3级或更高的不良事件。最常见的3-4级不良事件是中性粒细胞减少症(A组有9名[14%]参与者,B组有5名[15%]参与者)。贫血(9[14%]对1[3%]),疲劳(三[5%]对四[12%]),和腹泻(七[11%]对一[3%])。A组16名(25%)参与者和B组4名(12%)参与者发生严重不良事件,A组7名(11%)参与者和B组4名(12%)参与者与mDCF相关。A组9名(14%)参与者发生了与Atezolizumab相关的严重不良事件,包括三级输液相关反应(5%),3级感染中的两个(3%),和2级结肠炎,3级急性肾损伤,3级结节病,4级血小板计数在一名参与者中各减少(2%)。没有治疗相关的死亡。
结论:尽管不良事件的发生率较高,阿替珠单抗与mDCF联合使用是可行的,两组的剂量强度相似,尽管未达到主要疗效终点。PD-L1联合阳性评分为5分或更高的预测价值现在需要在未来的研究中得到证实。
背景:GERCOR,罗氏
BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2
study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus.
METHODS: In this randomised, open-label, non-comparative, phase 2
study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This
trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants.
RESULTS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths.
CONCLUSIONS: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies.
BACKGROUND: GERCOR, Roche.