Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway.
Department of Cancer Immunology, Oslo University Hospital, Oslo, Norway.
J Transl Med. 2020 Jul 3;18(1):269. doi: 10.1186/s12967-020-02421-w.
Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells.
ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression.
ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198.
针对 PD-1 或 CTLA-4 的免疫检查点抑制剂（CPI）的免疫疗法已成为几种癌症形式的重要治疗方式。在激素受体阳性乳腺癌（HR+BC）中，这种治疗方法在很大程度上尚未得到探索。我们已经开始了一项临床试验，ICON（CA209-9FN），评估 CPI 联合选定的化疗在转移性 HR+BC 患者中的疗效。肿瘤淋巴细胞浸润是预测 BC 化疗效果的指标。在 ICON 中，我们使用蒽环类药物，其被认为是“免疫原性”化疗药物，以及低剂量环磷酰胺，其已被报道可以对抗免疫抑制细胞。
ICON 是一项随机探索性 IIb 期研究，评估纳武单抗（nivo；抗 PD-1）和伊匹单抗（ipi；抗 CTLA-4）联合化疗在转移性 HR+BC 患者中的安全性和疗效。主要目的是评估毒性和无进展生存期。该试验将招募 75 名可评估的受试者，随机分为 2:3 两组（A:B）。A 组患者仅接受化疗，即聚乙二醇化脂质体多柔比星（PLD 20 mg/m 静脉注射，每 2 周 1 次）+环磷酰胺（cyclo；每天 50mg，每个 4 周周期的前 2 周）。B 组患者接受 PLD+cyclo+ipi（每 6 周静脉注射 1mg）+nivolumab（每 2 周静脉注射 240mg）。A 组患者在疾病进展后可接受 ipi+nivo。
ICON 是第一批联合化疗与 PD-1 和 CTLA-4 阻断的临床试验之一，也是 BC 中的第一个。有强烈的临床前依据支持探索是否蒽环类药物（被认为诱导免疫原性细胞死亡）与 CPI 协同作用，并联合 PD-1 和 CTLA-4 阻断，因为这些检查点在免疫反应的不同阶段都很重要。如果 ICON 试验提示可接受的安全性并提供临床疗效信号，则需要进一步研究。接受 ipi+nivo 而不联合化疗的 A 组交叉患者代表了第一批接受这种治疗的 BC 患者。ICON 试验包括一系列转化子项目，旨在解决临床重要的知识空白。这些研究可能会揭示疗效和耐药性的生物标志物或机制，从而为新型联合治疗方案和基于生物标志物的个体化治疗提供信息。试验注册 NCT03409198，2018 年 1 月 24 日；https://clinicaltrials.gov/ct2/show/record/NCT03409198。
