Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France.
INSERM U1015 & CIC1428, Gustave Roussy, Villejuif, France.
J Exp Clin Cancer Res. 2022 Jul 7;41(1):217. doi: 10.1186/s13046-022-02423-0.
We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425).
In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy.
A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4 PD1 OX40 T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP dendritic cells, CD3 T cells and FOXP3 Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4 CXCR3 CXCR5 memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels.
Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy.
ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered.
我们旨在确定口服抗血管生成酪氨酸激酶抑制剂尼达尼布与抗 PD-1 免疫疗法帕博利珠单抗联合用于晚期实体瘤患者的安全性和疗效（PEMBIB 试验；NCT02856425）。
在这项单中心 1b 期剂量递增队列研究中，我们评估了尼达尼布（剂量水平 1（DL1）= 150mg bid [每天两次]；DL2=200mg bid，口服）联合帕博利珠单抗（200mg Q3W，IV）的递增剂量。患者在开始帕博利珠单抗治疗前接受尼达尼布单药 1 周的导入剂量。主要目标是根据前 4 周内发生的剂量限制毒性（DLT）确定联合用药的最大耐受剂量（MTD）。次要目标是评估抗肿瘤疗效，并确定相关的免疫和血管生成参数，以便确定扩展队列的推荐尼达尼布剂量。在基线和治疗期间的肿瘤和血液样本上前瞻性地进行流式细胞术（FC）、免疫组化（IHC）和电化学发光多阵列，以确定与疗效相关的免疫标志物。
共纳入 13 例患者，12 例可评估 DLT（1 例患者在接受帕博利珠单抗治疗前撤回同意）。3 例接受 200mg bid 治疗的患者发生 DLT（3 级肝酶升高）。4 例患者发生 1-2 级免疫相关不良事件（irAE）。8 例患者因癌症进展而死亡。中位随访时间为 23.7 个月（95%CI：5.55-40.5）。3 例患者出现部分缓解（PR）（ORR=25%），5 例（42%）患者有持久的临床获益（DCB），定义为 PR 或稳定疾病（SD）≥6 个月。基线时，具有 DCB 的患者的血浆 Tie2、CXCL10、CCL22 和循环 CD4 PD1 OX40 T 细胞水平高于无 DCB 的患者。具有 DCB 的患者的基线肿瘤活检中还存在更多的树突状细胞-淋状细胞相关分子（DC-LAMP）树突状细胞、CD3 T 细胞和 FOXP3 Tregs。对于具有 DCB 的患者，尼达尼布单药导入治疗导致血液 CCL3、Tregs 和 CCR4 CXCR3 CXCR5 记忆性 CD4 T 细胞增加。在首次输注帕博利珠单抗后，具有 DCB 的患者的血浆 IL-6、IL-8、IL-27 水平降低。
尼达尼布 150mg bid 是与帕博利珠单抗联合使用的推荐剂量，目前正在多个扩展队列中进行研究。早期肿瘤和循环免疫因子与尼达尼布和帕博利珠单抗治疗的癌症结局相关。
ClinicalTrials.gov，NCT02856425。2016 年 8 月 4 日注册-前瞻性注册。
