Dermatology Unit, Outpatient Clinic, Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France.
Laboratoire d'immunomonitoring En Oncologie, University Paris-Saclay, Faculty of Pharmacy, Gustave Roussy Cancer Campus, Villejuif, France.
J Immunother Cancer. 2020 Aug;8(2). doi: 10.1136/jitc-2020-000627.
A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.
A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.
19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.
When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.
NCT01557114.
放疗与抗细胞毒性 T 淋巴细胞相关抗原 4（抗 CTLA-4）单克隆抗体的协同作用已在临床前得到证实。Mel-Ipi-Rx 期 1 研究旨在确定转移性黑色素瘤患者放疗联合伊匹单抗的最大耐受剂量（MTD）和安全性。
采用 3+3 剂量递增设计，第 4 周给予 9、15、18 和 24 Gy 的放疗，每周 4 次，第 4 周给予 10 mg/kg 伊匹单抗，每 3 周 4 次。第 12 周有临床获益证据的患者有资格从第 24 周开始每 12 周接受伊匹单抗 10 mg/kg 维持治疗，直至出现严重毒性或疾病进展。数据库锁定日期为 2019 年 4 月 30 日。分析照射病变和未照射病变的肿瘤生长率，以评估系统免疫抗肿瘤反应。在治疗前后进行血液免疫监测，以确定放疗是否可以改变伊匹单抗的药效动力学。
19 名患者于 2011 年 8 月至 2015 年 7 月接受伊匹单抗治疗。9 名患者接受了 4 剂伊匹单抗。所有患者均接受联合放疗。9 名患者发生 3 级不良事件，最常见的是结肠炎和肝炎。无药物相关死亡。接受 15 Gy 组的 6 名患者中有 2 名发生剂量限制毒性。MTD 为 9 Gy。2 例患者完全缓解，3 例部分缓解，7 例病情稳定，24 周时客观缓解率为 31%，临床获益率为 75%。中位随访时间为 5.8 年（Q1=4.5；Q3=6.8）。中位总生存期（95%CI）估计为 0.9 年（0.5-2）。中位无进展生存期（95%CI）为 0.4（0.2-1.4）。放疗联合伊匹单抗与 CD4+和 CD8+ICOS+T 细胞增加有关。CD8+增加与 PFS 显著相关。
当与 10 mg/kg 的伊匹单抗联合使用时，放疗的 MTD 为 9 Gy。伊匹单抗和放疗的这种联合似乎与抗肿瘤活性有关。CD8+增加与 PFS 显著相关。因此，免疫生物标志物可能有助于早期反应评估。
NCT01557114。
