Long Georgina V, Atkinson Victoria, Lo Serigne N, Guminski Alexander D, Sandhu Shahneen K, Brown Michael P, Gonzalez Maria, McArthur Grant A, Menzies Alexander M
Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia.
Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia.
Lancet Oncol. 2025 Mar;26(3):320-330. doi: 10.1016/S1470-2045(24)00735-6. Epub 2025 Feb 17.
Patients with melanoma brain metastases respond well to immunotherapy, but long-term comparative survival data are scarce. We aimed to assess the efficacy of ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases at 7 years.
This open-label, randomised, phase 2 study was conducted at four sites (two research institute cancer centres and two university teaching hospitals) in Australia. Patients aged 18 years or older with active, immunotherapy-naive melanoma brain metastases and Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Asymptomatic patients with no previous brain-directed therapy were randomly assigned (5:4) using the biased-coin minimisation method (after a safety run-in of six patients) to cohort A (intravenous ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks) or cohort B (intravenous nivolumab 3 mg/kg every 2 weeks). Patients with previous brain-directed therapy, neurological symptoms, or leptomeningeal disease were assigned to cohort C (non-randomised; intravenous nivolumab 3 mg/kg every 2 weeks). The primary endpoint was best intracranial response (complete or partial response) from week 12. Secondary survival endpoints included intracranial progression-free survival and overall survival. Safety was assessed from the first dose of treatment to at least 100 days after treatment discontinuation. Analyses were performed in patients who received at least one dose of study drug. The main analysis has been reported, and this is a long-term follow up of the ABC trial. This trial is registered with ClinicalTrials.gov, NCT02374242, and is ongoing.
Between Nov 4, 2014, and April 21, 2017, 89 patients were assessed for eligibility, 79 of whom were enrolled and assigned to cohort A (n=36), cohort B (n=27), or cohort C (n=16). Three patients (one in cohort A and two in cohort B) were excluded due to ineligibility. 17 (22%) of 76 patients were female and 59 (78%) were male. At data cutoff (March 26, 2024), the median follow-up was 7·6 years (IQR 6·9-8·2). Overall intracranial responses occurred in 18 (51% [95% CI 34-69]) patients from cohort A, five (20% [7-41]) from cohort B, and one (6% [0-30]) from cohort C. 7-year intracranial progression-free survival was 42% (95% CI 29-63) in cohort A, 15% (6-39) in cohort B, and 6% (1-42) in cohort C. 7-year overall survival was 48% (34-68) in cohort A, 26% (13-51) in cohort B, and 13% (3-46) in cohort C. Safety results were consistent with the primary analysis. 50 patients died, including 18 (51%) from cohort A, 18 (72%) from cohort B, and 14 (88%) from cohort C.
Our findings suggest that ipilimumab plus nivolumab maintains efficacy to at least 7 years in patients with active asymptomatic brain metastasis. Upfront ipilimumab plus nivolumab should be the standard of care for patients with melanoma brain metastasis; a trial investigating the role of stereotactic surgery in this new paradigm is ongoing.
Melanoma Institute Australia and Bristol Myers Squibb.
黑色素瘤脑转移患者对免疫疗法反应良好，但长期的比较生存数据稀缺。我们旨在评估7年时，伊匹木单抗联合纳武单抗对比单独使用纳武单抗治疗黑色素瘤脑转移患者的疗效。
这项开放标签、随机、2期研究在澳大利亚的4个地点（2个研究所癌症中心和2所大学教学医院）进行。年龄在18岁及以上、患有活动性、未接受过免疫治疗的黑色素瘤脑转移且东部肿瘤协作组体能状态为0 - 2的患者符合条件。未接受过脑定向治疗的无症状患者（经过6名患者的安全性导入期后）使用偏倚硬币最小化法以5:4的比例随机分配至队列A（静脉注射伊匹木单抗3 mg/kg加纳武单抗1 mg/kg，每3周一次，共4剂，然后纳武单抗3 mg/kg每2周一次）或队列B（静脉注射纳武单抗3 mg/kg每2周一次）。既往接受过脑定向治疗、有神经症状或软脑膜疾病的患者被分配至队列C（非随机；静脉注射纳武单抗3 mg/kg每2周一次）。主要终点是第12周时的最佳颅内反应（完全或部分缓解）。次要生存终点包括颅内无进展生存期和总生存期。安全性从首次治疗剂量评估至治疗停药后至少100天。对接受至少一剂研究药物的患者进行分析。主要分析已报告，这是ABC试验的长期随访。该试验已在ClinicalTrials.gov注册，编号为NCT02374242，正在进行中。
在2014年11月4日至2017年4月21日期间，89例患者接受了资格评估，其中79例入组并分配至队列A（n = 36）、队列B（n = 27）或队列C（n = 16）。3例患者（队列A 1例，队列B 2例）因不符合资格被排除。76例患者中17例（22%）为女性，59例（78%）为男性。在数据截止时（2024年3月26日），中位随访时间为7.6年（IQR 6.9 - 8.2）。队列A中发生总体颅内反应的有18例（51% [95% CI 34 - 69]），队列B中有5例（20% [7 - 41]），队列C中有1例（6% [0 - 30]）。队列A的7年颅内无进展生存率为42%（95% CI 29 - 63），队列B为15%（6 - 39），队列C为6%（1 - 42）。队列A的7年总生存率为48%（34 - 68），队列B为26%（13 - 51），队列C为13%（3 - 46）。安全性结果与主要分析一致。50例患者死亡，包括队列A中的18例（51%）、队列B中的18例（72%）和队列C中的14例（88%）。
我们的研究结果表明，伊匹木单抗联合纳武单抗在活动性无症状脑转移患者中至少7年保持疗效。一线使用伊匹木单抗联合纳武单抗应成为黑色素瘤脑转移患者的治疗标准；一项研究立体定向手术在这一新模式中作用的试验正在进行。
澳大利亚黑色素瘤研究所和百时美施贵宝公司。
