A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes.
A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes.
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DOI：
10.1080/2162402x.2020.1863631
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发表时间：
2021-01-31
期刊：
影响因子：
7.2
通讯作者：
Lukens JN
中科院分区：
文献类型：
--
作者：
Maity A;Mick R;Rengan R;Mitchell TC;Amaravadi RK;Schuchter LM;Pryma DA;Patsch DM;Maity AP;Minn AJ;Vonderheide RH;Lukens JN
我们在有≥2个转移病灶的黑色素瘤患者中进行了一项伊匹单抗放射治疗的I期剂量递增试验。在这里，我们报告了最终的完整临床分析。患者对单个病灶接受RT（6或8戈伊x 2或3个剂量），随后接受4个周期的易普利姆玛治疗。主要终点是RT的最大耐受剂量，次要终点是非辐射部位的反应。入组了22例未经治疗（n = 11）或治疗难治性（n = 11）IV期黑色素瘤患者。有31起治疗相关不良事件（AE），其中16起被认为与免疫相关。11例患者发生3级AE（无4/5级）。不存在与辐射/易普利姆玛组合相关的剂量限制性毒性。22例患者中有5例（22.7%，95% CI 7.8-45.4%）的最佳缓解为部分缓解，3例（13.6%）疾病稳定。中位总生存期为10.7个月（95% CI，4.9个月至不可估计），中位无进展生存期为3.6个月（95% CI，2.9个月至7.8个月）。7例患者在末次随访时仍存活（中位随访时间为89.2个月），其中大多数患者在进展后接受了pembrolizumab治疗。放疗后伊匹单抗耐受性良好，产生的反应率优于单用伊匹单抗的客观反应率。此外，32%的患者是长期存活者，其中大多数接受了pembrolizumab治疗。基于这些结果，在随后的II期试验中使用的推荐剂量为8戈伊x 3剂量。临床试验注册：NCT 01497808（www.clinicaltrials.gov）
We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8–45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov)