Importance Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors. Objective To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS). Design, Setting, and Participants A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023. Interventions Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab. Main Outcomes and Measures The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months. Results Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively. Conclusions and Relevance In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS. Trial Registration ClinicalTrials.gov Identifier: NCT03181100.

中文翻译：

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甲状腺间变性癌的抗程序性死亡配体 1 加靶向治疗：一项非随机临床试验。


重要性甲状腺未分化癌 （ATC） 是一种罕见且致命的癌症。尽管近年来在 BRAF 突变肿瘤患者中取得了进展，但最初有反应的患者最终死于疾病;此外，目前尚无针对非 BRAF 突变肿瘤的批准疗法。目的 确定匹配靶向治疗联合免疫检查点抑制剂治疗是否与总生存期 （OS） 的改善相关。设计、设置和参与者 在单中心、三级机构进行 2 期试验，具有平行队列，根据肿瘤突变状态分配靶向治疗。BRAF V600E 肿瘤突变患者接受 vemurafenib/cobimetinib 联合 atezolizumab （队列 1）;那些患有突变 RAS （NRAS、KRAS 或 HRAS） 或 NF1/2 肿瘤的患者接受 cobimetinib 联合 atezolizumab （队列 2）。没有任何这些变异的患者被分配接受贝伐珠单抗联合阿替利珠单抗 （队列 3）。患者于 2017 年 8 月 3 日至 2021 年 7 月 7 日入组。所有连续的、未接受过全身治疗的 ATC 活动性疾病患者且符合资格标准，均被考虑参与。该分析于 2023 年 9 月进行。干预措施 根据驱动突变将患者分配到靶向治疗组，如下所示： BRAF V600E （队列 1，维罗非尼加考比替尼）、RAS/NF （队列 2，考比替尼） 或非 BRAF/RAS/NF （队列 3，贝伐珠单抗）。所有患者均接受了 atezolizumab 治疗。主要结局和指标 该研究的主要结局是整个靶向治疗队列的中位 OS，而历史中位 OS 为 5 个月。结果 43 例 ATC 患者被纳入靶向治疗队列，其中 42 例被纳入初步分析。 这 3 个队列患者的中位 OS 为 19 个月 （95% CI，7.79-43.24）。每个队列的中位 OS 和无进展生存期如下：队列 1：43 个月 （95% CI，16-不可估计 [NE]），13.9 个月 （6.6-64.1）;队列 2：8.7 个月 （95% CI，5.1-37.0） 和 4.8 个月 （1.8-14.7）;队列 3 （血管内皮生长因子抑制剂组）：分别为 6.21 个月 （4.1-NE） 和 1.3 个月 （1.3-NE）。结论和相关性 在这项非随机临床试验中，atezolizumab 联合靶向治疗导致中位 OS 比历史里程碑更长，达到了研究的主要终点，队列 1 达到了最长的 OS。试验注册 ClinicalTrials.gov 标识符： NCT03181100.