Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers
Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers
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DOI：
10.1101/mcs.a003665
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发表时间：
2019-04-01
影响因子：
1.8
通讯作者：
Riely, Gregory J.
中科院分区：
文献类型：
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作者：
Drilon, Alexander;Schoenfeld, Adam J.;Riely, Gregory J.
KRAS G12D 突变/p53 缺陷的非小细胞肺癌 (NSCLC) 模型依赖于 NF-kappa B 通路，该通路可被蛋白酶体抑制剂硼替佐米下调。在之前的硼替佐米临床试验中观察到两名特殊反应者，两人都患有 KRAS G12D 突变 NSCLC，促使启动这项单中心 2 期试验。患有晚期 KRAS G12D 突变 NSCLC 的患者符合资格。硼替佐米以 1.3 mg/m(2) 皮下注射（第 1、4、8、11 天；21 天周期）直至出现进展或出现不可接受的毒性。主要目标是最佳客观反应（RECIST v1.1）。 16 名 KRAS G12D 突变肺腺癌患者接受了治疗。患者的平均包年吸烟史为 4 年（范围 0-45）。在本研究的第一阶段，一名患者观察到部分缓解（PR）（相对于基线为-66%），五名患者病情稳定（总体缓解率为6%，95% CI：0.2-30.2），并且没有增加更多患者。中位无进展生存期为 1 个月（95% CI：1-6）。中位总生存期为 13 个月（95% CI：6-NA）。最常见的治疗相关不良事件是疲劳（38%）和腹泻（26%）。 TP53 状态并不能预测探索性测试的反应。值得注意的是，这位 PR 患者患有一种独特的肺腺癌亚型——侵袭性粘液腺癌 (IMA)，并且临床改善迅速，疾病显着消退，此前在另外两名患有 IMA 的晚期 KRAS G12D 突变型肺癌患者中也观察到了这一点，他们在单独的临床试验中接受了硼替佐米治疗。 KRAS G12D 突变 NSCLC 可以实现对硼替佐米的特殊反应。然而，KRAS G12D 突变本身并不是反应的有力预测因子。只有在进一步阐明其他因素（例如同时发生的改变和组织学亚型（例如可以预测治疗敏感性的 IMA）后）才应进行进一步评估。
KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-kappa B pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed on prior clinical trials of bortezomib, both of whom had KRAS G12D-mutant NSCLC, prompting the initiation of this single-center phase 2 trial. Patients with advanced KRAS G12D-mutant NSCLC were eligible. Bortezomib was administered at 1.3 mg/m(2) subcutaneously (days 1, 4, 8, 11; 21-d cycle) until progression or unacceptable toxicity. The primary objective was best objective response (RECIST v1.1). Sixteen patients with KRAS G12D-mutant lung adenocarcinomas were treated. Patients had a median pack year smoking history of 4 (range 0-45). A partial response (PR) was observed in one patient (-66% from baseline) and stable disease in five patients on the first stage of this study (overall response rate of 6%, 95% CI: 0.2-30.2), and further patients were not accrued. The median progression-free survival was 1 mo (95% CI: 1-6). The median overall survival was 13 mo (95% CI: 6-NA). The most common treatment-related adverse events were fatigue (38%) and diarrhea (26%). TP53 status did not predict response on exploratory testing. Of note, the patient with a PR had a unique subtype of lung adenocarcinoma-invasive mucinous adenocarcinomas (IMA)-and had rapid clinical improvement and substantial disease regression, which was also previously observed in two other patients with advanced KRAS G12D-mutant lung cancer with IMAs who received bortezomib on separate clinical trials. Exceptional responses to bortezomib can be achieved in KRAS G12D-mutant NSCLCs. KRAS G12D mutation alone, however, is not a robust predictor of response. Further evaluation should only be performed after further elucidation of other factors such as co-occurring alterations and histologic subtype such as IMA that may predict sensitivity to therapy.