Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, New York.
Weill Cornell Medical College, New York, New York.
Clin Cancer Res. 2021 Jan 15;27(2):447-459. doi: 10.1158/1078-0432.CCR-20-2657. Epub 2020 Nov 4.
Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with -mutant cancers with the isoform-specific PI3K inhibitor taselisib.
Patients were enrolled on the basis of local mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.
A total of 166 patients with -mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront ( and ) and postprogression through reactivation of the PI3K pathway (, and ). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.
Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target -mutant tumors.
磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚单位 α（）中的体细胞突变，该基因编码 PI3K 的 p110α 催化亚基，存在于多种人类癌症中。虽然螺旋、调节和激酶结构域中的反复突变导致 PI3K 通路的组成性激活，但其他突变仍未被描述。为了进一步评估它们的临床可操作性，我们设计了一项针对携带 -突变癌症患者的篮子研究，这些患者接受了特异性同工型 PI3K 抑制剂 taselisib 的治疗。
根据局部突变检测，患者被纳入 11 个组织学特异性队列之一，并接受每日 6 或 4mg 的 taselisib 治疗，直到疾病进展。使用下一代测序panel 对基线和进展期（如有）的肿瘤 DNA 进行测序。进行了与治疗结果相关的基因组改变的探索性分析。
共纳入了 166 名患有 -突变癌症的患者。确证的缓解率为 9%。活性因肿瘤类型和突变等位基因而异，在头颈部鳞状细胞癌（15.4%）、宫颈癌（10%）和其他癌症中，以及在含有螺旋结构域突变的肿瘤中观察到确证的缓解。基因组分析确定了与 PI3K 抑制的初始（和）以及通过 PI3K 通路的再激活导致的后续耐药性相关的突变（、和）。在 taselisib 的较高剂量时，更频繁地进行剂量调整，表明治疗指数较窄。
taselisib 在测试的肿瘤类型中活性有限，不再进一步开发。这项基于基因组的研究提高了对使用 PI3K 抑制剂作为单药治疗靶向 -突变肿瘤的活性、局限性和耐药机制的理解。
