Shreenivas Aditya, Janku Filip, Gouda Mohamed A, Chen Hui-Zi, George Ben, Kato Shumei, Kurzrock Razelle
Medical College of Wisconsin (MCW) Cancer Center, Milwaukee, WI, USA.
Monte Rosa Therapeutics, Boston, MA, USA.
NPJ Precis Oncol. 2023 Sep 29;7(1):101. doi: 10.1038/s41698-023-00449-x.
Anaplastic lymphoma kinase (ALK) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in 3.3% of cancers. ALK fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small cell lung cancer (NSCLC), a rate that may be below the viability threshold of even large-scale treatment trials. Five ALK inhibitors -alectinib, brigatinib, ceritinb, crizotinib, and lorlatinib-are FDA approved for ALK-aberrant NSCLCs, and crizotinib is also approved for ALK-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability of ALK alterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence of ALK fusions/rearrangements, and response rates of ~50-85%. Moreover, there are numerous reports of ALK inhibitor activity in multiple solid and hematologic tumors (e.g., histiocytosis, leiomyosarcoma, lymphoma, myeloma, and colorectal, neuroendocrine, ovarian, pancreatic, renal, and thyroid cancer) bearing ALK fusions/rearrangements. Many reports used crizotinib or alectinib, but each of the approved ALK inhibitors have shown activity. ALK inhibitor activity is also seen in neuroblastoma, which bear ALK mutations (rather than fusions/rearrangements), but response rates are lower (10-20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearing ALK fusions/rearrangements.
间变性淋巴瘤激酶（ALK）改变（激活突变、扩增以及融合/重排）约在3.3%的癌症中出现。ALK融合/重排在超过50%的炎性肌纤维母细胞瘤（IMT）和间变性大细胞淋巴瘤（ALCL）中可被识别，但在非小细胞肺癌（NSCLC）以外的其他癌症中仅约占0.2%，这一比例甚至可能低于大规模治疗试验的可行性阈值。五种ALK抑制剂——阿来替尼、布加替尼、色瑞替尼、克唑替尼和劳拉替尼——已获美国食品药品监督管理局（FDA）批准用于治疗ALK异常的NSCLC，克唑替尼还被批准用于治疗ALK异常的IMT和ALCL，包括儿童患者。在此，我们回顾ALK改变的药物可治疗性，重点关注NSCLC以外的情况。重要的是，获批适应症的标志是存在ALK融合/重排，缓解率约为50% - 85%。此外，有大量报告称ALK抑制剂在多种实体瘤和血液系统肿瘤（如组织细胞增多症、平滑肌肉瘤、淋巴瘤、骨髓瘤以及结直肠癌、神经内分泌癌、卵巢癌、胰腺癌、肾癌和甲状腺癌）中对ALK融合/重排具有活性。许多报告使用的是克唑替尼或阿来替尼，但每种获批的ALK抑制剂均已显示出活性。在携带ALK突变（而非融合/重排）的神经母细胞瘤中也可见到ALK抑制剂的活性，但缓解率较低（约10% - 20%）。目前的数据表明，ALK抑制剂在携带ALK融合/重排的肿瘤中具有不依赖组织的活性。
