Lee Alexandria T M, Ou Sai-Hong Ignatius
University of California Irvine School of Medicine, Department of Medicine, Orange, CA, USA.
Chao Family Comprehensive Cancer Center, Orange, CA, USA.
Lung Cancer (Auckl). 2024 Feb 27;15:19-27. doi: 10.2147/LCTT.S446878. eCollection 2024.
Despite the development and approval of seven anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) spanning over three "generations" since the discovery of fusion positive () non-small cell lung cancer (NSCLC), there remains intrinsic and acquired resistances to these approved TKIs. Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations . However, and mutations are intrinsic genomic alterations that negatively modulate efficacy of ALK TKIs. Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.
尽管自发现间变性淋巴瘤激酶（ALK）融合阳性（）非小细胞肺癌（NSCLC）以来，已经研发并批准了跨越三代的七种ALK酪氨酸激酶抑制剂（TKIs），但这些已获批的TKIs仍存在内在和获得性耐药性。目前，正在研发第四代（4G）ALK TKI——NVL-655，以应对一些未满足的需求，如复合耐药突变。然而，和突变是内在的基因组改变，会对ALK TKIs的疗效产生负面影响。在基于CROWN试验洛拉替尼应作为一线ALK TKI首选的不断变化的格局中，中央β-折叠#6（Cβ6）突变可能会成为对洛拉替尼的潜在获得性耐药突变，而洛拉替尼可能对当前的ALK TKIs耐药。在此，我们思考如果能够在单个分子中实现，一种假定的第五代（5G）ALK TKI将需要具备哪些额外能力。我们提出针对一些内在耐药机制的随机试验方案，这将导致一种原型第五代（5G）ALK TKI获批，并且实际上对NSCLC患者有益，而不仅仅是为了药物获批这一唯一目的设计一个阳性关键优效试验。
