Narlapati Hema, Speirs Christina, Jones Ryan M, Berenberg Jeffrey
Internal Medicine, Tripler Army Medical Center, Honolulu, USA.
Radiation Oncology, Cancer Center of Hawaii, Honolulu, USA.
Cureus. 2024 Nov 13;16(11):e73645. doi: 10.7759/cureus.73645. eCollection 2024 Nov.
The anaplastic lymphoma kinase (ALK) gene plays crucial roles in both normal brain development and oncogenesis, particularly in non-small cell lung cancer (NSCLC). Metastatic ALK-positive NSCLC is characterized by ALK tyrosine kinase domain rearrangements, prompting the use of ALK tyrosine kinase inhibitors (TKIs) to target the mutation. While first-line treatment options include alectinib, brigatinib, and lorlatinib per National Comprehensive Cancer Network (NCCN) guidelines, therapeutic challenges arise in cases of disease progression. Management strategies may involve radiation therapy, switching to alternative ALK inhibitors, or testing for resistance mutations like ALK G1202R to guide treatment selection, with lorlatinib emerging as an alternative treatment option. Here, we present the case of a 35-year-old male diagnosed with metastatic ALK-positive NSCLC. Despite initial stability on alectinib therapy, disease progression necessitated therapeutic modification, including a switch to brigatinib and subsequent treatment with lorlatinib monotherapy. Notably, the patient achieved complete remission radiologically and clinically following treatment with lorlatinib, highlighting its efficacy in refractory disease settings. While molecular research supports lorlatinib's superior central nervous system (CNS) penetrability and systemic efficacy, the absence of head-to-head clinical trials presents a significant gap in evidence. Direct comparison of second and third-generation ALK inhibitors is essential to elucidate their comparative efficacy and adverse event profiles, which could refine current management guidelines. Furthermore, if lorlatinib proves superior in terms of progression-free survival, it may offer the potential to delay or obviate the need for radiation therapy, thus mitigating the risk of neurotoxic adverse events associated with these modalities.
间变性淋巴瘤激酶（ALK）基因在正常脑发育和肿瘤发生过程中均发挥着关键作用，尤其是在非小细胞肺癌（NSCLC）中。转移性ALK阳性NSCLC的特征是ALK酪氨酸激酶结构域重排，这促使人们使用ALK酪氨酸激酶抑制剂（TKIs）来靶向该突变。根据美国国立综合癌症网络（NCCN）指南，一线治疗方案包括阿来替尼、布加替尼和洛拉替尼，但在疾病进展的情况下会出现治疗挑战。管理策略可能包括放射治疗、改用其他ALK抑制剂或检测耐药突变（如ALK G1202R）以指导治疗选择，洛拉替尼已成为一种替代治疗选择。在此，我们报告一例35岁男性转移性ALK阳性NSCLC的病例。尽管患者最初接受阿来替尼治疗时病情稳定，但疾病进展需要调整治疗方案，包括改用布加替尼并随后接受洛拉替尼单药治疗。值得注意的是，患者在接受洛拉替尼治疗后在影像学和临床上均实现了完全缓解，突出了其在难治性疾病中的疗效。虽然分子研究支持洛拉替尼具有卓越的中枢神经系统（CNS）穿透性和全身疗效，但缺乏头对头的临床试验在证据方面存在重大差距。直接比较第二代和第三代ALK抑制剂对于阐明它们的相对疗效和不良事件谱至关重要，这可能会完善当前的管理指南。此外，如果洛拉替尼在无进展生存期方面被证明更具优势，它可能有潜力延迟或避免放射治疗的需要，从而降低与这些治疗方式相关的神经毒性不良事件的风险。
