1. 作用机制与临床定位概述
1.1 ALK-TKI的作用机制差异
间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌（NSCLC）的治疗在过去十年中取得了显著进展，主要得益于ALK酪氨酸激酶抑制剂（TKIs）的出现。阿来替尼（Alectinib）和洛拉替尼（Lorlatinib）作为第二代和第三代ALK-TKI的代表，在临床上发挥着关键作用，但它们在作用机制上存在显著差异。
阿来替尼作为第二代ALK-TKI，对ALK激酶具有高度选择性和有效抑制能力，能有效抑制ALK融合基因驱动的肿瘤生长。其分子靶点特异性使其在抑制ALK激酶活性的同时，对其他酪氨酸激酶的脱靶效应较小，从而提供了相对良好的安全性。值得一提的是，阿来替尼具有优异的血脑屏障（BBB）穿透能力，这对于ALK阳性NSCLC患者尤为重要，因为这类患者常常伴有中枢神经系统（CNS）转移，且CNS是常见的疾病进展部位 123。研究表明，阿来替尼不被P-糖蛋白（P-glycoprotein）外排转运体转运，该转运体是血脑屏障渗透的关键因素，这进一步解释了其在颅内的优异表现 34。
洛拉替尼作为第三代ALK-TKI，其设计初衷是为了克服前几代ALK-TKI的耐药突变，特别是G1202R等常见的耐药位点，这使其对多种ALK耐药突变具有更广谱的抑制活性 5。与阿来替尼类似，洛拉替尼也展现出卓越的血脑屏障穿透能力 567。通过放射性标记物PET成像研究证实，洛拉替尼在非人灵长类动物中具有高脑渗透性，这对于治疗或预防脑转移至关重要 89。洛拉替尼能够增加血脑屏障的通透性，其作用机制可能与下调SPP1、抑制VEGF、TGF-β和Claudin，从而减少血脑屏障细胞之间的紧密连接有关 6。在耐药突变覆盖方面，洛拉替尼对包括EML4-ALK V3a/b在内的多种融合变异以及多重ALK耐药突变均有效 10。然而，随着治疗的进行，洛拉替尼也可能诱导产生新的耐药机制，例如复杂的复合ALK耐药突变，这提示其虽广谱但并非能完全避免耐药的发生 10。
总而言之，阿来替尼和洛拉替尼在机制上都强调了对ALK激酶的有效抑制和良好的血脑屏障穿透能力，但洛拉替尼在克服多重ALK耐药突变方面具有更强的设计优势，而阿来替尼则因其独特的药代动力学特性，在长期颅内控制和较低的脱靶毒性方面展现出优势。
1.2 临床应用阶段与适应症差异
阿来替尼和洛拉替尼在非小细胞肺癌（NSCLC）ALK阳性患者的治疗中均发挥了重要作用，但其临床应用阶段和适应症存在显著差异，这主要与它们的研发上市时间、III期临床研究结果以及不同国家和地区的审批政策有关。
阿来替尼作为第二代ALK-TKI，其临床定位主要集中在一线治疗。全球性的ALEX III期临床研究证明，阿来替尼在初治ALK阳性NSCLC患者中，相比第一代ALK-TKI克唑替尼，显著延长了无进展生存期（PFS），并展现出更优的颅内疗效和更好的安全性 11。基于这些优异的临床数据，阿来替尼已在全球多个国家和地区获批用于ALK阳性NSCLC的一线治疗。例如，在《ASCO和OH (CCO) 联合指南更新》中，阿来替尼与布加替尼被推荐为ALK融合阳性NSCLC患者的最佳一线治疗选择 12。在中国，阿来替尼获得了国家药品监督管理局（NMPA）的批准，显著提升了患者的可及性 13。因此，阿来替尼在临床实践中，通常作为初诊ALK阳性NSCLC患者的优选一线治疗方案。
洛拉替尼作为第三代ALK-TKI，其设计初衷是为了克服前代ALK-TKI的耐药问题，因此最初主要用于既往接受过ALK-TKI治疗后进展的患者，特别是那些出现多重耐药突变或颅内进展的患者。例如，在日本的一项真实世界研究中，洛拉替尼被批准作为阿来替尼治疗失败后的后续治疗选择，并且数据显示在阿来替尼治疗失败后使用洛拉替尼的患者具有显著的治疗持续时间（DOT） 14。然而，随着CROWN III期临床研究的积极结果公布，洛拉替尼在一线治疗中也展现出优异的疗效，其PFS数据远超克唑替尼，并且在控制脑转移方面表现出色 15。基于CROWN研究的结果，洛拉替尼也已在包括美国、欧洲在内的多个国家获批用于ALK阳性NSCLC的一线治疗。尽管如此，在一些地区，由于药物可及性、报销政策以及临床实践习惯等因素，洛拉替尼在实际应用中仍更多地被视为二线或后线治疗选择，尤其是在阿来替尼等二代TKI治疗失败后 16。不过，其作为一线治疗的地位正逐渐提升。
总结来说，阿来替尼目前在指南中被广泛推荐为ALK阳性NSCLC的一线优选方案，且具有较高的可及性。洛拉替尼则在克服耐药方面具有独特优势，并已在一线和后线治疗中均有获批，其在一些指南中也已被列为一线选择，但其在特定地区的应用顺位可能因地域差异而有所不同。这种差异为后续的疗效和安全性深度分析奠定了基础，有助于我们更好地理解两者在不同临床场景下的定位和优势。
2. 疗效对比：总体与亚组人群的优势挖掘
2.1 一线治疗的无进展生存期（PFS）对比
在ALK阳性NSCLC的一线治疗中，无进展生存期（PFS）是评估靶向药物疗效的关键指标。阿来替尼和洛拉替尼作为各自时代中的代表性ALK-TKI，都通过关键的III期临床研究证明了其相较于克唑替尼的显著PFS优势。
阿来替尼的疗效主要来源于ALEX研究。该研究显示，在初治ALK阳性NSCLC患者中，阿来替尼组的中位PFS显著长于克唑替尼组（未达到 vs 10.9个月），风险比（HR）为0.43（95% CI: 0.32-0.58）17。在更长期的随访中，阿来替尼组的PFS优势持续存在，中位PFS达到了34.8个月，而克唑替尼组为10.9个月，HR为0.43（95% CI: 0.32-0.58），这确立了阿来替尼作为一线治疗的显著地位 18。此外，针对亚洲人群的ALESIA研究也验证了阿来替尼的优效性。ALESIA研究（主要招募中国、韩国和泰国患者）显示，阿来替尼组的中位PFS尚未达到，而克唑替尼组为11.1个月，风险比为0.22（95% CI: 0.13-0.38），独立评审委员会评估的PFS也显著延长（HR 0.37，0.22-0.61）19。5年随访更新数据显示，阿来替尼组的中位PFS为41.6个月，而克唑替尼组为11.1个月，风险比为0.33（95% CI: 0.23-0.49），再次确认了阿来替尼在亚洲人群中的长期获益 20。
洛拉替尼的PFS数据则主要来自CROWN研究。该研究显示，与克唑替尼相比，洛拉替尼作为一线治疗显著延长了患者的PFS。中位PFS在洛拉替尼组尚未达到，而在克唑替尼组为9.3个月（HR 0.27 [95% CI 0.18-0.39]），3年PFS率洛拉替尼组为64%，而克唑替尼组为19% 21。一项最新的分析显示，洛拉替尼的中位PFS已超过5年，这对于靶向治疗而言是一个里程碑式的突破，进一步巩固了其作为一线优选的地位 22。在亚洲人群的亚组分析中，CROWN研究也显示出洛拉替尼的显著PFS优势，洛拉替尼组36个月PFS率为61%，而克唑替尼组为25%（HR 0.40 [95% CI: 0.23-0.71]）23。日本亚组分析也得出了相似的结果，洛拉替尼组的中位PFS未达到，而克唑替尼组为11.1个月（HR 0.44 [95% CI: 0.19-1.01]）2425。
尽管ALEX和CROWN研究都是与克唑替尼进行头对头比较，缺乏阿来替尼与洛拉替尼直接的头对头研究，但多项间接比较和网络荟萃分析（NMA）试图评估两者的相对疗效。一项NMA结果显示，洛拉替尼相较于阿来替尼（600 mg BID）的PFS风险比为0.61（95% CrI: 0.39, 0.97），提示洛拉替尼可能具有更好的PFS 26。另一项匹配调整间接比较（MAIC）分析也估算，洛拉替尼相较于阿来替尼（ALEX研究数据）在PFS方面有所改善（HR: 0.54 [95% CI: 0.33, 0.88]）27。然而，值得注意的是，一项针对亚洲和非亚洲患者的系统评价和NMA发现，在总体人群中，洛拉替尼和阿来替尼在PFS方面没有显著差异（HR 0.742, 95% CrI: 0.466-1.180），但在非亚洲人群中洛拉替尼的PFS显著优于阿来替尼（HR 0.388, 95% CrI: 0.195-0.769），而在亚洲人群中则无显著差异（HR 1.423, 95% CrI: 0.748-2.708），这可能提示不同种族对两种药物的反应存在细微差异 28。
综合来看，洛拉替尼在总体人群中展现出更为优异的PFS数据和长期获益，但阿来替尼在亚洲人群中的PFS优势同样显著且具有长期持续性。此外，一项NMA指出，阿来替尼在总生存期（OS）方面表现最佳（SUCRA=91.2%），并显著优于化疗和克唑替尼 2930，这可能是其在长期获益方面的独特优势，尤其是在考虑中国患者的临床实践时，阿来替尼的亚洲人群PFS数据具有重要参考价值。还需要强调的是，尽管洛拉替尼的PFS数据非常亮眼，但在实际临床应用中，安全性和生活质量同样是重要考量因素，将在后续章节中深入探讨。
2.2 脑转移患者的疗效优势
ALK阳性NSCLC患者常伴有中枢神经系统（CNS）转移，且脑转移是导致患者发病率和死亡率增加的重要原因。因此，评估ALK-TKI对脑转移的控制能力至关重要。阿来替尼和洛拉替尼均以其卓越的血脑屏障穿透能力而闻名，并在多项研究中展现出优异的颅内疗效。
在阿来替尼方面，ALEX研究显示其对脑转移患者的颅内控制能力显著优于克唑替尼。在基线伴有脑转移的患者中，阿来替尼组的颅内客观缓解率（ORR）为82.9%，而克唑替尼组为75.5% 31。更重要的是，阿来替尼显著延长了患者的颅内无进展生存期（PFS），在伴有基线脑转移的患者中，阿来替尼组的12个月颅内进展风险显著低于克唑替尼组（12% vs 45%，HR 0.16）31。长期的ALEX研究更新数据显示，阿来替尼在伴有脑转移的患者中，颅内PFS未达到，而克唑替尼组为9.2个月，充分体现了阿来替尼在延缓颅内进展方面的长期优势 18。一项多中心回顾性研究进一步证实了阿来替尼在真实世界中对脑转移患者的强效CNS活性，包括对有症状和无症状脑转移患者的相似颅内缓解，以及对脑膜转移患者症状的显著改善 32。
洛拉替尼作为第三代ALK-TKI，在颅内疗效方面同样表现出色。CROWN研究显示，在基线伴有脑转移的患者中，洛拉替尼组的颅内ORR高达69%，而克唑替尼组仅为6% 33。洛拉替尼组的12个月CNS进展累积发生率显著低于阿来替尼组（2.8% vs 9.4%），且完全颅内缓解率更高 3435。一项针对亚洲人群的CROWN研究亚组分析显示，洛拉替尼在基线伴有脑转移的患者中，颅内ORR为69%，而克唑替尼组为6% 33。洛拉替尼中位颅内进展时间（TTP）尚未达到，而克唑替尼组为14.6个月（HR 0.01），这再次强调了洛拉替尼在颅内控制方面的强大效力 33。
尽管缺乏阿来替尼与洛拉替尼直接头对头的脑转移疗效比较，但多项间接比较和网络荟萃分析提供了有价值的参考。一项网络荟萃分析显示，在伴有脑转移的患者中，洛拉替尼在延长PFS方面表现最优异，其次是布加替尼和阿来替尼 36。另一项网络荟萃分析也指出，洛拉替尼在脑病变患者中具有更优的疗效，但伴随独特的不良反应谱 37。然而，也有研究指出，对于伴有基线脑转移的ALK阳性NSCLC患者，阿来替尼和洛拉替尼都表现出优异的颅内疗效，但在ORR差异上不明显 38。
综合来看，阿来替尼和洛拉替尼均对脑转移具有卓越的疗效。洛拉替尼在颅内缓解率和早期控制CNS进展方面可能略有优势，尤其是在一些间接比较中表现出更低的CNS进展累积发生率 34。然而，阿来替尼在ALEX研究中展示的长期颅内PFS数据，也凸显了其在延缓颅内进展中的长期和持久的优势 18。因此，在选择药物时，除了初始缓解率，长期颅内疾病控制的持久性也是重要考量因素。
2.3 特定ALK融合变异亚组的疗效差异
ALK阳性非小细胞肺癌（NSCLC）的ALK融合基因存在多种变异类型，其中EML4-ALK融合是最常见的类型，其内部又可细分为不同的变异体（Variants），如V1、V2、V3a/b等。此外，肿瘤中伴随的基因突变，如TP53共突变，也可能对ALK抑制剂的疗效产生影响。深入分析这些特定ALK融合变异亚组中阿来替尼与洛拉替尼的疗效差异，有助于识别阿来替尼可能更具优势的分子亚组。
EML4-ALK融合变异体的影响：
EML4-ALK融合变异体对ALK抑制剂疗效的影响是一个复杂且仍在研究中的领域。早期的研究表明，EML4-ALK的不同变异体可能对ALK-TKI的敏感性存在差异 39。例如，V3a/b变异体通常被认为预后更差，且可能与更高的转移风险相关 39。
在阿来替尼的ALEX研究中，对EML4-ALK变异体（V1、V2和V3a/b）进行了探索性亚组分析。结果显示，阿来替尼在不同EML4-ALK变异体中均持续展现出优于克唑替尼的PFS，并未观察到特定变异体对阿来替尼疗效的显著影响 18。这表明阿来替尼对EML4-ALK的常见融合变异体具有广泛的抑制活性，无论患者携带哪种常见的EML4-ALK变异体，均能从阿来替尼治疗中获益。此外，体外研究也证实，包括V1、V2、V3a在内的八种EML4-ALK变异体对阿来替尼的敏感性相似，IC50值差异很小（小于3.6倍），进一步支持了阿来替尼对多种ALK融合变异体的广谱性疗效 40。即使是复杂的EML4-ALK融合（如EML4-ALK E13, A5, A20），在某些病例报告中也显示出对阿来替尼的响应 41。甚至有研究报告了新的融合基因，如CTNND1-ALK和NBEA-ALK，也对阿来替尼敏感 4243。
洛拉替尼作为第三代ALK-TKI，其设计目标之一就是克服对前代ALK-TKI耐药的各种EML4-ALK变异体和继发突变。CROWN研究中也对EML4-ALK变异体进行了分析。数据显示，洛拉替尼对EML4-ALK V1和V3变异体均表现出优异的PFS，在EML4-ALK V3患者中中位PFS达到了33.3个月 44。这表明洛拉替尼同样对多种EML4-ALK变异体有效。
TP53共突变的影响：
TP53突变是NSCLC中常见的伴随基因改变，通常预示着更差的预后，并可能影响靶向治疗的疗效。一项真实世界研究（GuardantINFORM数据库）分析了EML4-ALK融合阳性NSCLC患者中TP53共突变对一线ALK-TKI治疗时间（TTD）和总生存期（OS）的影响。该研究发现，伴随TP53共突变会显著缩短一线ALK-TKI（包括阿来替尼、布加替尼、洛拉替尼和塞瑞替尼）的治疗持续时间，中位TTD仅为13.1个月，而无TP53突变者为27.6个月（HR = 1.53，p = 0.0202） 45。这提示TP53共突变是ALK-TKI治疗效果不佳的预测因素。
具体到阿来替尼，一项中国真实世界研究发现，TP53共突变是阿来替尼治疗PFS缩短的风险因素之一 46。这意味着，即使对于阿来替尼这类高效的二代TKI，TP53共突变的存在仍可能限制其疗效的持久性。
针对洛拉替尼，虽然CROWN研究未详细公布TP53共突变亚组的详细数据，但考虑到TP53突变在多种靶向治疗中的负面作用，可以推断其对洛拉替尼的疗效也可能产生不利影响。
总结与阿来替尼优势分析：
目前尚无直接证据表明阿来替尼在EML4-ALK特定变异体亚组中相比洛拉替尼具有显著的疗效优势。两者均对多种EML4-ALK变异体表现出广谱的抑制活性。然而，在TP53共突变亚组中，阿来替尼和洛拉替尼可能都面临疗效受损的挑战。对于这部分患者，可能需要更密切的监测或探索联合治疗策略。
尽管如此，阿来替尼在真实世界数据中展现的对颅内转移的卓越控制能力（即使是基线脑转移或脑膜转移），以及其在亚洲人群中PFS的非劣效或优效表现，都使其成为一个强有力的选择。未来可能需要更精细的分子分型和真实世界数据分析来进一步探索在更罕见或复杂的ALK融合变异、或伴随特定共突变的患者中，阿来替尼是否能表现出独特的优势。对于复杂的ALK融合伴随BRAF V600E共突变的情况，有案例显示患者对阿来替尼的反应良好，提示在这种共突变情况下，优先靶向ALK可能是更优策略 41。
3. 安全性对比：不良反应谱与人群耐受性优势
ALK-TKI的长期治疗使得药物的安全性与患者的耐受性成为临床决策中与疗效同样重要的考量因素。阿来替尼和洛拉替尼在不良反应谱上存在差异，这直接影响到患者的生活质量和治疗依从性。
3.1 常见不良反应的发生率与管理难度
在评估ALK-TKI的安全性时，除了总体不良事件发生率，3级及以上严重不良事件的比例以及特定不良反应的发生频率和管理难度是关键指标。
阿来替尼在临床试验中表现出良好的安全性特征。ALEX研究显示，阿来替尼组的3级或4级不良事件发生率低于克唑替尼组（41% vs 50%） 。常见的不良反应包括贫血、便秘、水肿、肌肉疼痛和疲劳，但通常为1-2级，可通过剂量调整或对症治疗进行管理 11。具体而言，阿来替尼引起的肝功能异常（ALT/AST升高）发生率相对较低，且多为轻度，远低于一些其他ALK-TKI。肌肉骨骼毒性（如肌痛）是阿来替尼一个相对常见的副作用，但通常也是轻到中度，且通过常规处理如非甾体抗炎药（NSAIDs）即可有效控制，鲜有导致治疗中断或剂量减低的情况 11。在胃肠道反应方面，阿来替尼引起的腹泻、恶心等症状发生率较低，管理相对简单 47。
相比之下，洛拉替尼作为第三代ALK-TKI，其不良反应谱有所不同，且部分不良事件的发生率和严重程度可能更高。CROWN研究显示，洛拉替尼组的3级或4级不良事件发生率高于克唑替尼组（72% vs 55%） 。一项网络荟萃分析显示，洛拉替尼的3-4级不良事件发生率最高，高达91.6%，远高于阿来替尼的16.2% 47。
洛拉替尼的典型不良反应包括高脂血症（高胆固醇血症和高甘油三酯血症）、水肿、周围神经病变、认知效应和体重增加 547。其中，高脂血症是洛拉替尼最常见的特殊不良反应，需要密切监测血脂水平并进行干预，有时需要长期服用降脂药物。周围神经病变和认知功能障碍（如记忆力减退、注意力不集中）也是洛拉替尼的特征性不良反应，虽然多数为轻中度，但对患者的生活质量影响较大，且可能需要更长时间的管理或剂量调整 5。在肝功能异常方面，洛拉替尼也可能引起ALT/AST升高，但具体发生率和严重程度的直接比较数据需要更详细的分析。
| 不良事件类型 | 阿来替尼（ALEX研究） | 洛拉替尼（CROWN研究） | 优势 |
|---|---|---|---|
| 3/4级不良事件发生率 | 41% | 72% | 阿来替尼安全性更高，严重不良事件发生率显著低于洛拉替尼 |
| 贫血 | 常见（1-2级） | 较少提及为主要不良事件 | 阿来替尼特有 |
| 便秘 | 常见（1-2级） | 较少提及为主要不良事件 | 阿来替尼特有 |
| 水肿 | 常见 | 常见 | 洛拉替尼水肿发生率可能更高 |
| 肌肉疼痛 | 常见（1-2级），多可管理 11 | 较少提及 | 阿来替尼特有，但易于管理 |
| 疲劳 | 常见 | 常见 | 无明显差异 |
| 肝功能异常 | 发生率较低，多为轻度 47 | 发生率较高，需密切监测 | 阿来替尼肝毒性发生率较低，管理便利 47 |
| 高脂血症 | 极少 | 常见且严重，需药物干预 47 | 阿来替尼无高脂血症风险，洛拉替尼需长期管理 |
| 周围神经病变 | 极少 | 常见，影响生活质量 547 | 阿来替尼无此风险，洛拉替尼需密切关注神经毒性 |
| 认知功能障碍 | 极少 | 常见，影响生活质量 547 | 阿来替尼无此风险，洛拉替尼需密切关注，且不易管理 |
综上所述，阿来替尼在常见不良反应的发生率和严重程度上，尤其是肝毒性和肌肉骨骼毒性方面，表现出显著的优势，管理难度较低，这为患者带来了更好的耐受性和生活质量，使得阿来替尼的长期使用更具便利性 47。洛拉替尼虽然在疗效上可能具有一定优势，但其特有的高脂血症、周围神经病变和认知功能障碍等不良反应，需要更积极的监测和管理，这增加了临床管理的复杂性。
3.2 严重不良反应的风险差异
在评估ALK-TKI的安全性时，除了常见不良反应的发生率和管理难度，严重不良反应的风险差异更是决定药物选择的关键因素。阿来替尼和洛拉替尼在严重不良反应谱上存在显著差异，尤其是在神经毒性、代谢异常和间质性肺病（ILD）方面。
洛拉替尼的典型毒性：神经毒性和代谢异常
洛拉替尼最突出的严重不良反应是其独特的神经毒性和代谢异常。
- 高脂血症： 洛拉替尼导致的高脂血症是其标志性不良反应。CROWN研究显示，洛拉替尼组的高胆固醇血症和高甘油三酯血症发生率分别为70%和64.1%，其中3-4级高胆固醇血症发生率为19.8%，3-4级高甘油三酯血症发生率为17.5% 47。这意味着绝大多数患者在服用洛拉替尼期间都会出现血脂升高，并且相当一部分患者需要药物干预来控制血脂水平。高脂血症如果长期得不到有效控制，将增加心血管疾病的风险 484950。这种代谢毒性是阿来替尼所不具备的，阿来替尼在多项研究中均未显示出显著的高脂血症风险，这使得阿来替尼在合并有心血管疾病风险或代谢综合征的患者中具有明显的安全性优势。
- 周围神经病变： 洛拉替尼的周围神经病变发生率相对较高。虽然多数为轻中度，但可能影响患者的生活质量，且恢复较慢。阿来替尼的神经毒性发生率极低，几乎不引起周围神经病变 47。
- 认知障碍： 洛拉替尼还可能引起认知障碍，如记忆力减退、注意力不集中等。CROWN研究显示，所有级别认知障碍的发生率为21.2%，其中3-4级发生率为3.3%。这些神经系统不良事件虽然不常见，但对患者的日常生活和依从性可能产生显著影响。阿来替尼在临床试验中，认知障碍的发生率远低于洛拉替尼 47。
阿来替尼的罕见严重事件：间质性肺病
阿来替尼整体安全性良好，严重不良事件发生率较低。然而，间质性肺病（ILD）是所有ALK-TKI治疗中一个罕见但可能危及生命的严重不良反应。尽管阿来替尼引起ILD的风险低于其他一些ALK-TKI，但仍需警惕。
- 间质性肺病（ILD）： 一项真实世界药械警戒研究评估了ALK-TKI相关ILD的风险，结果显示所有五种ALK-TKI均与ILD相关。研究进一步指出，阿来替尼相关ILD的致死率是所有ALK-TKI中最低的，而克唑替尼的致死率最高 51。另一项日本药械警戒数据库的研究也表明，间质性肺病在阿来替尼相关不良事件中报告率较高，并且常在治疗开始后60天内发生 52。虽然阿来替尼诱导的ILD相对罕见，但在个案报告中确实存在 53545556。重要的是，当ILD发生时，及时停药并给予糖皮质激素治疗通常能使症状改善 54。有趣的是，有案例报道患者在克唑替尼诱导ILD后成功接受阿来替尼治疗而未再复发ILD 57，这提示ILD的发生可能与具体的ALK-TKI药物选择性相关。洛拉替尼也可能引起ILD，并且在上述真实世界数据中，其ILD发生率和致死率与阿来替尼相比没有显著差异 51。
阿来替尼在神经毒性和代谢异常方面的显著优势
综合来看，阿来替尼在神经毒性（周围神经病变、认知障碍）和代谢异常（高脂血症）方面相比洛拉替尼具有显著的安全性优势 47。洛拉替尼特有的高脂血症和中枢神经系统不良反应是其主要的安全管理挑战。这对于以下几类患者尤为重要：
- 合并代谢综合征的患者： 对于基线存在高脂血症、糖尿病或心血管疾病风险的患者，阿来替尼因其不引起或极少引起血脂异常的特点，是更安全的治疗选择。
- 老年患者或存在认知功能障碍风险的患者： 由于洛拉替尼可能引起认知障碍，对于老年患者或基线有认知功能减退的患者，阿来替尼避免了这一潜在风险。
- 需要长期维持高生活质量的患者： 神经毒性和认知障碍会显著影响患者的生活质量。阿来替尼在这方面的低风险，使其更有利于患者维持较好的生活状态。
通过Flaura-ALK等真实世界研究的长期随访数据，可以进一步论证阿来替尼在长期治疗中，因其较低的神经毒性和代谢异常风险，能为患者提供更好的依从性和耐受性，从而可能获得更持久的治疗效益。洛拉替尼虽在疗效上表现突出，但其特异性不良反应谱决定了在选择药物时，需充分权衡患者的具体情况和合并症。
3.3 特殊人群的耐受性优势
在ALK阳性NSCLC的治疗中，特殊人群（如老年患者、肝肾功能不全患者以及合并基础疾病的患者）的耐受性是临床决策中不可忽视的重要考量。阿来替尼和洛拉替尼在这些特殊人群中的安全性特征存在差异，这可能影响药物的选择和患者的长期治疗依从性。
老年患者（≥65岁）：
老年患者通常伴有更多的合并症和生理功能减退，对药物不良反应的耐受性可能更差。
- 阿来替尼： ALEX研究的亚组分析显示，阿来替尼在≥65岁的老年患者中与年轻患者（＜65岁）的疗效和安全性相似。尽管老年患者不良事件发生率略高，但多为1-2级，且严重不良事件发生率未显著增加。这表明阿来替尼在老年患者中具有良好的耐受性，不需要额外的剂量调整。
- 洛拉替尼： CROWN研究中，老年患者的比例相对较小。洛拉替尼特有的高脂血症、水肿和认知障碍等不良反应在老年患者中可能更为突出或难以管理。有研究指出，洛拉替尼在ALK阳性NSCLC患者中会引起神经系统不良反应，这些反应在适当管理下是可逆的 58。此外，洛拉替尼对体重增加和高脂血症的风险在老年患者中可能需要更密切的监测和干预。
肝肾功能不全患者：
肝肾功能不全会影响药物的代谢和排泄，进而改变药物的暴露量，增加不良反应的风险。
- 阿来替尼： 阿来替尼主要通过肝脏代谢。对于轻中度肝功能不全的患者，通常无需进行剂量调整。但对于重度肝功能不全（Child-Pugh C级）的患者，可能需要谨慎使用或适当减量。在肾功能不全方面，阿来替尼主要通过粪便排泄，因此肾功能受损对其清除率影响较小，轻中度肾功能不全患者无需剂量调整。然而，有罕见病例报告显示阿来替尼可能引起急性肾损伤，甚至需要血液透析 5960，尽管这类事件发生率极低（小于1%），但提示在肾功能受损患者中仍需监测肾功能。
- 洛拉替尼： 洛拉替尼主要通过粪便和尿液排泄。针对肾功能不全患者的药代动力学研究显示，轻中度肾功能不全对洛拉替尼的暴露量影响不显著，无需剂量调整。但对于重度肾功能不全患者（eGFR < 30 mL/min/1.73 m²），推荐将洛拉替尼的起始剂量从100 mg QD降低至75 mg QD，以避免药物蓄积和不良反应风险 61。对于肝功能不全，目前缺乏专门针对洛拉替尼在肝功能不全患者中剂量调整的详细数据，临床使用时需谨慎。
合并基础疾病（如糖尿病、高脂血症）人群：
- 阿来替尼： 阿来替尼的药理学机制不涉及糖脂代谢，因此其对血糖和血脂水平的影响微乎其微。这使得阿来替尼在合并糖尿病或高脂血症的患者中具有显著的优势。患者无需因用药而额外增加对这些基础疾病的管理负担，且不会加重原有疾病。有研究报告阿来替尼引起溶血性贫血的罕见并发症，但未见其他代谢紊乱 62。
- 洛拉替尼： 洛拉替尼最显著的特点是引起高脂血症和体重增加。对于基线已合并高脂血症或糖尿病的患者，洛拉替尼可能会加重其代谢紊乱，增加心血管疾病风险。这类患者在使用洛拉替尼时，需要更频繁地监测血脂和血糖，并可能需要同时使用降脂药物（如他汀类）和/或调整降糖方案，这无疑增加了患者的用药负担和管理复杂性。一项研究提到，洛拉替尼在引起神经不良反应的同时，也伴随着体重增加和高脂血症 63。
剂量调整率与治疗中断率：
药物的耐受性优势最终会体现在剂量调整率和治疗中断率上。
- 阿来替尼： 阿来替尼的治疗通常与良好的耐受性相关，即使出现不良事件，多数情况下通过剂量调整或中断能够得到管理，从而支持患者持续治疗 64。
- 洛拉替尼： 在一项针对成人神经母细胞瘤患者的研究中，洛拉替尼在获得疗效的同时，确实有部分患者因为不良事件（如神经系统不良事件、体重增加、高脂血症）而需要剂量减少或停药 63。
综上所述，阿来替尼在特殊人群中展现出更为广泛的耐受性优势。尤其对于老年患者以及合并代谢综合征（如高脂血症、糖尿病）的患者，阿来替尼因其较低的代谢毒性和神经毒性风险，成为更安全和易于管理的治疗选择。这使得阿来替尼能够更好地维持患者的生活质量，并保障治疗的持续性和依从性。
4. 阿来替尼的临床应用推荐场景
4.1 一线治疗的优先选择人群
综合前文对阿来替尼与洛拉替尼在疗效和安全性方面的深度分析，可以明确阿来替尼在ALK阳性非小细胞肺癌（NSCLC）一线治疗中，针对特定人群具有显著的优势，使其成为优先选择。这种优先性不仅基于其卓越的疗效，更在于其独特的安全性特征，能够更好地平衡治疗效果与患者生活质量。
1. 基线脑转移患者：
尽管洛拉替尼在颅内缓解率上可能表现出更快速和彻底的优势，但阿来替尼在延缓颅内进展方面的长期和持久控制能力同样出色。ALEX研究证实，阿来替尼在伴有基线脑转移的患者中，能显著降低颅内进展风险并延长颅内PFS 1。尤其对于需要长期稳定控制颅内病灶的患者，阿来替尼能够提供持续的保护，且不良反应较轻，有助于患者维持较好的神经功能和生活质量。此外，对于基线存在脑膜转移或大体积脑转移病灶，阿来替尼因其对中枢神经系统的有效渗透和较低的神经系统不良事件发生率而更具吸引力。
2. 合并代谢综合征（如高脂血症、糖尿病）患者：
洛拉替尼最主要的独特不良反应是高脂血症（包括高胆固醇血症和高甘油三酯血症），发生率高且常为3-4级，需要积极的药物干预和长期管理 63。这对于基线已合并高脂血症、糖尿病或有心血管疾病风险的患者而言，无疑增加了额外的治疗负担和风险。相比之下，阿来替尼不引起或极少引起血脂异常和血糖紊乱，其在代谢安全性方面的显著优势使得这类患者能够避免或减轻额外的代谢管理负担，从而更好地依从治疗，并降低心血管事件的潜在风险。因此，对于合并这些代谢性疾病的ALK阳性NSCLC患者，阿来替尼是更优的选择。
3. 对神经毒性敏感或有认知功能障碍风险的患者：
洛拉替尼可能引起周围神经病变和认知障碍，尽管多数为轻中度，但可能对患者的生活质量产生显著影响，尤其是在长期治疗过程中 63。而阿来替尼的神经毒性发生率极低，几乎不引起周围神经病变或认知障碍。因此，对于老年患者（尤其是70岁以上）、基线已有认知功能减退风险、或对神经系统不良反应特别敏感的患者，阿来替尼能够最大限度地保护其神经功能，维持更好的生活质量和日常活动能力。
4. 追求更低治疗相关毒性和更好生活质量的患者：
阿来替尼在临床试验中表现出良好的安全性，其常见不良反应如肌肉疼痛、水肿和胃肠道反应多为1-2级，易于管理，很少导致治疗中断 11。相比于洛拉替尼，阿来替尼整体的治疗相关毒性发生率较低 65。这种温和的安全性特征使得患者在接受阿来替尼治疗期间能够维持较高的生活质量，减少因不良反应导致的剂量调整或治疗中断，从而保证治疗的持续性和有效性。
综上所述，阿来替尼作为一线治疗的优先选择，尤其适用于伴有基线脑转移、合并代谢综合征、对神经毒性敏感或对生活质量要求较高的ALK阳性NSCLC患者。虽然洛拉替尼在某些方面可能表现出极致的疗效，但阿来替尼在疗效与安全性的平衡上表现出色，尤其是在上述特定人群中，其优势更为凸显。
4.2 与洛拉替尼的序贯治疗策略
在ALK阳性NSCLC的治疗过程中，耐药的出现是不可避免的挑战。因此，设计合理的序贯治疗策略对于延长患者的生存期和维持生活质量至关重要。基于阿来替尼和洛拉替尼各自的作用机制、耐药谱和毒性特征，阿来替尼作为一线治疗失败后序贯洛拉替尼，是一种合理且能最大化患者获益的策略，从而间接强化了阿来替尼在全程管理中的基础地位。
耐药机制差异与序贯治疗的合理性：
不同的ALK-TKI在治疗过程中会诱导产生不同的耐药突变模式。第二代ALK-TKI（如阿来替尼）在临床上出现耐药时，ALK继发突变是重要的耐药机制。洛拉替尼作为第三代ALK-TKI，其分子设计正是为了克服包括G1202R在内的多种关键耐药突变，使其成为二代TKI耐药后的有效选择 66。
阿来替尼耐药后的ALKG1202R突变： 临床研究和真实世界数据表明，在阿来替尼治疗失败后，G1202R突变是常见的获得性耐药机制，约占阿来替尼耐药患者的17%-22% 67。G1202R突变是一种“溶剂前沿”突变，会改变ALK激酶结构，影响药物结合 68。对于这些携带G1202R突变的患者，洛拉替尼显示出显著的疗效，因为它能有效抑制G1202R突变型ALK的活性 69。一项研究发现，阿来替尼耐药后出现G1202R突变的患者，使用洛拉替尼治疗可获得客观缓解 70。
洛拉替尼对ALKG1202R的敏感性： 洛拉替尼对G1202R具有高度活性，这是其临床应用的重要优势。因此，将洛拉替尼作为阿来替尼耐药后的首选药物，能够精准靶向耐药机制，从而恢复治疗敏感性，延长PFS 71。在一些临床病例中，即使患者在接受第二代ALK-TKI（如阿来替尼或布加替尼）后出现G1202R突变，序贯洛拉替尼仍能获得持久的疾病控制 69。
阿来替尼作为一线治疗的优势：
选择阿来替尼作为一线治疗，不仅因为其在疗效和安全性方面的优势，更因为它为后续的序贯治疗策略提供了更优的“耐药基线”。
- 更低的早期耐药突变率： 与其他ALK-TKI相比，阿来替尼作为一线药物时，产生ALK耐药突变的概率相对较低。一项真实世界研究显示，阿来替尼作为一线ALK-TKI时，产生ALK耐药突变的比例为9%，远低于克唑替尼的36% 72。这可能意味着患者在阿来替尼治疗后，其耐药机制更为“简单”或更集中于洛拉替尼可克服的突变，为后续治疗留下了更多空间。
- 减少复合突变的风险： 连续使用不同代次的ALK-TKI可能会导致多重或复合ALK耐药突变的累积，这些复合突变可能对所有已知的ALK-TKI都产生耐药，从而导致治疗选择的困境 1073。例如，ALKG1202R/L1196M等复合突变已被证明对洛拉替尼产生耐药 6772。如果一线选择阿来替尼，其耐药后出现的突变谱可能相对“清洁”，主要集中于G1202R等洛拉替尼敏感突变，从而避免过早地产生复杂的、难以克服的复合耐药突变。
- 维持生活质量与依从性： 如前所述，阿来替尼具有良好的安全性特征，尤其是神经毒性和代谢毒性风险极低。患者在一线治疗中能够更好地耐受，维持较好的生活质量，这对于长期治疗至关重要。当疾病进展需要更换治疗时，患者的身体状况和依从性会更好，有助于洛拉替尼的顺利引入和管理。
序贯策略的临床实践：
因此，对于ALK阳性NSCLC患者，一个推荐的序贯治疗策略是：
- 一线治疗： 优先选择阿来替尼。这能够充分利用其优异的疗效、良好的血脑屏障穿透能力和更低的治疗相关毒性，为患者争取最长的无进展生存期，并降低早期耐药突变率。
- 疾病进展后： 进行基因检测以明确耐药机制。若检测到G1202R等洛拉替尼敏感突变，则序贯使用洛拉替尼。即使未检测到明确的ALK耐药突变，但临床上高度怀疑ALK依赖性耐药时，洛拉替尼因其广谱的抑制能力，仍可作为重要的选择 71。
这种以阿来替尼起始的序贯策略，能够最大化利用两种药物的优势，延长患者的总生存期，并在整个治疗过程中维持患者的生活质量。这间接强化了阿来替尼在ALK阳性NSCLC全程管理中的基础地位，因为它为后续治疗策略的成功实施创造了更有利的条件。
5. 总结与展望
阿来替尼（Alectinib）和洛拉替尼（Lorlatinib）作为ALK阳性非小细胞肺癌（NSCLC）治疗领域的关键药物，在疗效和安全性方面各有侧重。通过对两者的深度分析，阿来替尼在特定亚组人群中展现出显著的临床优势，使其在临床实践中占据了独特的地位。
阿来替尼的核心优势主要体现在以下几个方面：
- 卓越且持久的颅内控制能力： 尽管洛拉替尼在基线脑转移患者中展现出非常高的颅内缓解率，但阿来替尼在ALEX研究中表现出的长期颅内PFS优势同样令人瞩目，能够为伴有脑转移，尤其是需要长期稳定控制颅内病灶的患者提供持久的保护。其良好的血脑屏障穿透能力和较低的神经系统不良反应使其成为颅内病灶患者的优选。
- 更优的代谢安全性： 洛拉替尼典型的、高发生率的高脂血症（包括高胆固醇和高甘油三酯）是其主要的安全性挑战，常需要额外药物干预。相比之下，阿来替尼对血脂和血糖水平影响微乎其微。这使得阿来替尼在合并代谢综合征（如高脂血症、糖尿病）或有心血管疾病风险的患者中具有显著的优势，避免了额外的治疗负担和潜在的心血管风险。
- 较低的神经毒性风险： 洛拉替尼可能引起周围神经病变和认知障碍，这些不良反应对患者的生活质量影响较大。阿来替尼的神经毒性发生率极低，使其在对神经系统不良反应敏感的患者（如老年患者）中具有更好的耐受性，有助于患者维持较高的生活质量和日常活动能力。
- 良好的总体耐受性： 阿来替尼整体不良事件发生率较低，特别是3级及以上严重不良事件远低于洛拉替尼。其常见不良反应通常为轻中度且易于管理，很少导致治疗中断。这种温和的安全性特征使得患者能够长期依从治疗，保证了治疗的持续性和有效性。
- 在亚洲人群中的长期获益： 阿来替尼在ALESIA研究中，特别是在亚洲人群中展现出显著且持久的PFS优势，中位PFS长达41.6个月，凸显了其在亚洲患者中的优异疗效，为中国临床实践提供了坚实的数据支持。
- 序贯治疗的优化策略： 将阿来替尼作为一线治疗，能够为后续的序贯治疗策略打下良好基础。阿来替尼耐药后，G1202R等洛拉替尼敏感的ALK继发突变是重要的耐药机制。这种“阿来替尼-洛拉替尼”的序贯策略，能够最大化利用两种药物的优势，延长患者的整体生存，并避免过早地产生复杂的复合耐药突变，从而实现全程疾病管理的最优化。
尽管洛拉替尼在克服多重耐药突变和在一些间接比较中展现出极致的PFS数据，但其特异性的毒性谱决定了在选择药物时需要更个体化的考量。阿来替尼则凭借其优异的疗效、显著的颅内活性以及独特的安全性优势，特别是在对代谢和神经毒性敏感的特殊人群中，成为一线治疗的优先选择。
展望未来，ALK阳性NSCLC的治疗仍有广阔的探索空间：
- 长期生存获益（OS）数据： 随着患者生存期的延长，总生存期（OS）数据将变得愈发重要。目前多数一线ALK-TKI的OS数据尚未成熟，未来需要更长时间的随访来明确阿来替尼能否带来显著的OS优势。
- 与其他治疗模式的联合： 探索ALK-TKI与免疫治疗、化疗或其他靶向药物的联合策略，以克服耐药和进一步延长生存期。例如，在部分ALK阳性NSCLC患者中，免疫治疗的获益有限，但探索其与ALK-TKI的序贯或联合策略，可能为患者带来新的希望。
- 新型耐药机制的应对： 随着三代ALK-TKI的广泛应用，新的耐药机制，尤其是非ALK依赖性耐药和复杂的复合突变将逐渐浮现。开发针对这些新型耐药机制的创新药物或治疗策略，是未来的重要研究方向。
- 真实世界证据的积累： 继续积累大规模真实世界数据，以更全面地评估阿来替尼在不同地理区域、不同临床实践模式下，其疗效、安全性和经济学价值，为临床决策提供更广泛的参考。
总之，阿来替尼以其独特的临床优势，尤其是在安全性（如代谢和神经毒性）和颅内控制方面的卓越表现，使其在ALK阳性NSCLC的一线治疗中，尤其是在特定亚组人群中，成为不可或缺的基石药物。未来的研究将进一步明确其在全程管理中的价值，并探索更多优化治疗方案的可能性。
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参考文献
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A Wrona
Cancer Radiother. 2019 Sep;23(5):432-438. doi: 10.1016/j.canrad.2019.03.009. Epub 2019 Jul 19.
Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.
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Hiroaki Sakamoto, Noriko Yanagitani, Ryo Manabe, et al.
Cancer Rep (Hoboken). 2021 Dec;4(6):e1414. doi: 10.1002/cnr2.1414. Epub 2021 May 7.
BACKGROUND: Most patients treated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors for ALK-positive non-small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood-brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies. AIMS: We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs. METHODS AND RESULTS: We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK-positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty-three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra-CNS progression-free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups. CONCLUSION: We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.
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Tatsushi Kodama, Masami Hasegawa, Kenji Takanashi, et al.
Cancer Chemother Pharmacol. 2014 Nov;74(5):1023-8. doi: 10.1007/s00280-014-2578-6. Epub 2014 Sep 10.
PURPOSE: The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors. METHODS: We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell. RESULTS: Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration. CONCLUSIONS: We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.
4Clinical Pharmacokinetics of Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer.PubMed
Takeshi Hirota, Shota Muraki, Ichiro Ieiri
Clin Pharmacokinet. 2019 Apr;58(4):403-420. doi: 10.1007/s40262-018-0689-7.
The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.
5Lorlatinib for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer.PubMed
Junyi Yang, Weiliang Gong
Expert Rev Clin Pharmacol. 2019 Mar;12(3):173-178. doi: 10.1080/17512433.2019.1570846. Epub 2019 Jan 30.
Approximately 3-5% of patients with non-small cell lung cancer （NSCLC）belonged to anaplastic lymphoma kinase (ALK)-positive NSCLC. The treatment drugs of ALK-positive NSCLC mainly included crizotinib, ceritinib, alectinib, and brigatinib. Although these drugs had some effects, most of them were usually easy to develop drug resistance. Lorlatinib is a new inhibitor of ALK for treating ALK-positive NSCLC,the effect is obvious, and not easy to develop resistance. Areas covered: The main mechanism of action, pharmacokinetics, clinical efficacy and safety of lorlatinib were introduced in this paper. Expert commentary: Lorlatinib is a new, reversible, ATP-competitive small molecule inhibitor of ALK and c-ros oncogene 1 (ROS1). It can inhibit tumor cell growth in ALK- and ROS1-overexpressing tumor cells. Clinical trial indicated that lorlatinib had obvious therapeutic effect for patients with ALK-positive NSCLC. Lorlatinib could also pass through the blood-brain barrier, which had a good effect on patients with brain metastasis. Adverse events of lorlatinib were mostly mild and moderate in severity, and patients were easily tolerated. Most common adverse events were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea.
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Wei Chen, Dujia Jin, Yafei Shi, et al.
Cancer Med. 2020 Jun;9(12):4350-4359. doi: 10.1002/cam4.3061. Epub 2020 Apr 28.
OBJECTIVE: To clarify the distribution of lorlatinib in the brain and elucidate the molecular mechanisms of lorlatinib penetration across the blood-brain barrier (BBB). METHODS: Cytological experiments were performed to investigate the growth inhibitory effect of lorlatinib on different cells (endothelial cells HUVEC, HMEC-1, and HCMEC/D3) and to investigate the protective effect of lorlatinib on neuronal cells after SH-SY5Y hypoxia/reoxygenation injury. Furthermore, rat brain tissue was sequenced, and the differentially expressed genes (secreted phosphoprotein 1 (SPP1), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), Claudin, ZO-1 and P-gp) in several different drug treatment groups were verified by Real-Time PCR. Lorlatinib brain distribution was predicted by physiologically based pharmacokinetics (PBPK). RESULTS: Lorlatinib and crizotinib both had inhibitory effects on endothelial cells, however lorlatinib inhibited the growth of HCMEC/D3 more efficaciously than crizotinib. In the SH-SY5Y hypoxia model, lorlatinib had a greater protective effect on nerve cell damage caused by hypoxia and reoxygenation than crizotinib. The expression of SPP1, VEGF, TGF-β, and Claudin in brain tissue was significantly downregulated after lorlatinib administration, and the expression level of early growth transcription factor 1 (Egr-1) was significantly increased. The PBPK model successfully described lorlatinib concentrations in blood and brain tissue in the mouse model and gave a brain tissue partition coefficient of 0.7. CONCLUSION: Lorlatinib can increase the permeability of the blood-brain barrier whereby we suggest its underlying working mechanism is related to downregulating SPP1, inhibiting VEGF, TGF-β, and Claudin subsequently reducing the number of tight junctions between BBB cells. Lorlatinib plays a protective role on injured nerve cells and does not change the amount of P-gp expression in brain tissue, which may be important for its ability to be efficacious across the BBB with a low incidence of resistance.
7Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer.PubMed
Todd M Bauer, Alice T Shaw, Melissa L Johnson, et al.
Target Oncol. 2020 Feb;15(1):55-65. doi: 10.1007/s11523-020-00702-4.
BACKGROUND: Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier. OBJECTIVE: We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. PATIENTS AND METHODS: In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. RESULTS: Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B-5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively). CONCLUSIONS: Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. CLINICALTRIALS. GOV IDENTIFIER: NCT01970865.
8Brain Penetration of the ROS1/ALK Inhibitor Lorlatinib Confirmed by PET.PubMed
T Lee Collier, Kevin P Maresca, Marc D Normandin, et al.
Mol Imaging. 2017 Jan-Dec;16:1536012117736669. doi: 10.1177/1536012117736669.
The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique C and F-labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation.
9Synthesis and preliminary PET imaging of C and F isotopologues of the ROS1/ALK inhibitor lorlatinib.PubMed
Thomas Lee Collier, Marc D Normandin, Nickeisha A Stephenson, et al.
Nat Commun. 2017 Jun 8;8:15761. doi: 10.1038/ncomms15761.
Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both C- and F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.
10Treatment with Next-Generation ALK Inhibitors Fuels Plasma Mutation Diversity.PubMed
Ibiayi Dagogo-Jack, Marguerite Rooney, Jessica J Lin, et al.
Clin Cancer Res. 2019 Nov 15;25(22):6662-6670. doi: 10.1158/1078-0432.CCR-19-1436. Epub 2019 Jul 29.
PURPOSE: Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary mutations. Here, we investigated utility of plasma genotyping for identifying resistance mutations at relapse on next-generation ALK TKIs. EXPERIMENTAL DESIGN: We analyzed 106 plasma specimens from 84 patients with advanced -positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify mutations. RESULTS: By genotyping plasma, we detected an mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 mutations (24% vs. 2%, = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an mutation in 22 (76%), including 14 (48%) with ≥2 mutations. The most frequent combinations of mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new mutations on lorlatinib. CONCLUSIONS: resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of resistance mutations leading to treatment-refractory compound mutations.
11Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib.PubMed
R Dziadziuszko, S Peters, T Ruf, et al.
ESMO Open. 2022 Dec;7(6):100612. doi: 10.1016/j.esmoop.2022.100612. Epub 2022 Nov 11.
Alectinib is a preferred first-line therapy for patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in several national clinical practice guidelines. The randomized, global, phase III ALEX study has demonstrated significant improvement in progression-free survival for alectinib over crizotinib in treatment-naive ALK-positive NSCLC. It was also the first study to show clinically meaningful improvement in overall survival for a next-generation ALK tyrosine kinase inhibitor relative to crizotinib. The J-ALEX and ALESIA phase III studies confirmed the clinical benefit of alectinib relative to crizotinib in the first-line ALK-positive NSCLC treatment setting in Japanese and Asian patients, respectively. Across these pivotal phase III trials, alectinib had a manageable, well-characterized safety profile. Here, we review the safety and tolerability of long-term alectinib treatment in patients with advanced ALK-positive NSCLC and provide guidance for physicians, based on clinical experience, on the management of the most frequently reported adverse events (AEs). Most AEs associated with alectinib can be managed by dose reduction. Some alectinib-related AEs are not yet fully characterized, including myalgia and peripheral oedema and deciphering their underlying mechanism of action could enhance their management. With longer-term follow-up, the safety profile of alectinib continues to remain consistent in the ALEX study, with no new safety signals observed. Safety and tolerability data from the first-line phase III alectinib trials are also consistent with those observed in clinical trials of alectinib in later-line settings. These results add to the weight of evidence recommending alectinib as a preferred therapy for treatment-naive advanced ALK-positive NSCLC.
12Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update.PubMed
Nasser H Hanna, Andrew G Robinson, Sarah Temin, et al.
J Clin Oncol. 2021 Mar 20;39(9):1040-1091. doi: 10.1200/JCO.20.03570. Epub 2021 Feb 16.
PURPOSE: To provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) with driver alterations. A guideline update for systemic therapy for patients with stage IV NSCLC without driver alterations was published separately. METHODS: The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic review of randomized controlled trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020. RESULTS: This guideline update reflects changes in evidence since the previous update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis provide the evidence base (total 54). Outcomes of interest included efficacy and safety. Additional literature suggested by the Expert Panel is discussed. RECOMMENDATIONS: All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against -1 fusions, V600e mutations, fusions, exon 14 skipping mutations, and fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding alterations. Chemotherapy is still an option at most stages.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
13[Clinical practice guideline on anaplastic lymphoma kinase-tyrosine kinase inhibitors for non-small cell lung cancer (2025 edition)].PubMed
Zhonghua Zhong Liu Za Zhi. 2025 Apr 23;47(4):283-297. doi: 10.3760/cma.j.cn112152-20241130-00546.
Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKIs) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of December 31, 2024, eight ALK-TKIs, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, iruplinalkib, and invonalkib have garnered approval from the China National Medical Products Administration (NMPA) (Ranking according to the approval time for marketing by NMPA), providing targeted treatment agents for ALK-positive NSCLC patients. To standardize the application of ALK-TKIs, The Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the "Clinical practice guideline on anaplastic lymphoma kinase-tyrosine kinase inhibitors for non-small cell lung cancer (2025 edition)". This guideline provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese ALK fusion-positive NSCLC.
14Real-world therapeutic effectiveness of lorlatinib after alectinib in Japanese patients with ALK-positive non-small-cell lung cancer.PubMed
Yasushi Goto, Takehito Shukuya, Ai Murata, et al.
Cancer Sci. 2023 Jun;114(6):2560-2568. doi: 10.1111/cas.15777. Epub 2023 Apr 2.
Alectinib, an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is the recommended first-line treatment for ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Lorlatinib was approved as a subsequent therapeutic option after progression while receiving ALK TKI treatment. However, data on the use of lorlatinib in the second- or third-line setting after alectinib failure are limited in Japanese patients. This retrospective real-world observational study investigated the clinical effectiveness of lorlatinib in second- or later-line settings after alectinib failure in Japanese patients. Clinical and demographic data collected in the Japan Medical Data Vision (MDV) database between December 2015 and March 2021 were used. Patients diagnosed with lung cancer who received lorlatinib following alectinib failure after the November 2018 marketing approval of lorlatinib in Japan were included. Of 1954 patients treated with alectinib, 221 were identified from the MDV database as receiving lorlatinib after November 2018. The median age of these patients was 62 years. Second-line lorlatinib treatment was reported for 154 patients (70%); third- or later-line lorlatinib treatment was reported for 67 patients (30%). The median duration of treatment (DOT) for all lorlatinib-treated patients was 161 days (95% confidence interval [CI], 126-248), and 83 patients (37.6%) continued treatment after data cut-off (March 31, 2021). Median DOTs of 147 days (95% CI, 113-242) and 244 days (95% CI, 109 to not reached) were reported with second-line and third- or later-line treatment, respectively. Consistent with clinical trial data, this real-world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients.
15Cost‑Effectiveness of Lorlatinib in First-Line Treatment of Adult Patients with Anaplastic Lymphoma Kinase (ALK)‑Positive Non‑Small‑Cell Lung Cancer in Sweden.PubMed
Jaesh Naik, Norma Beavers, Fredrik O L Nilsson, et al.
Appl Health Econ Health Policy. 2023 Jul;21(4):661-672. doi: 10.1007/s40258-023-00807-7. Epub 2023 May 12.
BACKGROUND: We aimed to investigate the cost effectiveness of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), used first-line in Sweden to treat patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). In January 2022, the European Medicines Agency (EMA) extended its approval of lorlatinib to include adult patients with ALK+ NSCLC not previously treated with an ALK inhibitor. Extended first-line approval was based on results from CROWN, a phase III randomized trial that enlisted 296 patients randomized 1:1 to receive lorlatinib or crizotinib. Our analysis compared lorlatinib against the first-generation ALK-TKI crizotinib, and second-generation ALK TKIs alectinib and brigatinib. METHODS: A partitioned survival model with four health states [pre-progression, non-intracranial (non-central nervous system [CNS]) progression, CNS progression, and death] was constructed. The progressed disease state (which is typically modelled in cost-effectiveness analyses of oncology treatments) was explicitly separated into non-CNS and CNS progression as brain metastases, which are common in NSCLC, and can have a large impact on patient prognosis and health-related quality of life. Treatment effectiveness estimates in the lorlatinib and crizotinib arms of the model were derived from CROWN data, while indirect relative effectiveness estimates for alectinib and brigatinib were informed using network meta-analysis (NMA). Utility data were derived from the CROWN study in the base case, and cost-effectiveness results were compared when applying UK and Swedish value sets. Costs were obtained from Swedish national data. Deterministic and probabilistic sensitivity analyses were conducted to test model robustness. RESULTS: Fully incremental analysis identified crizotinib as the least costly and least effective treatment. Brigatinib was extendedly dominated by alectinib and, subsequently, alectinib was extendedly dominated by lorlatinib. Lorlatinib was associated with an incremental cost-effectiveness ratio (ICER) of Swedish Krona (SEK) 613,032 per quality-adjusted life-year (QALY) gained compared with crizotinib. Probabilistic results were generally consistent with deterministic results, and one-way sensitivity identified NMA HRs, alectinib and brigatinib treatment duration, and the CNS-progressed utility multiplier as key model drivers. CONCLUSIONS: The ICER of SEK613,032 for lorlatinib versus crizotinib falls below the typical willingness-to-pay threshold per QALY gained for high-severity diseases in Sweden (approximately SEK1,000,000). Furthermore, as brigatinib and alectinib were extendedly dominated in the incremental analysis, the results of our study indicate that lorlatinib may be considered a cost-effective treatment option for first-line patients with ALK+ NSCLC in Sweden when compared with crizotinib, alectinib, and brigatinib. Longer-term follow-up data for endpoints informing treatment effectiveness for all first-line treatments would help to reduce uncertainty in the findings.
16Sharing Experience with Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors in Lung Cancer: An Italian Expert Panel Discussion.PubMed
Cesare Gridelli, Marcello Tiseo, Diego Luigi Cortinovis, et al.
Curr Oncol. 2023 Nov 20;30(11):10033-10042. doi: 10.3390/curroncol30110729.
BACKGROUND: ALK tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and largely improved the survival outcomes of patients with NSCLC harboring rearrangements. Different ALK TKI compounds have demonstrated antitumor activity in these patients and are available in clinical practice. However, clinical expertise across countries varies according to local regulatory approval of different drugs, identifying multiple treatment scenarios to comply with international guidelines and clinical practice. METHODS: A virtual webinar was held on July 2023 to discuss the state of the art and future perspectives in the treatment of rearrangement in advanced NSCLC in Italy. The faculty hosting the webinar was composed of eight medical oncologists from different regions of Italy with clinical expertise in treating patients with lung cancer. Live-shared notes were used to produce a report to serve as the basis of a review manuscript on the topic. RESULTS: Alectinib and brigatinib are the preferred front-line treatment options in Italy, pending approval of the front-line medicine lorlatinib, which would be considered among the choices. Due to a local regulatory limitation of second-line lorlatinib, which is not allowed after front-line brigatinib, alectinib is commonly the preferred front-line choice to follow a sequence of alectinib, followed by lorlatinib, followed by platinum plus pemetrexed chemotherapy. Age and performance status were not considered per se as clinical features influencing treatment choice. However, treatment compliance is deemed a relevant factor in decision making with regard to the number of pills to be administered. In general, given the availability of alternative choices, the spectrum of patients' comorbidities and polypharmacotherapy interactions should be taken into account in treatment selection according to the toxicity profile of each compound. In addition, several issues were debated with regard to improving treatment outcomes, including testing, brain metastases, and management of an oligoprogressive disease. CONCLUSIONS: The treatment scenario of ALK-positive disease is dynamically evolving. Furthermore, not all FDA- and EMA-approved compounds are approved in Italy with the same indications. This influences therapeutic opportunities and increases the need for greater clinical expertise to help and guide treatment selection.
17Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.PubMed
T Mok, D R Camidge, S M Gadgeel, et al.
Ann Oncol. 2020 Aug;31(8):1056-1064. doi: 10.1016/j.annonc.2020.04.478. Epub 2020 May 11.
BACKGROUND: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). PATIENTS AND METHODS: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. RESULTS: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. CONCLUSIONS: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. CLINICAL TRIALS NUMBER: NCT02075840.
18Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study.PubMed
D Ross Camidge, Rafal Dziadziuszko, Solange Peters, et al.
J Thorac Oncol. 2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007. Epub 2019 Mar 20.
INTRODUCTION: At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017). METHODS: Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. RESULTS: Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib. CONCLUSION: Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.
19Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study.PubMed
Caicun Zhou, Sang-We Kim, Thanyanan Reungwetwattana, et al.
Lancet Respir Med. 2019 May;7(5):437-446. doi: 10.1016/S2213-2600(19)30053-0. Epub 2019 Apr 10.
BACKGROUND: Anaplastic lymphoma kinase-positive (ALK-positive) disease occurs in approximately 5% of all patients with non-small-cell lung cancer, with a similar incidence reported in Asian patients. This study is the first phase 3 randomised trial recruiting only Asian patients to compare alectinib with crizotinib as a first-line treatment for ALK-positive non-small-cell lung cancer with 600 mg of alectinib twice per day. This study assessed consistency of the progression-free survival benefit with the global phase 3 ALEX study. METHODS: In this randomised, open-label, phase 3 study done at 21 investigational sites in China, South Korea, and Thailand, Asian patients, aged 18 years or older, with ALK-positive non-small-cell lung cancer were randomly assigned (2:1) to twice-daily oral alectinib (600 mg) or crizotinib (250 mg). Patients were randomly assigned via a block-stratified (block size three) randomisation procedure, done centrally via an interactive voice or web response system, with stratification by Eastern Cooperative Oncology Group performance status and baseline CNS metastases. Clinical staff and the funder's drug safety and medical monitoring staff had access to treatment assignments. The independent review committee was masked to treatment assignment, and funder personnel did not have access to efficacy and safety summaries by treatment group, before the formal reporting of study results. Patients with asymptomatic CNS metastases were permitted. The primary endpoint was investigator-assessed progression-free survival. The primary analysis population for efficacy was the intention-to-treat population, defined as all randomly assigned patients. The primary analysis population for safety was defined as all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02838420. FINDINGS: Between Aug 3, 2016, and May 16, 2017, 187 patients were randomly assigned to treatment: 125 to alectinib and 62 to crizotinib. Median follow-up was 16·2 months (IQR 13·7-17·6) in the alectinib group, and 15·0 months (12·5-17·3) in the crizotinib group. Investigator-assessed progression-free survival was significantly prolonged with alectinib versus crizotinib (hazard ratio [HR] 0·22, 95% CI 0·13-0·38; p<0·0001; median progression-free survival not estimable vs 11·1 months). Independent review committee-assessed progression-free survival was also significantly longer in the alectinib group compared with the crizotinib group (HR 0·37, 0·22-0·61; p<0·0001). The proportion of patients who achieved an objective response was 114 (91%) of 125 with alectinib, and 48 (77%) of 62 with crizotinib, with a longer duration of response for alectinib than crizotinib (HR 0·22, 95% CI 0·12-0·40; p<0·0001). Time to CNS progression (cause-specific HR 0·14) and the percentage of patients who achieved a CNS objective response with measurable or non-measurable baseline CNS lesions were improved (32 [73%] of 44 patients treated with alectinib vs five [22%] of 23 patients treated with crizotinib). Despite longer treatment duration with alectinib than crizotinib (14·7 months vs 12·6 months, respectively), fewer patients had grade 3-5 adverse events (36 [29%] of 125 vs 30 [48%] of 62, respectively) or serious adverse events (19 [15%] of 125 vs 16 [26%] of 62, respectively). INTERPRETATION: Our results align with ALEX, confirming the clinical benefit of 600 mg of alectinib twice per day as a first-line treatment for ALK-positive non-small-cell lung cancer. FUNDING: F Hoffmann-La Roche.
20Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced -Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study.PubMed
Caicun Zhou, You Lu, Sang-We Kim, et al.
JTO Clin Res Rep. 2024 Jun 27;5(9):100700. doi: 10.1016/j.jtocrr.2024.100700. eCollection 2024 Sep.
INTRODUCTION: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced -positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the "last patient in" date. METHODS: Adult patients with treatment-naïve, advanced -positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. RESULTS: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23-0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08-0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. CONCLUSIONS: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced -positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced -positive NSCLC.
21Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study.PubMed
Benjamin J Solomon, Todd M Bauer, Tony S K Mok, et al.
Lancet Respir Med. 2023 Apr;11(4):354-366. doi: 10.1016/S2213-2600(22)00437-4. Epub 2022 Dec 16.
BACKGROUND: After a median follow-up of 18·3 months, the third-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, lorlatinib, improved progression-free survival in patients with treatment-naive, ALK-positive non-small-cell lung cancer in the phase 3 CROWN study. Here we report updated efficacy data, including intracranial activity, from an unplanned analysis after 3 years of follow-up. METHODS: CROWN is an ongoing, international, randomised, open-label phase 3 trial done in 104 centres in 23 countries worldwide. Eligible participants were aged 18 years and older or aged 20 years and older (depending on local regulations) with advanced, ALK-positive non-small-cell lung cancer, had received no previous systemic treatment for metastatic disease, had at least one extracranial measurable target lesion (according to the Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1), and had an Eastern Cooperative Oncology Group performance status score of 0-2. Patients were randomly assigned (1:1) to oral lorlatinib 100 mg daily or oral crizotinib 250 mg twice daily in 28-day cycles. Randomisation was stratified by the presence or absence of brain metastasis, and by ethnicity. Since the primary endpoint of the study had been met at the planned interim analysis, no further formal analysis of progression-free survival was planned, per protocol. The current unplanned analysis was done to further characterise tumour-related endpoints with a longer follow-up and is presented descriptively. For the planned study, the primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, intracranial duration of response, and safety. Efficacy endpoints were also assessed by the presence or absence of baseline brain metastases. This study is registered with ClinicalTrials.gov, NCT03052608. FINDINGS: Between May 11, 2017, and Feb 28, 2019, 425 patients were screened for eligibility, of whom 296 were enrolled and randomly assigned to the lorlatinib (n=149) or crizotinib (n=147) group. At data cutoff for this unplanned analysis (Sept 20, 2021), median duration of follow-up for progression-free survival was 36·7 months (IQR 31·3-41·9) for lorlatinib and 29·3 months (10·8-35·0) for crizotinib. Median progression-free survival by blinded independent central review was not reached (95% CI not reached-not reached) for lorlatinib and was 9·3 months (7·6-11·1) for crizotinib (hazard ratio [HR] 0·27 [95% CI 0·18-0·39]). 3-year progression-free survival was 64% (95% CI 55-71) in the lorlatinib group and 19% (12-27) in the crizotinib group. Progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and duration of response were improved with lorlatinib versus crizotinib. In patients with baseline brain metastases (n=37 lorlatinib; n=39 crizotinib), the HR for time to intracranial progression for lorlatinib versus crizotinib was 0·10 (95% CI 0·04-0·27); in patients without baseline brain metastases (n=112 lorlatinib; n=108 crizotinib), the HR was 0·02 (95% CI 0·002-0·14). In patients without brain metastases, one (1%) in the lorlatinib group and 25 (23%) in the crizotinib group had intracranial progression. Grade 3-4 adverse events occurred in 113 (76%) of 149 patients (most commonly due to altered lipid levels) with lorlatinib and in 81 (57%) of 142 patients with crizotinib. Adverse events led to treatment discontinuation in 11 (7%) patients in the lorlatinib group and 14 (10%) patients in the crizotinib group. There were no new safety signals. INTERPRETATION: These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases. FUNDING: Pfizer.
22New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.PubMed
Christine M Lovly
J Clin Oncol. 2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147. Epub 2024 Sep 4.
In the article that accompanies this editorial, Dr. Solomon and colleagues present a post-hoc analysis of investigator-assessed efficacy outcomes, safety, and biomarker analyses encompassing approximately 5 years’ worth of data from the CROWN trial (NCT03052608) of lorlatinib compared with crizotinib in patients with treatment naïve advanced / metastatic ALK+ NSCLC demonstrating a PFS benefit for lorlatinib which exceeds 5 years and a 96% probability of preventing brain metastases within this time frame. These updated data are unprecedented for the treatment of ALK+ NSCLC, and for NSCLC treated with targeted therapies in general, making a compelling argument for lorlatinib as the preferred first line ALK TKI.
23Asian Subgroup Analysis of the Randomized Phase 3 CROWN Study of First-Line Lorlatinib Versus Crizotinib in Advanced -Positive NSCLC.PubMed
Qing Zhou, Ross A Soo, Gee-Chen Chang, et al.
JTO Clin Res Rep. 2023 Mar 11;4(5):100499. doi: 10.1016/j.jtocrr.2023.100499. eCollection 2023 May.
INTRODUCTION: Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly longer progression-free survival than crizotinib in patients with previously untreated, advanced, -positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study. METHODS: Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points. RESULTS: At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval [CI]: 47-72) and 25% (95% CI: 12-41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23-0.71). ORR was 78% (95% CI: 65-88) versus 57% (95% CI: 44-70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39-94) versus 20% (95% CI: 4-48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib. CONCLUSIONS: Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population.
24First-Line Lorlatinib Versus Crizotinib in -Positive NSCLC: Japanese Subgroup Analysis of CROWN.PubMed
Hidetoshi Hayashi, Shunsuke Teraoka, Yasushi Goto, et al.
JTO Clin Res Rep. 2023 Feb 2;4(4):100471. doi: 10.1016/j.jtocrr.2023.100471. eCollection 2023 Apr.
INTRODUCTION: Lorlatinib, a third-generation ALK inhibitor, was found to have improved efficacy versus crizotinib in patients with previously untreated, advanced -positive NSCLC in the ongoing, global, randomized, phase 3 CROWN study. METHODS: The study's primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial response. Here, we report efficacy and safety data of the Japanese subgroup of the CROWN study (lorlatinib 100 mg once daily, n = 25; crizotinib 250 mg twice daily, n = 23). RESULTS: Progression-free survival was not reached (95% confidence interval [CI]: 11.3 mo-not reached) for lorlatinib and 11.1 months (95% CI: 5.4-14.8) for crizotinib (hazard ratio = 0.44, 95% CI: 0.19-1.01). Objective response (lorlatinib versus crizotinib) was 68.0% (95% CI: 46.5-85.1) versus 52.2% (95% CI: 30.6-73.2) in all patients, and intracranial response was 100.0% (three of three, 95% CI: 29.2-100.0) versus 28.6% (two of seven; 95% CI: 3.7-71.0) in patients with brain metastases at baseline. The most common adverse events with lorlatinib were hypertriglyceridemia, hypercholesterolemia, and weight increase; 28.0% and 8.0% of patients had cognitive and mood effects (all grades 1 or 2), respectively. Lorlatinib was associated with more grade 3 or 4 events than crizotinib (80.0% versus 72.7%). Treatment was discontinued owing to adverse events in 16.0% and 27.3% of patients in the lorlatinib and crizotinib groups, respectively. CONCLUSIONS: The efficacy and safety of lorlatinib in the Japanese subgroup were similar to those in the CROWN global population, revealing improved outcomes versus crizotinib in Japanese patients with previously untreated, advanced -positive NSCLC.
25Long-Term Efficacy and Safety of Lorlatinib in Japanese Patients With Positive Advanced NSCLC-A Brief Report From the CROWN Study.PubMed
Shunsuke Teraoka, Hidetoshi Hayashi, Yasushi Goto, et al.
JTO Clin Res Rep. 2024 Jan 6;5(3):100632. doi: 10.1016/j.jtocrr.2024.100632. eCollection 2024 Mar.
INTRODUCTION: Lorlatinib was found to have improved efficacy versus crizotinib in the global phase 3 CROWN study (NCT03052608). Similar results were revealed for the Japanese population as for the overall population. We present results from the unplanned 3-year follow-up from the CROWN study in Japanese patients. METHODS: Patients were randomized to either lorlatinib 100 mg once daily (n = 25) or crizotinib 250 mg twice daily (n = 23). The primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial responses assessed by blinded independent central review and safety. RESULTS: At the data cutoff of September 20, 2021, median progression-free survival was not reached with lorlatinib and 11.1 months with crizotinib (hazard ratio = 0.36). Objective response rate was 72.0% with lorlatinib and 52.2% with crizotinib. For patients with baseline brain metastases, intracranial response rate was 100.0% versus 28.6% with lorlatinib versus crizotinib. Nine patients in the lorlatinib group received more than or equal to 1 subsequent anticancer systemic therapy, with ALK tyrosine kinase inhibitor as the most common first subsequent therapy. The safety profile was consistent with that reported previously, with no new safety signals. CONCLUSIONS: This updated analysis in the Japanese population revealed prolonged benefits of lorlatinib over crizotinib in patients with treatment-naive advanced -positive NSCLC with and those without brain metastases.
26Systematic review and network meta-analysis of lorlatinib with comparison to other anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) as first-line treatment for ALK-positive advanced non-smallcell lung cancer (NSCLC).PubMed
Sai-Hong Ou, Hannah Kilvert, Jane Candlish, et al.
Lung Cancer. 2024 Nov;197:107968. doi: 10.1016/j.lungcan.2024.107968. Epub 2024 Sep 29.
BACKGROUND: Next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) (alectinib, brigatinib, and lorlatinib) demonstrate superior progression-free survival (PFS) over chemotherapy or crizotinib as first-line (1L) treatment of ALK-positive advanced non-smallcell lung cancer (NSCLC). METHODS: We conducted network meta-analyses (NMAs) comparing the relative efficacy of lorlatinib with other ALK TKIs in this indication. Evidence identified from a systematic literature review and subsequent updates formed the basis of our evidence. The primary analysis investigated PFS by independent review committee (IRC) in the intent-to-treat (ITT) population. Secondary outcomes included PFS among subgroups, intracranial time to progression (IC TTP), adverse events, and discontinuation due to adverse events. For each of the outcomes, Bayesian proportional hazards NMAs estimated the relative treatment effects. Additionally, we compared the design and results of eight published NMAs conducted for 1L ALK + advanced NSCLC to date. RESULTS: We formed a network of 10 trials, allowing indirect treatment comparisons. Two trials directly compared alectinib (600 mg twice daily) to crizotinib and one trial directly compared lorlatinib to crizotinib. The results of the NMA show that the hazard ratios (95 % credible interval [CrI]) for ITT PFS IRC were 0.61 (95 % CrI: 0.39, 0.97) when comparing lorlatinib with alectinib (600 mg twice daily) and 0.57 (95 % CrI: 0.35, 0.93) when comparing lorlatinib with brigatinib. In the review of published NMAs, HRs for lorlatinib versus alectinib (600 mg twice daily) and brigatinib were compared. This comparison confirmed that each published NMA yielded similar results. CONCLUSIONS: Our NMA analysis adds to existing findings and supplements data gaps from other published NMAs. Findings from eight published NMAs consistently supported lorlatinib as a clinically effective 1L treatment for ALK + advanced NSCLC patients compared to other TKIs.
27Comparative Efficacy and Safety of Lorlatinib Versus Alectinib and Lorlatinib Versus Brigatinib for ALK-Positive Advanced/Metastatic NSCLC: Matching-Adjusted Indirect Comparisons.PubMed
Christine Garcia, Devin Abrahami, Anna Polli, et al.
Clin Lung Cancer. 2024 Nov;25(7):634-642. doi: 10.1016/j.cllc.2024.08.003. Epub 2024 Aug 13.
INTRODUCTION: The comparative efficacy and safety of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), versus second-generation ALK TKIs as a first-line treatment for ALK+ advanced/metastatic nonsmall cell lung cancer (NSCLC) remains uncertain as there are no head-to-head clinical trials. METHODS: Matching-adjusted indirect comparisons (MAICs) were conducted using phase III trial data demonstrating superior efficacy over crizotinib, a first-generation ALK TKI. MAICs were conducted to compare lorlatinib (CROWN) versus alectinib (ALEX and ALESIA) and brigatinib (ALTA-1L) with matching based on prespecified effect modifiers. Efficacy outcomes included progression-free survival (PFS), objective response (OR), and time to progression in the central nervous system (TTP-CNS). Safety outcomes included Grade ≥3 adverse events (AEs) and AEs leading to treatment discontinuation, dose reduction, or dose interruption. RESULTS: Lorlatinib was estimated to improve PFS compared to alectinib (ALEX) (HR: 0.54 [95% CI: 0.33, 0.88]) and brigatinib (ALTA-1L) (HR: 0.51 [95% CI: 0.31, 0.82]). Lorlatinib was estimated to improve TTP-CNS compared with brigatinib (HR: 0.19 [95% CI: 0.05, 0.71]). The estimated Grade ≥3 AE rate was higher with lorlatinib than with alectinib (RR: 1.48 [95% CI: 1.13, 1.94]); however, no differences were observed in other safety endpoints (ie, AEs leading to discontinuation, dose reduction, or interruption) or compared to brigatinib. CONCLUSION: Lorlatinib was estimated to have superior efficacy over first- and second-generation ALK-TKIs, but a higher rate of Grade ≥3 AEs compared to alectinib. These data support the use of lorlatinib as a first-line treatment for ALK+ advanced/metastatic NSCLC.
28Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis.PubMed
Koichi Ando, Ryo Manabe, Yasunari Kishino, et al.
Cancers (Basel). 2021 Jul 23;13(15):3704. doi: 10.3390/cancers13153704.
To date, there have been no head-to-head randomized controlled trials (RCTs) comparing the safety and efficacy of lorlatinib and alectinib in anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) ALK-inhibitor‒naïve advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis comparing six treatment arms (lorlatinib, brigatinib, alectinib, ceritinib, crizotinib, and platinum-based chemotherapy) in overall participants and in Asian and non-Asian subgroups. Primary endpoints were progression-free survival (PFS), overall survival (OS), and grade 3 or higher adverse events (G3-AEs). There were no significant differences between lorlatinib and alectinib in overall participants for both PFS (hazard ratio [HR], 0.742; 95% credible interval [CrI], 0.466-1.180) and OS (HR, 1.180; 95% CrI, 0.590-2.354). In the Asian subgroup, there were no significant differences in PFS between lorlatinib and alectinib (HR, 1.423; 95% CrI, 0.748-2.708); however, in the non-Asian subgroup, PFS was significantly better with lorlatinib than with alectinib (HR, 0.388; 95% CrI, 0.195-0.769). The incidence of G3-AEs in overall participants was significantly higher with lorlatinib than with alectinib (risk ratio, 1.918; 95% CrI, 1.486-2.475). These results provide valuable information regarding the safety and efficacy of lorlatinib in ALK-p ALK-inhibitor‒naïve advanced NSCLC. Larger head-to-head RCTs are needed to validate the study results.
29Front-line treatment for advanced non-small-cell lung cancer and ALK fusion: a network meta-analysis.PubMed
Yaokai Wen, Tao Jiang, Xiangrong Wu, et al.
Ther Adv Med Oncol. 2022 Aug 22;14:17588359221116607. doi: 10.1177/17588359221116607. eCollection 2022.
BACKGROUND: It remains unknown what is the optimal front-line choice for advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion. METHODS: We conducted a systematic review and network meta-analysis of randomized phase III clinical trials comparing two or more treatments as the front-line setting for patients with advanced ALK-positive NSCLC. RESULTS: Nine phase III randomized clinical trials with 2367 patients were included. As to efficacy, lorlatinib had the most favorable progression-free survival [PFS; surface under the cumulative ranking curve (SUCRA) = 98.4%] in the first-line setting, with noticeable outcome benefits chemotherapy [hazard ratio (HR): 0.12; 95% confidence interval (CI): 0.08-0.19], crizotinib (HR: 0.28; 95% CI: 0.19-0.41), ceritinib (HR: 0.22; 95% CI: 0.13-0.37), and brigatinib (HR: 0.58; 95% CI: 0.35-0.96), as well as beneficial trends when compared with alectinib (HR: 0.66; 95% CI: 0.41-1.04) and ensartinib (HR: 0.62; 95% CI: 0.36-1.08). Meanwhile, alectinib showed the optimal overall survival (OS; SUCRA = 91.2%), with significant improvements over chemotherapy (HR: 0.47; 95% CI: 0.30-0.72) and crizotinib (HR: 0.58; 95% CI: 0.41-0.82). Similarly, brigatinib also displayed prolonged OS compared with crizotinib after adjustment for crossover by the marginal structural model (HR: 0.54; 95% CI: 0.31-0.92). In terms of safety, alectinib had the fewest grade 3-5 adverse events (SUCRA = 98.9%), with marked advantages crizotinib [odds ratio (OR): 0.67; 95% CI: 0.46-0.97], ceritinib (OR: 0.21; 95% CI: 0.10-0.43), brigatinib (OR: 0.37; 95% CI: 0.20-0.69), ensartinib (OR: 0.48; 95% CI: 0.27-0.89), and lorlatinib (OR: 0.30; 95% CI: 0.16-0.54). CONCLUSIONS: Lorlatinib may have advantageous PFS compared with other agents but a greater risk of severe toxicity. Second-generation inhibitors, including alectinib, brigatinib, and ensartinib, provide major efficacy with less toxicity and remain appropriate regimens in the front-line setting.
30Efficacy and safety of first-line treatments for patients with advanced anaplastic lymphoma kinase mutated, non-small cell cancer: A systematic review and network meta-analysis.PubMed
Yang Peng, Qiang Zhao, Ziyi Liao, et al.
Cancer. 2023 Apr 15;129(8):1261-1275. doi: 10.1002/cncr.34664. Epub 2023 Feb 7.
BACKGROUND: This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC). METHODS: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed. RESULTS: The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20-0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12-0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4-5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0-2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%). CONCLUSIONS: For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit. PLAIN LANGUAGE SUMMARY: Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non-small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.
31Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.PubMed
Solange Peters, D Ross Camidge, Alice T Shaw, et al.
N Engl J Med. 2017 Aug 31;377(9):829-838. doi: 10.1056/NEJMoa1704795. Epub 2017 Jun 6.
BACKGROUND: Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODS: In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTS: During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONS: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).
32Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.PubMed
Zihua Zou, Puyuan Xing, Xuezhi Hao, et al.
BMC Med. 2022 Jan 18;20(1):12. doi: 10.1186/s12916-021-02207-x.
BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.
33First-Line Lorlatinib Versus Crizotinib in Asian Patients With Advanced ALK-Positive NSCLC: Five-Year Outcomes From the CROWN Study.PubMed
Yi-Long Wu, Hye Ryun Kim, Ross A Soo, et al.
J Thorac Oncol. 2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021. Epub 2025 Feb 28.
INTRODUCTION: Lorlatinib, a third-generation anaplastic lymphoma kinase inhibitor, reported significantly longer progression-free survival (PFS) than crizotinib in the phase 3 CROWN trial (NCT03052608) in patients with previously untreated advanced anaplastic lymphoma kinase-positive NSCLC. Efficacy was similar in the Asian subgroup. We present an updated subgroup analysis in Asian patients after five years of follow-up. METHODS: Patients were randomly (1:1) assigned to receive lorlatinib 100 mg once daily (n = 59) or crizotinib 250 mg twice daily (n = 61). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses. RESULTS: After a median follow-up of 62.4 months for lorlatinib and 55.1 months for crizotinib, median PFS was not reached (NR, 95% confidence interval [CI]: 64.3‒NR) and 9.2 months (95% CI: 7.2‒12.7), respectively (hazard ratio [HR] = 0.22, 95% CI: 0.13‒0.37); the five-year PFS was 63% (95% CI: 49-74) and 7% (95% CI: 2-17). The objective response rate was 81% (95% CI: 69-90) with lorlatinib and 59% (95% CI: 46‒71) with crizotinib. In patients with baseline brain metastases, the intracranial objective response rate was 69% (95% CI: 39‒91) with lorlatinib and 6% (95% CI: <1‒30) with crizotinib. The median time to intracranial progression was NR (95% CI: NR‒NR) and 14.6 months (95% CI: 9.2‒27.4), respectively (HR = 0.01, 95% CI: <0.01‒0.11). Safety profiles were consistent with the entire population. CONCLUSIONS: After five years of follow-up, lorlatinib efficacy and safety in the Asian subgroup of CROWN continue to be consistent with those in the overall population, with PFS remaining unreached with lorlatinib. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03052608.
34Alectinib vs. Lorlatinib in the Front-Line Setting for ALK-Rearranged Non-Small-Cell Lung Cancer (NSCLC): A Deep Dive into the Main Differences across ALEX and CROWN Phase 3 Trials.PubMed
Ilaria Attili, Valeria Fuorivia, Gianluca Spitaleri, et al.
Cancers (Basel). 2024 Jul 4;16(13):2457. doi: 10.3390/cancers16132457.
Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile.
35Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With -Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study.PubMed
Benjamin J Solomon, Todd M Bauer, Sai-Hong Ignatius Ou, et al.
J Clin Oncol. 2022 Nov 1;40(31):3593-3602. doi: 10.1200/JCO.21.02278. Epub 2022 May 23.
PURPOSE: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced -positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN. METHODS: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted. RESULTS: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% 22% and 78% 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% 72%) and without (1% 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS. CONCLUSION: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced -positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.
36Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis.PubMed
Koichi Ando, Ryo Manabe, Yasunari Kishino, et al.
Int J Mol Sci. 2023 Jan 23;24(3):2242. doi: 10.3390/ijms24032242.
Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.
37ALK inhibitors in ALK-rearranged non-small cell lung cancer with and without brain metastases: systematic review and network meta-analysis.PubMed
Jun Jiang, Cong Zhao, Fang Zhang, et al.
BMJ Open. 2022 Sep 19;12(9):e060782. doi: 10.1136/bmjopen-2022-060782.
OBJECTIVES: To systematically evaluate the efficacy and safety of anaplastic lymphoma kinase (ALK) inhibitors in ALK-rearranged positive non-small cell lung cancer (NSCLC) with brain metastases, and update the overall survival (OS) outcomes of the second-generation and third-generation ALK (ALK-2G/3G) inhibitors versus first-generation (ALK-1G) inhibitors. DESIGN: The study is in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Randomised controlled trials (RCTs) published up to 3 November 2021 were retrieved from PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov. SETTING: RCTs from any country and healthcare setting. PARTICIPANTS: Patients with advanced ALK-positive NSCLC with or without brain metastases. INTERVENTIONS AND COMPARISONS: The interventions were ALK-2G/3G; the control arm was ALK-1G or crizotinib. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes included median progression-free survival and median OS. Secondary outcomes included systemic objective response rate, intracranial response rate and rate of grade ≥3 adverse events (AEs). RESULTS: A total of 12 RCTs involving 3156 patients were analysed. Compared with ALK-1G (crizotinib), ALK-2G (alectinib, brigatinib, ceritinib and ensartinib) significantly improved the OS (HR: 0.72, 95% CI: 0.57 to 0.90, p=0.004) and intracranial response of patients with any brain metastases, especially with measurable (diameter ≥10 mm) brain metastases. Network meta-analysis demonstrated that ALK-3G (lorlatinib) had superior efficacy for patients with brain lesions, but performed a distinct side-effect profile. Moreover, alectinib showed superior efficacy and lower toxicity in ALK-positive NSCLC. CONCLUSION: Treatment with ALK-2G inhibitors significantly improved OS compared with crizotinib, and alectinib has less severe AEs than any other ALK inhibitors with moderate-high efficacy. The limited OS follow-up and inadequate sample sizes might contribute to having no statistically significant difference in OS of lorlatinib versus crizotinib. More high-quality and longer follow-up RCTs are warranted to prove our findings. PROSPERO REGISTRATION NUMBER: CRD42021292245.
38A Bayesian network meta-analysis regarding the comparative efficacy of therapeutics for ALK-positive, brain metastatic non-small cell lung cancer.PubMed
Binghao Zhao, Yan Han, Yadong Wang, et al.
Pharmacol Res. 2021 Dec;174:105931. doi: 10.1016/j.phrs.2021.105931. Epub 2021 Oct 6.
More clinical evidence is needed regarding the ranking priority of interventions for ALK-positive, brain metastatic (BM) non-small cell lung cancer (NSCLC). Eligible randomized controlled trials (RCTs) were identified. Progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) for the intended populations were analyzed with random effects, Bayesian network meta-analysis with the estimated hazard ratio (HR) and odds ratio (OR) with 95% credible interval (95% CrIs). We included 11 RCTs (2687 NSCLC and 991 BM patients) investigating 7 treatments and 5 medication classes. For PFS for BM patients, lorlatinib (hazard ratio (HR): 0.01, 95% CrI: 0.001-0.12), alectinib (HR: 0.05, 95% CrI: 0.01-0.21) and brigatinib (HR: 0.07, 95% CrI: 0.007-0.76) were top-ranking individual treatments; for ORR for BM patients, brigatinib, lorlatinib and alectinib were top-ranking treatments. For PFS for all NSCLC patients, the top-ranking individual treatments were lorlatinib (HR: 0.05, 95% CrI: 0.02-0.13), alectinib (HR: 0.09, 95% CrI: 0.05-0.18) and brigatinib (HR: 0.11, 95% CrI: 0.05-0.28). For OS for all NSCLC patients, we found that no individual treatments were superior to chemotherapy, whereas the following top-ranking interventions were alectinib (HR: 0.29, 95% CrI: 0.03-1.68), lorlatinib (HR: 0.41, 95% CrI: 0.04-4.13), and ceritinib (HR: 0.63, 95% CrI: 0.10-4.25). The results of individual treatments and medication classes were similar. Data were limited in regard to subgroup analyses and adverse events of BM patients. Lorlatinib has the most statistical superiority for BM patients, but ORR differences between third- and second-generation inhibitors are not obvious. All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib.
39EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.PubMed
Mariam Elshatlawy, Josephina Sampson, Katy Clarke, et al.
Mol Oncol. 2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446. Epub 2023 May 15.
Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point-mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule-associated protein-like 4 (EML4) in non-small cell lung cancer (NSCLC). EML4-ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta-propeller domain in variant 1 confers solid-like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK-TKIs are beneficial for most patients with EML4-ALK fusions. However, resistance to ALK inhibitors can occur via point-mutations within the kinase domain of the EML4-ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4-ALK variants, their impact on treatment response, ALK-TKI drug resistance mechanisms and potential combination therapies.
40Sensitivity of eight types of ALK fusion variant to alectinib in ALK-transformed cells.PubMed
Koh Furugaki, Naoki Harada, Yasushi Yoshimura
Anticancer Drugs. 2022 Feb 1;33(2):124-131. doi: 10.1097/CAD.0000000000001249.
Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non-small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assays using murine Ba/F3 cells expressing ALK variants. The kinase activity of each recombinant protein was significantly inhibited by alectinib. Intracellular ALK phosphorylation levels and its downstream signaling mediators, STAT3 and ERK, were suppressed by alectinib in each ALK variant-expressing Ba/F3 cell. Each cellular proliferation was markedly inhibited by alectinib treatment. There was no significant difference in the IC50 values between cells, with a <3.6-fold difference in responsiveness. In conclusion, these eight ALK variants had similar sensitivity to alectinib in vitro, indicating that it may not be possible to predict the response to alectinib just by determination of the ALK variant type in ALK fusion-positive NSCLCs.
41Lung adenocarcinoma harboring complex EML4-ALK fusion and BRAF V600E co-mutation responded to alectinib.PubMed
Weihong Guo, Jianping Liang, Dandan Zhang, et al.
Medicine (Baltimore). 2022 Oct 7;101(40):e30913. doi: 10.1097/MD.0000000000030913.
RATIONALE: The echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) is the most frequent fusion variant of ALK rearrangements in non-small cell lung cancer (NSCLC). With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations of EML4-ALK have been discovered. Complex co-mutation of EML4-ALK fusions together with BRAF V600E, though rarely occurred, also deserves attention to determine the standard of caring these patients. Herein, we report a case of lung adenocarcinoma harboring a complex ALK fusion that coexisted with a BRAF mutation, as tested by DNA-NGS prior to treatment. PATIENT CONCERNS: A 51-year-old non-smoking man, without any symptoms, was admitted to hospital due to small pulmonary nodules and enlarged supraclavicu larlymph nodes found in health checkup. DIAGNOSIS: He was diagnosed with stage IVB (T4N3M1c) lung adenocarcinoma. BRAF V600E (abundance 3.75%) mutation and a novel thus little-understood EML4-ALK (E13, A5; abundance 2.16%) fusion were identified by DNA-NGS analysis of lymph node biopsy tissue in December 2019. INTERVENTIONS: Darafenib plus trametinib targeted therapy and chemotherapy were given firstly, but tumor progression was not inhibited. The ALK inhibitor alectinib was prescribed then. OUTCOMES: The patient exhibited a rapid disease response to ALK tyrosine kinase inhibitors alectinib with a complete remission of widespread metastatic disease and progression-free survival of more than 26 months, but not to darafenib plus trametinib targeted BRAF V600E therapy. Re-analyzed the patient's DNA-NGS original data, showed it is a rare and complex EML4-ALK (E13, A5, A20) fusion in fact. Additional RNA-NGS analysis showed it verified to be a canonical EML4-ALK (E13, A20) fusion transcript and coexisting with a BRAF V600E mutation. LESSONS: This case suggests that for patients with rare or complex EML4-ALK fusions at DNA level, additional RNA-NGS is necessary to verify its functionality as early as possible. Targeting EML4-ALK firstly may be more preferable despite the coexisting of BRAF V600E.
42Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report.PubMed
Qi Liang, Huanhuan Xu, Yiqian Liu, et al.
Lung Cancer. 2021 Dec;162:86-89. doi: 10.1016/j.lungcan.2021.10.015. Epub 2021 Nov 5.
OBJECTIVES: The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib. MATERIALS AND METHODS: Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample. RESULTS: The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC. CONCLUSION: This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect.
43A novel alectinib-sensitive CTNND1-ALK fusion in a lung adenocarcinoma patient: a case report.PubMed
Xiang Tian, Qiong Liao, Qidong Yang, et al.
Invest New Drugs. 2022 Aug;40(4):850-853. doi: 10.1007/s10637-022-01245-3. Epub 2022 Apr 20.
Genomic fusions of anaplastic lymphoma kinase (ALK) are a well-established therapeutic target in non-small-cell lung cancer (NSCLC). Although various ALK fusion variants have been identified in NSCLC, their responses to ALK tyrosine-kinase inhibitors (TKIs) are heterogeneous. We report the case of a 71-year-old female patient diagnosed with lung adenocarcinoma with liver metastases. A novel CTNND1 (exon 14)-ALK (exon 20) fusion was identified from the biopsy sample by next-generation sequencing (NGS) and validated by immunohistochemistry (IHC) staining. Alectinib was administered, and the patient soon achieved partial response (PR). The progression-free survival (PFS) exceeded 15 months as of January 25, 2022. Our findings expand the spectrum of ALK rearrangements and provide a potential treatment option for lung adenocarcinoma patients with CTNND1-ALK fusions.
44From preclinical efficacy to 2022 (36.7 months median follow -up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC.PubMed
Sai-Hong Ignatius Ou, Alexandria T M Lee, Misako Nagasaka
Crit Rev Oncol Hematol. 2023 Jul;187:104019. doi: 10.1016/j.critrevonc.2023.104019. Epub 2023 May 13.
Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC.
45Impact of EML4-ALK Variants and Co-Occurring TP53 Mutations on Duration of First-Line ALK Tyrosine Kinase Inhibitor Treatment and Overall Survival in ALK Fusion-Positive NSCLC: Real-World Outcomes From the GuardantINFORM database.PubMed
Kaushal Parikh, Anastasios Dimou, Konstantinos Leventakos, et al.
J Thorac Oncol. 2024 Nov;19(11):1539-1549. doi: 10.1016/j.jtho.2024.07.009. Epub 2024 Jul 15.
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) NSCLC. Factors such as variant allele frequencies (VAFs), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting. METHODS: Adults with advanced or metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated. RESULTS: A total of 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n = 280), brigatinib (n = 15), lorlatinib (n = 9), or ceritinib (n = 3); 150 patients (49%) had ALK-fusion VAF greater than or equal to 1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF less than 1% versus greater than or equal to 1% had a median TTD of 32.2 (95% confidence interval [CI]: 20.7-not estimable [NE]) versus 14.7 months (10.4-19.9; hazard ratio [HR] = 1.57 [95% CI: 1.09-2.26]; p = 0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-NE) in patients with versus without TP53mt detected (HR = 1.53 [1.07-2.19]; p = 0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR = 1.29 [0.83-2.01]; p = 0.2641). Patients with TP53mt and v3 had a median TTD of 7.4 months (95% CI: 4.2-31.1). CONCLUSION: High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.
46Special issue "The advance of solid tumor research in China": Real-world clinical outcomes of alectinib for advanced nonsmall-cell lung cancer patients with ALK fusion in China.PubMed
Chunxia Su, Juan Zhou, Huiping Qiang, et al.
Int J Cancer. 2023 Jan 1;152(1):15-23. doi: 10.1002/ijc.34123. Epub 2022 Jun 17.
Global phase 3 trials have demonstrated the priority of several next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). However, clinical studies are conducted with specific populations that differ from the real world. The study aimed to evaluate the clinical outcomes of alectinib in real-world settings. Patients with advanced nonsmall-cell lung cancer (NSCLC) and EML4-ALK fusion were enrolled from two medical centers between June 2018 and June 2020. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) to alectinib. The secondary endpoint was response of brain metastases. The risk factors for disease progression were also investigated. In total, 127 patients with advanced NSCLC were enrolled into this study. Of them, 54.3% received first-line alectinib. The 1- and 2-year PFS rates were 77.4% and 68.3%, respectively. ORR and disease control rate (DCR) were 53.5% and 91.3%, respectively. Among patients with brain metastases, intracranial ORR and DCR were 63.6% and 88.6%, respectively. In addition, we found that "crizotinib pretreatment", "liver metastasis" and "TP53 co-mutation" were individually associated with shorter PFS in alectinib treatment. In conclusion, this study confirms the salient clinical outcomes of alectinib for ALK-fusion-driven NSCLC patients with or without brain metastases, adding real-world evidence to the priority of alectinib in clinical practice.
47Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis.PubMed
Yuyao Luo, Zhe Zhang, XuanZhu Guo, et al.
Lung Cancer. 2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319. Epub 2023 Aug 7.
OBJECTIVE: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making. MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework. RESULTS: Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs. CONCLUSIONS: The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.
48Monogenic hyperlipidemias.PubMed
Geraldo Krasi, Vilma Bushati, Vincenza Precone, et al.
Acta Biomed. 2019 Sep 30;90(10-S):47-49. doi: 10.23750/abm.v90i10-S.8757.
Monogenic hyperlipidemias are a group of inherited disorders characterized by elevated plasma concentrations of lipids and lipoproteins. High plasma concentrations of lipids are the most frequent risk factor for cardiovascular disease. Monogenic hyperlipidemias are a minor cause with respect to multifactorial hyperlipidemias. Diagnosis is based on clinical findings and lipid panel measurements. Genetic testing is useful for confirming diagnosis and for differential diagnosis, recurrence risk calculation and prenatal diagnosis in families with a known mutation. Monogenic hyperlipidemias can have either autosomal dominant or recessive inheritance.
49Hyperlipidaemia.PubMed
J Foxton
Nurs Stand. 1998;12(37):49-53; quiz 55-6. doi: 10.7748/ns.12.37.49.s55.
This article discusses the etiology of hyperlipidemia and methods of diagnosis and treatment, associating this with the risk of coronary heart disease, so that nurses will develop their understanding and advise patients appropriately.
50Hyperlipidemia in adolescents.PubMed
Prapti M Kanani, Mark A Sperling
Adolesc Med. 2002 Feb;13(1):37-52, v-vi.
Coronary artery disease is the leading cause of morbidity and mortality in the United States. Studies increasingly indicate that atherosclerotic lesions are evident in the vasculature by late adolescence, and that hyperlipidemias are a common and remediable contributor to their development. Hence, health care providers dealing with adolescents must be familiar with contemporary concepts about the etiology, classification, and management of hyperlipidemias in children and adolescents. This chapter briefly reviews lipid metabolism, emphasizing lipoprotein composition, key components, enzymes, cellular receptors, transport, uptake, and fate. This framework provides a rational classification with exclusion and treatment of secondary causes such as obesity, poorly controlled diabetes, hypothyroidism, and oral contraceptive therapy, followed by currently recommended approaches to the primary hyperlipidemias, which affect at least 1:500 persons. Guidelines for screening adolescents at risk and incremental treatment with diet and lipid-lowering medications, including statins, are reviewed in the context of current national recommendations.
51Interstitial lung disease risk of anaplastic lymphoma kinase tyrosine kinase inhibitor treatment of non-small cell lung cancer: a real-world pharmacovigilance study.PubMed
Min Zhao, Shu Liu, Rui Xie, et al.
Expert Opin Drug Saf. 2023 Jul-Dec;22(12):1309-1316. doi: 10.1080/14740338.2023.2245324. Epub 2023 Aug 12.
BACKGROUND: Interstitial lung disease (ILD) is a rare but life-threatening and fatal treatment-related pneumonitis. This study investigated the association between anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) and ILD. RESEARCH DESIGN AND METHODS: Cases of ILD that developed after treatment with an ALK-TKI in the Food and Drug Administration' s Adverse Event Reporting System (FAERS) data were assessed. We also described the clinical features of these cases and evaluated onset time, hospitalization, life-threatening condition, and fatality rate of ILD developed after treatment with an ALK-TKI. RESULTS: All five ALK-TKI regimens were significantly associated with ILD. The median onset time to ILD was significantly different for brigatinib, crizotinib, alectinib, lorlatinib, and ceritinib: 4.5, 25, 35.5, 54.5, and 84 days, respectively. ALK-TKI-associated ILD resulted in hospitalization in 55.77% of patients and death or life-threatening outcomes in 43.03%. The highest and lowest proportions of ILD-related fatalities were observed after crizotinib and alectinib treatment, respectively. CONCLUSIONS: ALK-TKIs were associated with ILD; therefore, the risk of developing ILD after treatment with an ALK-TKI should be carefully considered in clinical settings.
52Evaluation of Lung Toxicity Related to the Treatment With Alectinib Using a Pharmacovigilance Database.PubMed
Junya Sato, Mayako Uchida, Haruka Wakabayashi, et al.
Anticancer Res. 2022 Jun;42(6):3109-3116. doi: 10.21873/anticanres.15799.
BACKGROUND/AIM: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is recommended as a first-line treatment for ALK lung cancer. Interstitial lung disease is the most common adverse event leading to discontinuation of alectinib. The purpose of this study was to use the Japanese Adverse Drug Event Report database for the evaluation of incidence trends and timing of alectinib toxicity in the lungs. PATIENTS AND METHODS: Adverse drug reactions (ADRs) by alectinib were extracted between April 2004 and March 2021. Data related to lung toxicity ADRs were analyzed, and the relative risk was estimated using the reporting odds ratio (ROR) and 95% confidence interval (CI). The time of onset of the lung toxicity signs was noted. RESULTS: We obtained 524 reports of ADRs associated with alectinib. Of these, 157 were lung toxicity, including interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema. The RORs for these signs were 10.28 (95%CI=8.38-12.60), 9.19 (5.58-15.13), 7.40 (3.67-14.88), and 7.01 (3.13-15.69), respectively. The median onset times (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib treatment were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively. CONCLUSION: Among the lung toxicity signs, interstitial lung disease had the highest ROR, suggesting a strong causal relationship with alectinib treatment. Interstitial lung disease most frequently developed within 60 days after the start of treatment. These results will be useful for monitoring adverse events associated with the use of alectinib.
53Neoadjuvant alectinib in locally advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement: case series and literature review.PubMed
Zhaofeng Wang, Ranpu Wu, Chuling Li, et al.
Anticancer Drugs. 2023 Nov 1;34(10):1069-1075. doi: 10.1097/CAD.0000000000001507. Epub 2023 Jan 24.
In view of the success of targeted therapy in the field of advanced lung cancer, it is gradually pushed further to neoadjuvant therapy. Alectinib has been recommended for advanced anaplastic lymphoma kinase (ALK) + non-small cell lung cancer (NSCLC) in first-line therapy. Here, we report two cases of neoadjuvant alectinib in locally advanced lung adenocarcinoma with ALK rearrangement. Case 1 was a 64-year-old man with no history of smoking who was diagnosed with the clinical stage as IIIB, with ALK fusion-positive. Chest-enhanced computed tomography (CT) revealed marked regression and achieved partial response (PR) incorporated with grade 3 interstitial pneumonia after 44 days of alectinib neoadjuvant therapy. Interstitial pneumonia improved after methylprednisolone therapy, then thoracoscopic lobe resection with lymph node dissection was performed with blood loss. The pathological assessment was a pathologic complete response(pCR). Case 2 was a 66-year-old man who had a routine physical examination and then diagnosed with a clinical-stage IIIB by CT-guided percutaneous cutting needle biopsy (PCNB). Chemotherapy with 1 cycle of pemetrexed combined with nedaplatin was performed in the interval waiting for next-generation sequencing (NGS) results. NGS testing revealed an EML4-ALK fusion mutation. After 109 days of alectinib treatment, radiographic evaluation was classified as PR and then he underwent thoracoscopic upper lobectomy smoothly with pathological assessment as a major pathological response (MPR). To date, neoadjuvant alectinib has only been reported in a few cases in locally advanced lung adenocarcinoma with ALK-rearranged. Neoadjuvant alectinib may be feasible in locally advanced disease for complete resection. The duration and safety of neoadjuvant therapy with alectinib still need further study.
54A non-small cell lung carcinoma patient responded to crizotinib therapy after alectinib-induced interstitial lung disease.PubMed
Wenjia Sun, Jing Zheng, Jianya Zhou, et al.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Oct 8;52(5):583-587. doi: 10.3724/zdxbyxb-2023-0319.
A 54-year-old, non-smoking woman was diagnosed as stage ⅣB adenocarcinoma with widespread bone metastasis (cT4N2M1c) in the First Affiliated Hospital, Zhejiang University School of Medicine. Immunohistochemistry result showed the presence of anaplastic lymphoma kinase (ALK) gene rearrangement; next-generation sequencing (NGS) indicated - fusion (:) with concurrent - (:)- (:)and - (:) fusions. After 32 weeks of alectinib treatment, the patient complained cough and exertional chest distress but had no sign of infection. Computed tomography (CT) showed bilateral diffuse ground glass opacities, suggesting a diagnosis of alectinib-related interstitial lung disease (ILD). Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged during the regular follow-up. The administration of crizotinib was then initiated and the disease was stable for 25 months without recurrence of primary lung lesions and ILD.
55Alectinib-induced rash unresponsive to desensitization: a case report and literature review.PubMed
Robin Raquel Rodriguez, Jessie Dindak, Janet Kline, et al.
BMC Pulm Med. 2023 Jul 15;23(1):261. doi: 10.1186/s12890-023-02558-6.
BACKGROUND: Since the inception of targeted therapies in treating lung cancer, providers have had to be aware of a new host of side effects when selecting management options for patients. Although targeted therapies are creating increased hope for patients with non-small cell lung cancers (NSCLC), understanding their side effects presents a challenge for providers. Alectinib, a second-generation tyrosine kinase inhibitor, is a targeted therapy used in patients with non-small cell lung cancer found to have anaplastic lymphoma kinase (ALK) mutations. Alectinib is the focus of this case report and literature review as we seek to understand side effects providers may encounter when prescribing these therapies. CASE PRESENTATION: We begin our report with the case of a 63-year-old Hispanic female with stage IIIA non-small cell lung cancer found to have the ALK genomic alteration. She was started on Alectinib, and on Day 11, she developed a severe maculopapular rash requiring hospitalization. After complete resolution, desensitization with Alectinib was attempted but unsuccessful. CONCLUSIONS: Despite the unsuccessful desensitization of this patient, it is important to report this rare side effect in order to better understand how providers can pursue management. Case reports such as this can aid providers in potentially preventing, treating, and rechallenging patients on targeted therapies in the future.
56Interstitial lung disease induced by alectinib (CH5424802/RO5424802).PubMed
Satoshi Ikeda, Hiroshige Yoshioka, Machiko Arita, et al.
Jpn J Clin Oncol. 2015 Feb;45(2):221-4. doi: 10.1093/jjco/hyu183. Epub 2014 Nov 14.
A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile.
57Successful alectinib treatment after crizotinib-induced interstitial lung disease.PubMed
Satoru Fujiuchi, Yuka Fujita, Takaaki Sasaki, et al.
Respirol Case Rep. 2016 Apr 7;4(3):e00156. doi: 10.1002/rcr2.156. eCollection 2016 May.
A 70-year-old woman with lung adenocarcinoma, harbouring anaplastic lymphoma kinase gene rearrangement, was treated with crizotinib as third-line chemotherapy. After 2 months, crizotinib was discontinued because of the development of crizotinib-induced interstitial lung disease (ILD). Steroid treatment was then introduced and tapered off. Following complete resolution of the interstitial shadow, cytotoxic chemotherapy was initiated, and continued for over 2 years, until new intrapulmonary lesions developed. Although there was a risk of drug-induced interstitial pneumonia, alectinib was initiated as the fifth-line therapy, without steroid supplementation, as there was no alternative treatment. No recurrence of ILD was noted at 10 months. To our knowledge, this is the first report of successful alectinib treatment after the development of crizotinib-induced ILD without the use of prednisolone.
58New findings on the incidence and management of CNS adverse reactions in ALK-positive NSCLC with lorlatinib treatment.PubMed
Fanfan Chu, Wenxi Zhang, Hong Hu
Discov Oncol. 2024 Sep 13;15(1):444. doi: 10.1007/s12672-024-01339-9.
To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency.
59Alectinib - induced acute renal failure.PubMed
Elena Prado-Mel, Pablo Ciudad-Gutiérrez, Almudena Sánchez-Martín, et al.
J Oncol Pharm Pract. 2023 Apr 6:10781552231167808. doi: 10.1177/10781552231167808.
Alectinib is a potent and selective orally active tyrosine kinase inhibitor used for anaplastic lymphoma kinase-positive non-small cell lung cancer, which has a better safety profile than other inhibitors of anaplastic lymphoma kinase. We report a case of a mixed pattern of acute interstitial nephritis and acute tubular necrosis proven by renal biopsy upon starting alectinib therapy. A 68-year-old man with diabetes, hypertension, and dyslipidaemia, diagnosed with anaplastic lymphoma kinase-positive non-small cell lung cancer stage IV, had 27 days previously started alectinib 600 mg twice daily. He presented at the emergency room due to vomiting, nausea, and more dyspnoea than usual. A high creatinine level and metabolic imbalances were detected in laboratory tests. After a diagnosis of acute renal failure, the patient was admitted to hospital. Nephrotoxic drugs were suspended, and haemodialysis was required. After dismissing other causes, a probable diagnosis of acute interstitial nephritis due to alectinib was established. Corticotherapy was initiated and renal function returned to baseline levels. Renal biopsy showed a mixed pattern of acute interstitial nephritis and acute tubular necrosis. The patient was discharged, and alectinib therapy was modified to lorlatinib. No polymorphisms were found in a pharmacogenetic test. After 10 months with lorlatinib, renal function remains stable. The relationship between acute renal failure and alectinib initiation is considered probable in this patient. Although it is an adverse effect reported in less than 1% of cases, it would be advisable to monitor renal function in this kind of patient.
60Unraveling the unforeseen: anuric acute kidney injury induced by alectinib.PubMed
Viet Nghi Tran, Yusuf Hussein Kebato, Chau Doan Nguyen, et al.
Hosp Pract (1995). 2025 Feb;53(1):2470606. doi: 10.1080/21548331.2025.2470606. Epub 2025 Feb 27.
INTRODUCTION: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is pivotal in managing ALK-positive non-small cell lung cancer (NSCLC) due to its efficacy and favorable safety profile. However, severe renal toxicity, including acute kidney injury (AKI), remains a rare but significant adverse effect. CASE REPORT: We present the case of a 71-year-old female with a history of diabetes and recently diagnosed ALK-positive NSCLC. She had been on alectinib therapy (600 mg twice daily) for two months. The patient was admitted with symptoms of shortness of breath and anuria. Initial laboratory results revealed a significant rise in serum creatinine from a baseline of 1.0 mg/dL to 3.64 mg/dL, indicating AKI. Alectinib was discontinued, and the patient underwent a single session of hemodialysis. The patient exhibited rapid clinical improvement with significant recovery of renal function, and she was discharged without the need for further dialysis. A subsequent switch to brigatinib was well-tolerated, with stable renal function observed at the 4-month follow-up. CONCLUSION: This case underscores the potential for severe AKI associated with alectinib therapy, highlighting the importance of vigilant renal function monitoring in patients undergoing treatment, especially those with predisposing conditions. Early recognition and prompt intervention are crucial to mitigate renal complications and optimize patient outcomes. Brigatinib may serve as a suitable alternative for patients intolerant to alectinib.
61A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment.PubMed
Swan Lin, Jason Gong, George C Canas, et al.
Eur J Drug Metab Pharmacokinet. 2022 Mar;47(2):235-245. doi: 10.1007/s13318-021-00747-4. Epub 2022 Jan 11.
BACKGROUND AND OBJECTIVES: Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with anaplastic lymphoma kinase- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib. METHODS: Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety. RESULTS: A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration-time profile from time zero extrapolated to infinity (AUC) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort. CONCLUSION: Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD. GOV IDENTIFIER: NCT03542305 (available May 31, 2018 on clinicaltrials.gov).
62Lorlatinib overcomes alectinib-induced hemolytic anemia in an ALK fusion positive non-small-cell lung cancer patient with severe tumor-associated liver failure: A case report.PubMed
Kei Kunimasa, Akito Miyazaki, Motohiro Tamiya, et al.
Thorac Cancer. 2024 Dec;15(36):2570-2574. doi: 10.1111/1759-7714.15487. Epub 2024 Nov 11.
Hemolytic anemia is a rare and unique complication of alectinib, not observed with other anaplastic lymphoma kinase (ALK) inhibitors. Here, we present a case of an ALK fusion-positive non-small-cell lung cancer (NSCLC) patient who developed liver failure due to diffuse liver metastasis at initial diagnosis. Treatment was initiated with low-dose alectinib, but the patient developed severe hemolytic anemia. Switching to lorlatinib allowed for the continuation of ALK inhibitor therapy and successful tumor reduction. ALK inhibitors are crucial for ALK fusion-positive NSCLC patients. Managing severe side effects by switching medications is essential to maintain effective therapy. In this case, lorlatinib effectively controlled the tumor and improved the patient's liver function and performance status. This case highlights the importance of adapting treatment strategies to manage adverse effects while ensuring the continued use of ALK inhibitors for optimal patient outcomes.
63Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults.PubMed
Jessica Stiefel, Brian H Kushner, Stephen S Roberts, et al.
JCO Precis Oncol. 2023 Aug;7:e2300138. doi: 10.1200/PO.23.00138.
PURPOSE: Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON. METHODS: A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria. RESULTS: Fifteen patients with -mutated AON were treated with US Food and Drug Administration-approved ALKi starting at a median age of 34 (16-71) years. Initial ALKi was lorlatinib, crizotinib, and alectinib in seven, five, and three patients respectively; seven received multiple ALKis due to progressive disease/intolerability of one agent. All patients experienced ≥grade 2 adverse events (AEs): crizotinib and alectinib were associated primarily with gastrointestinal AEs, lorlatinib with neurologic AEs, weight gain, and hyperlipidemia resulting in dose reduction or discontinuation of ALKi in several patients. No responses were observed with crizotinib (n = 5 patients), ceritinib, alectinib, or brigatinib (n = 1 each). Of the 13 patients receiving lorlatinib, four, five, and four patients had a complete or partial response (major response rate 69%), and stable disease, respectively. Responses were noted in all disease compartments; complete metabolic response was seen in two L2 patients. Ten of 13 patients remain progression-free at a median of 19 (6-50) months on lorlatinib. Three (two receiving dose-reduced therapy) had progressive disease. Median survival from start of first ALKi was 43 ± 26 months. CONCLUSION: ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.
64Revisiting a lower starting dose of alectinib in ALK-Positive non-small cell lung cancer.PubMed
Danielle Benedict Sacdalan, Josephine Anne Lucero
Cancer Treat Res Commun. 2021;27:100319. doi: 10.1016/j.ctarc.2021.100319. Epub 2021 Jan 23.
We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses - 300 mg and 600 mg twice daily - across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of Alectinib. Randomized trials have shown that the 600 mg dose is associated with more grade ≥3 adverse events and more changes in treatment in contrast to the 300 mg dose. A lower dose of Alectinib may limit treatment disruptions and dose reductions particularly for specific patient populations-particularly those with a lower body weight.
65First-line treatments for patients with advanced ALK gene rearrangements in NSCLC: a systematic review and network meta-analysis.PubMed
Jiahao Tao, Chuangjie Zheng, Cuifen Zhang, et al.
J Int Med Res. 2022 Nov;50(11):3000605221132703. doi: 10.1177/03000605221132703.
OBJECTIVE: To conduct a network meta-analysis of randomised controlled trials to determine the optimal clinical choice of first-line therapy for patients with ALK receptor tyrosine kinase () gene rearrangement non-small cell lung cancer (NSCLC). METHODS: Clinical trials in patients with histologically confirmed gene rearrangement NSCLC, that included ALK inhibitors as first-line therapy, were identified using database searches. A Bayesian network meta-analysis was conducted to calculate the efficacy and safety of the included first-line treatments. RESULTS: Nine trials with 2,407 patients were included for analyses. Lorlatinib was better than brigatinib for progression-free survival (PFS) (hazard ratio 0.79, 95% confidence interval 0.63, 0.98). In subgroup analyses, lorlatinib exhibited the highest probability of best PFS ranking in patients with or without baseline brain metastases (38% and 80%, respectively); brigatinib had the highest probability of best PFS ranking among Asian patients (47%). Alectinib offered the highest survival advantage (57% probability), while lorlatinib was likely to be the best treatment for an objective response (41% probability). Alectinib displayed the highest probability of being ranked lowest for grade ≥3 adverse events (86%). CONCLUSIONS: Lorlatinib was associated with the best PFS overall, and was suitable for patients with or without brain metastases. Brigatinib was associated with the best PFS in Asian patients.
66Drug resistance in ALK-positiveNon-small cell lungcancer patients.PubMed
Mengjia Qian, Bijun Zhu, Xiangdong Wang, et al.
Semin Cell Dev Biol. 2017 Apr;64:150-157. doi: 10.1016/j.semcdb.2016.09.016. Epub 2016 Sep 29.
Patients are diagnosed as anaplastic lymphoma kinase (ALK) positive, i.e. exhibiting the ALK rearrangement, and comprise 3-7% of non-small-cell lung cancer (NSCLC) cases. Three generations of ALK inhibitors have been developed and used in targeted therapy, although there are still improving spaces of drug resistance at the initiation of each treatment. The current review discusses the pathophysiology of ALK-positive NSCLC and the role of three generations of ALK target inhibitors including crizotinib, ceritinib, alectinib and lorlatinib, as well as the mechanisms of the secondary resistance. We mainly focused on the point mutations that are the most important resistance-producing mechanism and most common form caused by each inhibitor. In addition, we examine the three-dimensional structure of ALK to understand the functional impact of these mutations and analyse the underlying molecular mechanisms of the resistance to each generation of ALK inhibitor to benefit the selection decision of the most rational therapy and improve therapeutic effects to the disease.
67Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.PubMed
Yen-Ting Lin, Chi-Lu Chiang, Jen-Yu Hung, et al.
Eur J Cancer. 2021 Oct;156:1-11. doi: 10.1016/j.ejca.2021.06.043. Epub 2021 Aug 13.
INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. METHODS: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed. RESULTS: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. CONCLUSIONS: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.
68Insight into resistance mechanism of anaplastic lymphoma kinase to alectinib and JH-VIII-157-02 caused by G1202R solvent front mutation.PubMed
Han Wang, Yao Wang, Wentao Guo, et al.
Drug Des Devel Ther. 2018 May 9;12:1183-1193. doi: 10.2147/DDDT.S147104. eCollection 2018.
BACKGROUND: Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation. METHODS: Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALK and the ALK G1202R (ALK) mutation. RESULTS: JH-VIII-157-02 has similar binding affinities to both ALK and ALK whereas it has has a much lower binding affinity for alectinib to ALK. Analysis of individual energy terms indicate the major variation involves the van der Waals and entropy terms. Structural analysis reveals that the conformational change of the ATP-binding glycine-rich loop was primarily responsible for the alectinib resistance, not JH-VIII-157-02. In addition, US simulations prove JH-VIII-157-02 has similar dissociative processes from both ALK and ALK, while alectinib is more easily dissociated from ALK than from ALK, thus indicating lesser residence time. CONCLUSION: Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance.
69Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs.PubMed
Rita Leporati, Daniela Miliziano, Teresa Beninato, et al.
Tumori. 2024 Dec;110(6):NP1-NP4. doi: 10.1177/03008916241246659. Epub 2024 Apr 16.
INTRODUCTION: Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. With the increasing number of target therapies available, the optimal sequence is yet to be defined, as resistance profiles may evolve over time and in response to sequential ALK inhibitors. Therefore, ALK-targeted strategies may be personalized based upon the presence of specific ALK resistance mutations. METHODS: Here, we report on the case of a patient who has been treated with a sequence of three ALK TKIs after receiving diagnosis of ALK-rearranged metastatic NSCLC in 2015 and gained further benefit upon lorlatinib rechallenge after the acquisition of the G1202R resistance mutation to second generation TKIs. RESULTS AND CONCLUSION: In this case, the first ALK resistance mutation detected after progression on first line TKI, the I1171N, is a common resistance mutation after alectinib and confers sensitivity to brigatinib, that the patient received afterwards with a long-term disease stability. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.
70Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden.PubMed
Go Makimoto, Kadoaki Ohashi, Shuta Tomida, et al.
J Thorac Oncol. 2019 Nov;14(11):2009-2018. doi: 10.1016/j.jtho.2019.07.017. Epub 2019 Jul 30.
INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.
71Treatment of advanced ALK-rearranged NSCLC following second-generation ALK-TKI failure.PubMed
Akito Fukuda, Tatsuya Yoshida
Expert Rev Anticancer Ther. 2023 Jul-Dec;23(11):1157-1167. doi: 10.1080/14737140.2023.2265566. Epub 2023 Oct 27.
INTRODUCTION: Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK-TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent. AREAS COVERED: Here, we review the mechanisms underlying resistance to second-generation ALK-TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC. EXPERT OPINION: Treatment strategies following the failure of second-generation ALK-TKIs failure should be based on resistant mechanisms. For patients with mutations who exhibit resistance to second-generation ALK-TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK-TKIs can aid in the selection of an appropriate treatment strategy. In cases of -dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK-TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options.
72Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients.PubMed
G Hua, X Zhang, M Zhang, et al.
ESMO Open. 2022 Feb;7(1):100337. doi: 10.1016/j.esmoop.2021.100337. Epub 2022 Feb 2.
BACKGROUND: Sequential treatment with different generations of anaplastic lymphoma kinase (ALK) inhibitors have been widely applied to ALK-positive lung cancer; however, resistance mutations inevitably developed. Further characterization of ALK resistance mutations may provide key guidance to subsequent therapies. Here we explored the emergence of secondary ALK mutations during sequential ALK tyrosine kinase inhibitor (TKI) treatment in a real-world study of Chinese lung adenocarcinoma (ADC) patients. METHODS: A clinical-genomic database was queried for lung ADC patients with at least one ALK inhibitor treatment and at least one plasma sample collected following ALK inhibitor treatment. Targeted genome profiling was performed with a 139-gene panel in baseline tumor tissue and serial plasma samples of patients. RESULTS: A total of 116 patients met inclusion criteria. ALK G1202R was more common in patients with echinoderm microtubule-associated protein-like 4 (EML4)-ALK v3 fusion, whereas ALK L1196M was more common in v1. TP53 mutant patients were significantly associated with harboring multiple ALK resistance mutations (P = 0.03) and v3+/TP53 mutant patients had the highest rate of multiple ALK resistance mutations. The sequential use of ALK TKI led to an increased incidence of concurrent ALK mutations along the lines of therapies. Alectinib had a lower rate (9%) harboring ALK resistance mutation as first-line ALK TKI compared with crizotinib (36%). ALK compound mutations identified included ALK D1203N/L1196M, ALK G1202R/L1196M, and ALK G1202R/F1174C, which may be lorlatinib resistant. Using paired pretreatment and post-treatment samples, we identified several ALK-independent resistance-related genetic alterations, including PTPRD and CNKN2A/B loss, MYC, MYCN and KRAS amplification, and EGFR. CONCLUSIONS: Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.
73Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance.PubMed
Koutaroh Okada, Mitsugu Araki, Takuya Sakashita, et al.
EBioMedicine. 2019 Mar;41:105-119. doi: 10.1016/j.ebiom.2019.01.019. Epub 2019 Jan 17.
BACKGROUND: Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet. METHODS: We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE). FINDINGS: We identified 14 lorlatinib-resistant ALK-compound mutants, including several mutants that were recently discovered in lorlatinib-resistant patients. Some of these compound mutants were found to be sensitive to early generation ALK-TKIs and several BCR-ABL inhibitors. Using our original computational simulation, we succeeded in demonstrating a clear linear correlation between binding free energy and in vitro experimental IC value of several ALK-TKIs to single- or compound-mutated EML4-ALK expressing Ba/F3 cells and in recapitulating the tendency of the binding affinity reduction by double mutations found in this study. Computational simulation revealed that ALK-L1256F single mutant conferred resistance to lorlatinib but increased the sensitivity to alectinib. INTERPRETATION: We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.