Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■已经开发了几种间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKIs）用于治疗棘皮动物微管相关蛋白样4（EML4）-ALK重排的非小细胞肺癌（NSCLC），新一代药物布加替尼，阿莱替尼和洛拉替尼显示出延长的反应。随着可用的靶向治疗的数量不断增加，最佳序列尚未定义，因为耐药谱可能随着时间的推移和对序贯ALK抑制剂的反应而演变。因此,ALK靶向策略可以基于特定ALK抗性突变的存在而个性化。
■这里，我们报道了1例患者,该患者在2015年接受ALK重排转移性NSCLC诊断后接受了3个ALKTKIs序列治疗,并在获得第二代TKIs的G1202R耐药突变后通过氯拉替尼再激发获得进一步获益.
■在这种情况下，在一线TKI进展后检测到的第一个ALK抗性突变，I1171N,是阿来替尼之后的常见耐药突变，并赋予对布加替尼的敏感性，患者接受治疗后病情长期稳定。化疗间隔后检测到的第二个ALK耐药突变，G1202R,是第二代ALKTKIs后最常见的抗性突变，并且与对第三代TKIs的敏感性有关，比如lorlatinib.一例EML4-ALK重排的NSCLC患者显示，用下一代ALKTKIs序贯治疗，包括重新挑战，可以引起深刻的反响，即使在严重预处理的患者中，并且ALK靶向策略可以通过考虑不同ALK抗性突变的存在来个性化。
■这里，我们报道了1例患者,该患者在2015年接受ALK重排转移性NSCLC诊断后接受了3个ALKTKIs序列治疗,并在获得第二代TKIs的G1202R耐药突变后通过氯拉替尼再激发获得进一步获益.
■在这种情况下，在一线TKI进展后检测到的第一个ALK抗性突变，I1171N,是阿来替尼之后的常见耐药突变，并赋予对布加替尼的敏感性，患者接受治疗后病情长期稳定。化疗间隔后检测到的第二个ALK耐药突变，G1202R,是第二代ALKTKIs后最常见的抗性突变，并且与对第三代TKIs的敏感性有关，比如lorlatinib.一例EML4-ALK重排的NSCLC患者显示，用下一代ALKTKIs序贯治疗，包括重新挑战，可以引起深刻的反响，即使在严重预处理的患者中，并且ALK靶向策略可以通过考虑不同ALK抗性突变的存在来个性化。
