Department of Hematology, Oncology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg, Germany.
Medical Oncology Department, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal; Multidisciplinary Thoracic Tumors Unit - Pulmonology Department, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal.
J Geriatr Oncol. 2022 Nov;13(8):1071-1083. doi: 10.1016/j.jgo.2022.04.013. Epub 2022 May 5.
Lung cancer remains the leading cause of cancer-related deaths worldwide, with most patients diagnosed at an advanced age. The treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the introduction of molecular guided therapy. Despites the challenges when considering treatment of older adults, they are still systematically underrepresented in registrational trials. This review aims to summarize the existing evidence on treatment of older patients with lung cancer with a targetable driver mutation or alteration (EGFR, ALK, ROS, BRAF, MET, RET, KRAS and NTRK), and consider the evidence from a geriatric oncology perspective. Early generation EGFR-tyrosine kinase inhibitors (TKIs). TKIs are fairly well-studied in older adults and have been shown to be safe and efficient. However, older adult-specific data regarding the standard-of-care first-line agent osimertinib are lacking. Erlotinib, dacomitinib, and afatinib may be more toxic than other EGFR-TKIs. Next generation ALK-TKIs are preferred over crizotinib due to increased efficacy, as demonstrated in phase III trials. Alectinib seems to be safer than crizotinib, while brigatinib is associated with increased toxicity. Lorlatinib overcomes most resistance mutations, but data regarding this agent have only recently emerged. Regarding ROS1-fusion positive NSCLC, crizotinib is an option in older adults, while entrectinib is similarly effective but shows increased neurotoxicity. In BRAF-mutant NSCLC, the combination darbafenib/tramectinib is effective, but no safety data for older adults exist. MET alterations can be targeted with capmatinib and tepotinib, and registrational trials included primarily older patients, due to the association of this alteration with advanced age. For RET-rearranged-NSCLC selpercatinib and pralsetinib are approved, and no differences in safety or efficacy between older and younger patients were shown. KRAS mutations, which are more frequent in older adults, became recently druggable with sotorasib, and advanced age does not seem to affect safety or efficacy. In NTRK-fusion positive tumors, larotrectinib and entrectinib have tumor agnostic approval, however, not enough data on older patients are available. Based on currently available data, molecularly-guided therapy for most alterations is safe and efficacious in older adults with oncogene-driven advanced NSCLC. However, for many TKIs, older adult-specific data are lacking, and should be subject of future prospective evaluations.
肺癌仍然是全球癌症相关死亡的主要原因，大多数患者在年龄较大时被诊断出来。随着分子靶向治疗的引入，非小细胞肺癌（NSCLC）的治疗已经发生了革命性的变化。尽管在考虑治疗老年人时存在挑战，但他们在注册试验中的代表性仍然不足。本综述旨在总结现有证据，探讨针对可靶向驱动突变或改变（EGFR、ALK、ROS、BRAF、MET、RET、KRAS 和 NTRK）的老年肺癌患者的治疗方法，并从老年肿瘤学的角度考虑这些证据。第一代 EGFR 酪氨酸激酶抑制剂（TKI）。TKI 在老年人中得到了相当多的研究，并且已被证明是安全有效的。然而，关于标准治疗一线药物奥希替尼的老年患者特异性数据仍然缺乏。厄洛替尼、达克替尼和阿法替尼可能比其他 EGFR-TKI 更具毒性。下一代 ALK-TKI 由于在 III 期试验中显示出更高的疗效，因此优于克唑替尼。阿来替尼似乎比克唑替尼更安全，而布加替尼则与毒性增加有关。劳拉替尼克服了大多数耐药突变，但关于该药物的数据最近才出现。对于 ROS1 融合阳性 NSCLC，克唑替尼是老年人的一种选择，而恩曲替尼的疗效相似，但神经毒性增加。在 BRAF 突变型 NSCLC 中，达拉非尼/曲美替尼联合治疗有效，但尚无关于老年人的安全性数据。MET 改变可以用卡马替尼和特泊替尼进行靶向治疗，并且由于这种改变与年龄较大有关，所以注册试验主要包括老年患者。对于 RET 重排 NSCLC，塞普替尼和普拉替尼已获得批准，并且在安全性或疗效方面，老年患者与年轻患者之间没有差异。KRAS 突变在老年人中更为常见，最近索托拉西布使其具有可治疗性，并且年龄较大似乎不会影响安全性或疗效。在 NTRK 融合阳性肿瘤中，拉罗替尼和恩曲替尼具有肿瘤不可知的批准，但缺乏足够的老年患者数据。基于目前可用的数据，对于大多数改变，针对致癌基因驱动的晚期 NSCLC 的老年患者，分子靶向治疗是安全有效的。然而，对于许多 TKI，缺乏老年患者特异性数据，应成为未来前瞻性评估的主题。
