medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/ms2023-434medsovet-7929Research ArticleТАРГЕТНАЯ ТЕРАПИЯTARGET THERAPY OF TUMORSВыбор оптимального варианта первой линии терапии ALK-позитивного метастатического немелкоклеточного рака легкихFirst-line treatment option for patients with ALK-positive metastatic NSCLChttps://orcid.org/0000-0003-0092-0459КорниецкаяА. Л.KornietskayaA. L.

Корниецкая Анна Леонидовна - к.м.н., ведущий научный сотрудник отдела лекарственного лечения опухолей.

125834, Москва, 2-й Боткинский проезд, д. 3

Аnna L. Kornietskaya - Cand. Sci. (Med.), Senior Researcher, Department of Chemotherapy, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

kornietskaya@mail.ruhttps://orcid.org/0000-0003-4879-2687БолотинаЛ. В.BolotinaL. V.

Болотина Лариса Владимировна - д.м.н., заведующая отделением химиотерапии.

125834, Москва, 2-й Боткинский проезд, д. 3

Larisa V. Bolotina - Dr. Sci. (Med.), Head of Chemotherapy Department, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

lbolotina@yandex.ruhttps://orcid.org/0000-0002-1993-3842ЕвдокимоваС. Ф.EvdokimovaS. F.

Евдокимова Сэвиндж Физулиевна – аспирант.

125834, Москва, 2-й Боткинский проезд, д. 3

Sevindzh F. Evdokimova - Postgraduate Student, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

evdokimova.sevindzh@gmail.comhttps://orcid.org/0000-0002-6244-9159ПризоваН. С.PrizovaN. S.

Призова Наталия Сергеевна - к.м.н., врач-онколог отделения химиотерапии.

125834, Москва, 2-й Боткинский проезд, д. 3

Natalia S. Prizova - Cand. Sci. (Med.), Oncologist of Chemotherapy Department, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

sonrisa3n@mail.ruhttps://orcid.org/0000-0003-3196-1368КарагодинаЮ. Б.KaragodinaYu. B.

Карагодина Юлия Борисовна - научный сотрудник.

125834, Москва, 2-й Боткинский проезд, д. 3

Yulia B. Karagodina - Researcher, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

yuliaborisovnakaragodina@gmail.comhttps://orcid.org/0000-0002-8721-8437СавчинаВ. В.SavchinaV. V.

Савчина Виктория Владимировна - научный сотрудник.

125834, Москва, 2-й Боткинский проезд, д. 3

Viktoria V. Savchina - Researcher, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

savchina_v.v@mail.ruhttps://orcid.org/0000-0003-4927-5585ФеденкоА. А.FedenkoA. A.

Феденко Александр Александрович - д.м.н.,руководитель отдела лекарственного лечения опухолей.

125834, Москва, 2-й Боткинский проезд, д. 3

Alexander A. Fedenko - Dr. Sci. (Med.), Head of Chemotherapy Department, Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center.

3, 2nd Botkinskiy Proezd, Moscow, 125834

fedenko@eesg.ruМосковский научно-исследовательский онкологический институт имени П.А. Герцена – филиал Национального медицинского исследовательского центра радиологииРоссияHertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological CenterRussian Federation2023231120230227479Copyright © Корниецкая А.Л., Болотина Л.В., Евдокимова С.Ф., Призова Н.С., Карагодина Ю.Б., Савчина В.В., Феденко А.А., 20242024Корниецкая А.Л., Болотина Л.В., Евдокимова С.Ф., Призова Н.С., Карагодина Ю.Б., Савчина В.В., Феденко А.А.Kornietskaya A.L., Bolotina L.V., Evdokimova S.F., Prizova N.S., Karagodina Y.B., Savchina V.V., Fedenko A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/7929

Занимая лидирующие позиции в структуре онкологической заболеваемости и смертности, немелкоклеточный рак легких (НМРЛ) представляет собой крайне гетерогенную группу заболеваний. Наличие большого спектра драйверных мутаций при НМРЛ привело к принципиально иному пониманию стратегии лечения данной когорты больных и существенному улучшению отдаленных онкологических результатов даже при метастатическом процессе. Хромосомные перестройки с участием локусов гена киназы анапластической лимфомы (ALK) на 2-й хромосоме выявляются примерно у 3–5% пациентов с метастатическим НМРЛ (мНМРЛ) и в большинстве случаев сопряжены не только с рядом специфических клинических признаков, но и высокой чувствительностью к таргетной терапии ингибиторами тирозинкиназы (ИТК). Кризотиниб был первым одобренным ингибитором ALK, однако, несмотря на достигаемый ответ у большинства пациентов в течение первых двух лет с момента начала терапии, развивалось прогрессирование заболевания, зачастую за счет интракраниального поражения. Появление препаратов второго – церитиниб, алектиниб, бригатиниб и третьего поколений – лорлатиниб привело к статистически значимому улучшению выживаемости без прогрессирования (ВБП), а также контролю в отношении интракраниальных проявлений заболевания и смене первоначальной стратегии лечения этих пациентов. Помимо этого, разработка ИТК новых поколений позволила решить проблему приобретенной резистентности, а также добиться наилучших результатов при наличии таких неблагоприятных факторов, как наличие мутации TP53 и/или при малочувствительных к ингибиторам ALK вариантах транслокации внутриклеточного киназного домена белка ALK с терминальным концом эхинодермального микротубулярного белка 4 (EML4). Таким образом, прогресс терапевтических возможностей лечения ALK-позитивного мНМРЛ полностью изменил течение заболевания, что привело к существенному увеличению общей выживаемости (ОВ) не только при последовательном применении ИТК разных поколений, но и при выборе максимально эффективного варианта первой линии. В данной статье мы представим анализ данных в отношении эффективности и токсичности ИТК 3-го поколения лорлатиниба в первой линии терапии ALK+ мНМРЛ.

Non-small cell lung cancer (NSCLC) that occupies a leading place in the pattern of cancer incidence and mortality is a highly heterogeneous group of diseases. The presence of a wide spectrum of NSCLC driver mutations has led to a fundamentally different understanding of the treatment strategy for this cohort of patients and a significant improvement in long-term oncological outcomes, even in the metastatic process. Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene loci on chromosome 2 are found in approximately 3–5% of patients with metastatic NSCLC (mNSCLC) and in most cases are associated not only with a number of specific clinical features, but also with high sensitivity to targeted therapy with tyrosine kinase inhibitors (TKI). Crizotinib was the first approved ALK inhibitor, but although most patients achieved response within the first two years after start of the treatment, disease progression occurred often due to intracranial injury. The development of second-(ceritinib, alectinib), brigatinib and third-generation (lorlatinib) drugs has led to a statistically significant improvement in progression-free survival (PFS) rates, as well as control over intracranial manifestations of the disease and a change in the initial treatment strategy for these patients. In addition, new-generations of TKIs were developed to solve the problem of acquired resistance, as well as to achieve the best outcomes in the presence of such unfavourable factors as the presence of a TP53 mutation and/or ALK inhibitor low-sensitive translocation variants of the intracellular kinase domain of EML4 (echinoderm microtubule‐associated protein‐like 4)‐ALK (anaplastic lymphoma kinase) protein. Thus, advances in the therapeutic options for ALK-positive mNSCLC has completely changed the course of the disease, resulting in a significant increase in overall survival (OS) rates not only with the sequential use of different generation TKIs, but also with the choice of the most effective first-line option. In this article, we present an analysis of data on the efficacy and toxicity of lorlatinib, a third-generation TKI, in the first-line treatment for ALK+ mNSCLC.

метастатический немелкоклеточный рак легкихингибиторы тирозинкиназылорлатинибALK-позитивный рак легкогометастазы в центральную нервную системуmetastatic non-small cell lung cancertyrosine kinase inhibitorslorlatinibALK-positive lung cancermetastases to the central nervous systemReferencesShaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011;17(8):2081–2086. https://doi.org/10.1158/1078-0432.CCR-10-1591.Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011;17(8):2081–2086. https://doi.org/10.1158/1078-0432.CCR-10-1591.Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol. 2021;12(4):217–237. https://doi.org/10.5306/wjco.v12.i4.217.Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol. 2021;12(4):217–237. https://doi.org/10.5306/wjco.v12.i4.217.Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer. 2013;82(2):179–189. https://doi.org/10.1016/j.lungcan.2013.07.025.Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer. 2013;82(2):179–189. https://doi.org/10.1016/j.lungcan.2013.07.025.Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–2394. https://doi.org/10.1056/NEJMoa1214886.Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–2394. https://doi.org/10.1056/NEJMoa1214886.Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T et al.; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–2177. https://doi.org/10.1056/NEJMoa1408440.Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T et al.; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–2177. https://doi.org/10.1056/NEJMoa1408440.Schrank Z, Chhabra G, Lin L, Iderzorig T, Osude C, Khan N et al. Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance. Cancers (Basel). 2018;10(7):224. https://doi.org/10.3390/cancers10070224.Schrank Z, Chhabra G, Lin L, Iderzorig T, Osude C, Khan N et al. Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance. Cancers (Basel). 2018;10(7):224. https://doi.org/10.3390/cancers10070224.Ahnert RJ, Gray N, Mok T, Gainor J. What It Takes to Improve a First-Generation Inhibitor to a Second- or Third-Generation Small Molecule. Am Soc Clin Oncol Educ Book. 2019:39:196–205. https://doi.org/10.1200/EDBK_242209.Ahnert RJ, Gray N, Mok T, Gainor J. What It Takes to Improve a First-Generation Inhibitor to a Second- or Third-Generation Small Molecule. Am Soc Clin Oncol Educ Book. 2019:39:196–205. https://doi.org/10.1200/EDBK_242209.Puig de la Bellacasa R, Karachaliou N, Estrada-Tejedor R, Teixidó J, Costa C, Borrell JI. ALK and ROS1 as a joint target for the treatment of lung cancer: a review. Transl Lung Cancer Res. 2013;2(2):72–86. https://doi.org/10.3978/j.issn.2218-6751.2013.03.1.Puig de la Bellacasa R, Karachaliou N, Estrada-Tejedor R, Teixidó J, Costa C, Borrell JI. ALK and ROS1 as a joint target for the treatment of lung cancer: a review. Transl Lung Cancer Res. 2013;2(2):72–86. https://doi.org/10.3978/j.issn.2218-6751.2013.03.1.Wang W-C, Shiao H-Y, Lee C-C, Fung K-S, Hsieh H-P. Anaplastic lymphoma kinase (ALK) inhibitors: A review of design and discovery. Med Chem Commun. 2014;5(9):1266–1279. https://doi.org/10.1039/C4MD00048J.Wang W-C, Shiao H-Y, Lee C-C, Fung K-S, Hsieh H-P. Anaplastic lymphoma kinase (ALK) inhibitors: A review of design and discovery. Med Chem Commun. 2014;5(9):1266–1279. https://doi.org/10.1039/C4MD00048J.Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim D-W. et al. Updated 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. Ann Oncol. 2020;31(8):1056–1064. https://doi.org/10.1016/j.annonc.2020.04.478.Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim D-W. et al. Updated 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. Ann Oncol. 2020;31(8):1056–1064. https://doi.org/10.1016/j.annonc.2020.04.478.Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. https://doi.org/10.1056/NEJMoa1311107.Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. https://doi.org/10.1056/NEJMoa1311107.Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829–838. https://doi.org/10.1056/NEJMoa1704795.Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829–838. https://doi.org/10.1056/NEJMoa1704795.Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–242. https://doi.org/10.1016/S1470-2045(15)00488-X.Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–242. https://doi.org/10.1016/S1470-2045(15)00488-X.Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2027–2039. https://doi.org/10.1056/NEJMoa1810171.Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2027–2039. https://doi.org/10.1056/NEJMoa1810171.Kim D-W, Tiseo M, Ahn M-J, Reckamp KL, Hansen KH, Kim S-W et al. Brigatinib in Patients with Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017;35(22):2490–2498. https://doi.org/10.1200/JCO.2016.71.5904.Kim D-W, Tiseo M, Ahn M-J, Reckamp KL, Hansen KH, Kim S-W et al. Brigatinib in Patients with Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017;35(22):2490–2498. https://doi.org/10.1200/JCO.2016.71.5904.Shaw AT, Bauer TM, Marinis FD, Felip E, Goto Y, Liu G et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020;383(21):2018–2029. https://doi.org/10.1056/NEJMoa2027187.Shaw AT, Bauer TM, Marinis FD, Felip E, Goto Y, Liu G et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020;383(21):2018–2029. https://doi.org/10.1056/NEJMoa2027187.Solomon BJ, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, Felip E. et al. Final Overall Survival Analysis from a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(22):2251–2258. https://doi.org/10.1200/JCO.2017.77.4794.Solomon BJ, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, Felip E. et al. Final Overall Survival Analysis from a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(22):2251–2258. https://doi.org/10.1200/JCO.2017.77.4794.Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917–929. https://doi.org/10.1016/S0140-6736(17)30123-X.Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917–929. https://doi.org/10.1016/S0140-6736(17)30123-X.Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): An open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29–39. https://doi.org/10.1016/S0140-6736(17)30565-2.Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): An open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29–39. https://doi.org/10.1016/S0140-6736(17)30565-2.Nakagawa K, Hida T, Nokihara H, Morise M, Azuma K, Kim YH. et al. Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2020;139:195–199. https://doi.org/10.1016/j.lungcan.2019.11.025.Nakagawa K, Hida T, Nokihara H, Morise M, Azuma K, Kim YH. et al. Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2020;139:195–199. https://doi.org/10.1016/j.lungcan.2019.11.025.Camidge DR, Kim HR, Ahn M-J, Yang JCH, Han J-Y, Hochmair MJ et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020;38(31):3592–3603. https://doi.org/10.1200/JCO.20.00505.Camidge DR, Kim HR, Ahn M-J, Yang JCH, Han J-Y, Hochmair MJ et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020;38(31):3592–3603. https://doi.org/10.1200/JCO.20.00505.Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452–463. https://doi.org/10.1016/S1470-2045(15)00614-2.Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452–463. https://doi.org/10.1016/S1470-2045(15)00614-2.Crino L, Ahn MJ, de Marinis F, Groen HJ, Wakelee H, Hida T et al. Multicenter Phase II Study of Whole-Body and Intracranial Activity with Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated with Chemotherapy and Crizotinib: Results From ASCEND-2. J Clin Oncol. 2016;34(24):2866–2873. https://doi.org/10.1200/JCO.2015.65.5936.Crino L, Ahn MJ, de Marinis F, Groen HJ, Wakelee H, Hida T et al. Multicenter Phase II Study of Whole-Body and Intracranial Activity with Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated with Chemotherapy and Crizotinib: Results From ASCEND-2. J Clin Oncol. 2016;34(24):2866–2873. https://doi.org/10.1200/JCO.2015.65.5936.Ou SH, Ahn JS, de Petris L, Govindan R, Yang JC, Hughes B et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol. 2016;34(7):661–668.https://doi.org/10.1200/jco.2015.63.9443.Ou SH, Ahn JS, de Petris L, Govindan R, Yang JC, Hughes B et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol. 2016;34(7):661–668.https://doi.org/10.1200/jco.2015.63.9443.Ahn M, Camidge DR, Tiseo M, Reckamp K, Hansen K, Kim S et al. OA 05.05 Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial. J Thorac Oncol. 2017;12(11):S1755–S1756. https://doi.org/10.1016/j.jtho.2017.09.350.Ahn M, Camidge DR, Tiseo M, Reckamp K, Hansen K, Kim S et al. OA 05.05 Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial. J Thorac Oncol. 2017;12(11):S1755–S1756. https://doi.org/10.1016/j.jtho.2017.09.350.Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: Results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654–1667. https://doi.org/10.1016/S1470-2045(18)30649-1.Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: Results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654–1667. https://doi.org/10.1016/S1470-2045(18)30649-1.Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin CC, Soo RA et al. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2019;37(16):1370–1379. https://doi.org/10.1200/JCO.18.02236.Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin CC, Soo RA et al. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2019;37(16):1370–1379. https://doi.org/10.1200/JCO.18.02236.Hida T, Seto T, Horinouchi H, Maemondo M, Takeda M, Hotta K et al. Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9. Cancer Sci. 2018;109(9):2863–2872. https://doi.org/10.1111/cas.13721.Hida T, Seto T, Horinouchi H, Maemondo M, Takeda M, Hotta K et al. Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9. Cancer Sci. 2018;109(9):2863–2872. https://doi.org/10.1111/cas.13721.Lin MM, Pan X, Hou P, Allen S, Baumann P, Hochmair MJ. Treatment duration of brigatinib in patients enrolled in the international expanded access program (EAP). Ann Oncol. 2019;30(Suppl. 2):ii48. https://doi.org/10.1093/annonc/mdz063.006.Lin MM, Pan X, Hou P, Allen S, Baumann P, Hochmair MJ. Treatment duration of brigatinib in patients enrolled in the international expanded access program (EAP). Ann Oncol. 2019;30(Suppl. 2):ii48. https://doi.org/10.1093/annonc/mdz063.006.Chen J, O’Gorman MT, James LP, Klamerus KJ, Mugundu G, Pithavala YK. Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study. Clin Pharmacokinet. 2021;60(10):1313–1324. https://doi.org/10.1007/s40262-021-01015-z.Chen J, O’Gorman MT, James LP, Klamerus KJ, Mugundu G, Pithavala YK. Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study. Clin Pharmacokinet. 2021;60(10):1313–1324. https://doi.org/10.1007/s40262-021-01015-z.Horn L, Whisenant JG, Wakelee H, Reckamp KL, Qiao H, Leal TA et al. Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer. J Thorac Oncol. 2019;14(11):1901–1911. https://doi.org/10.1016/j.jtho.2019.08.003.Horn L, Whisenant JG, Wakelee H, Reckamp KL, Qiao H, Leal TA et al. Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer. J Thorac Oncol. 2019;14(11):1901–1911. https://doi.org/10.1016/j.jtho.2019.08.003.Frost N, Christopoulos P, Kauffmann-Guerrero D, Stratmann J, Riedel R, Schaefer M et al. Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program. Ther Adv Med Oncol. 2021;13:1758835920980558. https://doi.org/10.1177/1758835920980558.Frost N, Christopoulos P, Kauffmann-Guerrero D, Stratmann J, Riedel R, Schaefer M et al. Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program. Ther Adv Med Oncol. 2021;13:1758835920980558. https://doi.org/10.1177/1758835920980558.Okada K, Araki M, Sakashita T, Ma B, Kanada R, Yanagitani N et al. Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance. EBioMedicine. 2019;41:105–119. https://doi.org/10.1016/j.ebiom.2019.01.019.Okada K, Araki M, Sakashita T, Ma B, Kanada R, Yanagitani N et al. Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance. EBioMedicine. 2019;41:105–119. https://doi.org/10.1016/j.ebiom.2019.01.019.O’Regan L, Barone G, Adib R, Woo CG, Jeong HJ, Richardson EL et al. EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7. J Cell Sci. 2020;133(9):jcs241505. https://doi.org/10.1242/jcs.241505.O’Regan L, Barone G, Adib R, Woo CG, Jeong HJ, Richardson EL et al. EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7. J Cell Sci. 2020;133(9):jcs241505. https://doi.org/10.1242/jcs.241505.Christopoulos P, Endris V, Bozorgmehr F, Elsayed M, Kirchner M, Ristau J et al. EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer. Int J Cancer. 2018;142(12):2589–2598. https://doi.org/10.1002/ijc.31275.Christopoulos P, Endris V, Bozorgmehr F, Elsayed M, Kirchner M, Ristau J et al. EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer. Int J Cancer. 2018;142(12):2589–2598. https://doi.org/10.1002/ijc.31275.Noh KW, Lee MS, Lee SE, Song JY, Shin HT, Kim YJ et al. Molecular break-down: A comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. J Pathol. 2017;243(3):307–319. https://doi.org/10.1002/path.4950.Noh KW, Lee MS, Lee SE, Song JY, Shin HT, Kim YJ et al. Molecular break-down: A comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. J Pathol. 2017;243(3):307–319. https://doi.org/10.1002/path.4950.Christopoulos P, Kirchner M, Endris V, Stenzinger A, Thomas M. EML4-ALK V3, treatment resistance, and survival: Refining the diagnosis of ALK+ NSCLC. J Thorac Dis. 2018;10(Suppl. 17):1989–1991. https://doi.org/10.21037/jtd.2018.05.61.Christopoulos P, Kirchner M, Endris V, Stenzinger A, Thomas M. EML4-ALK V3, treatment resistance, and survival: Refining the diagnosis of ALK+ NSCLC. J Thorac Dis. 2018;10(Suppl. 17):1989–1991. https://doi.org/10.21037/jtd.2018.05.61.Bearz A, Martini JF, Jassem J, Kim S-W, Chang G-C, Shaw AT et al. Phase 3 trial of lorlatinib in treatment-naïve patients (Pts) with ALK-positive advanced non-small cell lung cancer (NSCLC): Comprehensive plasma and tumor genomic analyses. J Clin Oncol. 2022;40(16 Suppl.):9070. https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.9070Bearz A, Martini JF, Jassem J, Kim S-W, Chang G-C, Shaw AT et al. Phase 3 trial of lorlatinib in treatment-naïve patients (Pts) with ALK-positive advanced non-small cell lung cancer (NSCLC): Comprehensive plasma and tumor genomic analyses. J Clin Oncol. 2022;40(16 Suppl.):9070. https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.9070Solomon BJ, Bauer TM, Mok TSK, Liu G, Mazieres J, de Marinis F et al. Efficacy 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. Lancet Respir Med. 2023;11(4):354–366. https://doi.org/10.1016/S2213-2600(22)00437-4.Solomon BJ, Bauer TM, Mok TSK, Liu G, Mazieres J, de Marinis F et al. Efficacy 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. Lancet Respir Med. 2023;11(4):354–366. https://doi.org/10.1016/S2213-2600(22)00437-4.Bauer TM, Felip E, Solomon BJ, Thurm H, Peltz G, Chioda MD, Shaw AT. Clinical Management of Adverse Events Associated with Lorlatinib. Oncologist. 2019;24(8):1103–1110. https://doi.org/10.1634/theoncologist.2018-0380.Bauer TM, Felip E, Solomon BJ, Thurm H, Peltz G, Chioda MD, Shaw AT. Clinical Management of Adverse Events Associated with Lorlatinib. Oncologist. 2019;24(8):1103–1110. https://doi.org/10.1634/theoncologist.2018-0380.Ou S-HI, Lee ATM, Nagasaka M. From preclinical efficacy to 2022 (36.7 months median follow-up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC. Crit Rev Oncol Hematol. 2023;187:104019. https://doi.org/10.1016/j.critrevonc.2023.104019.Ou S-HI, Lee ATM, Nagasaka M. From preclinical efficacy to 2022 (36.7 months median follow-up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC. Crit Rev Oncol Hematol. 2023;187:104019. https://doi.org/10.1016/j.critrevonc.2023.104019.Peng Y, Zhao Q, Liao Z, Ma Y, Ma D. Efficacy 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. Cancer. 2023;129(8):1261–1275.Peng Y, Zhao Q, Liao Z, Ma Y, Ma D. Efficacy 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. Cancer. 2023;129(8):1261–1275.

The authors declare that there are no conflicts of interest present.