Efficacy and safety of lorlatinib as first-line treatment for advanced ALK-mutated non-small cell lung cancer: A clinical case study

In recent years, approaches to the pharmacological treatment of non-small cell lung cancer (NSCLC) have significantly evolved due to a deeper understanding of tumor biology and, consequently, the active development of personalized medicine and the introduction of targeted therapies. The identification of activating mutations, including ALK gene rearrangements, enables long-term objective control, which is particularly crucial in young patients with extensive metastatic disease and brain metastases (BM). The high rate of central nervous system (CNS) metastases characteristic of ALK-positive NSCLC underscores the importance of selecting therapeutic agents with high intracranial activity. Lorlatinib, a third-generation ALK tyrosine kinase inhibitor (TKI), is capable of crossing the blood-brain barrier and effectively suppressing resistance mutations that may develop during treatment with crizotinib or second-generation TKIs. Initially, lorlatinib was used in the second-line and subsequent lines of therapy; however, updated results from the CROWN study have demonstrated its unprecedented efficacy as a first-line treatment, including in patients with BM. Currently, lorlatinib is approved in the Russian Federation for the treatment of ALK-positive advanced NSCLC in both previously treated patients and as a first-line therapy. This paper presents a clinical case of a 49-yearold patient with advanced ALK-positive NSCLC and brain metastases. Following the diagnostic phase, which included videoassisted thoracoscopy and morphological verification, the patient underwent a course of chemotherapy with cisplatin and pemetrexed. Subsequently, based on the results of molecular genetic testing, lorlatinib was initiated at a dose of 100 mg/day. Within a month, a significant regression of CNS metastases was observed. Therapy was accompanied by minimal side effects, including hypercholesterolemia and elevated liver enzymes, which were successfully managed with lipid-lowering agents and physical activity. During targeted therapy, the patient has maintained stable disease for 26 months, showing a strong clinical response without the need for dose reduction. This case report highlights the efficacy and tolerability of lorlatinib in the treatment of ALK-positive NSCLC with BM and underscores its potential in clinical practice.

1. Каприн АД, Старинский ВВ, Шахзадова АО (ред.). Состояние онкологической помощи населению России в 2022 году. М.: МНИОИ им. П.А. Герцена - филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2022. 239 с. Режим доступа: https://oncology-association.ru/wp-content/ uploads/2023/08/sop-2022-el.versiya_compressed.pdf.

2. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. https://doi.org/10.3322/caac.21834.

3. Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(1):39-51. https://doi.org/10.1016/j.jtho.2015.09.009.

4. Antonia SJ, Borghaei H, Ramalingam SS, Horn L, De Castro Carpeño J, Pluzanski A et al. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis. Lancet Oncol. 2019;20(10):1395-1408. https://doi.org/10.1016/S1470-2045(19)30407-3.

5. Singhi EK, Horn L, Sequist LV, Heymach J, Langer CJ. Advanced Non–Small Cell Lung Cancer: Sequencing Agents in the EGFR-Mutated/ALK-Rearranged Populations. Am Soc Clin Oncol Educ Book. 2019;39:e187-e197. https://doi.org/10.1200/EDBK_237821.

6. Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim DW 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.

7. 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.

8. Beardslee T, Lawson J. Alectinib and Brigatinib: New Second-Generation ALK Inhibitors for the Treatment of Non-Small Cell Lung Cancer. J Adv Pract Oncol. 2018;9(1):94-101. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC6296421/.

9. 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.

10. Griesinger F, Roeper J, Pöttgen C, Willborn KC, Eberhardt WEE. Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms. Oncotarget. 2018;9(80):35181-35194. https://doi.org/10.18632/oncotarget.26073.

11. Ito K, Yamanaka T, Hayashi H, Hattori Y, Nishino K, Kobayashi H et al. Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study. Eur J Cancer. 2021;145:183-193. https://doi.org/10.1016/j.ejca.2020.12.026.

12. Duruisseaux M, Besse B, Cadranel J, Pérol M, Mennecier B, Bigay-Game L et al. Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study. Oncotarget. 2017;8(13):21903-21917. https://doi.org/10.18632/oncotarget.15746.

13. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T et al. 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.

14. 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.

15. Solomon BJ, Liu G, Felip E, Mok TSK, Soo RA, Mazieres J et al. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol. 2024;42(29):3400-3409. https://doi.org/10.1200/JCO.24.00581.

16. Hansen KH, Johansen JS, Urbanska EM, Meldgaard P, Hjorth-Hansen P, Kristiansen C et al. Clinical outcomes of ALK+ non-small cell lung cancer in Denmark. Acta Oncol. 2023;62(12):1775-1783. https://doi.org/10.1080/0284186X.2023.2263153.

17. Solomon BJ, Bauer TM, Ou S-HI, Liu G, Hayashi H, Bearz A et al. Post Hoc Analysis of Lorlatinib Intracranial Efcacy and Safety in Patients With ALKPositive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study. J Clin Oncol. 2022;40(31):3593-3602. https://doi.org/10.1200/JCO.21.02278..