{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T21:57:02Z","timestamp":1787954222480,"version":"build-2784847793"},"reference-count":25,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Anaplastic lymphoma kinase (ALK) rearrangement is a well-established oncogenic driver alteration in non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs), particularly lorlatinib, have significantly improved the prognosis of ALK-positive NSCLC patients. Although high programmed death-ligand 1 (PD-L1) expression (\u226550%) is generally associated with favorable responses to immune checkpoint inhibitors (ICIs), PD-L1 has not been shown to reliably predict ICI benefit in ALK-rearranged disease, and optimal management after ALK TKI resistance remains challenging. Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS \u2265 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression.<\/jats:p>","DOI":"10.3390\/curroncol33050258","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:01:18Z","timestamp":1777474878000},"page":"258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Overcoming Acquired MET-Driven Resistance to First-Line Lorlatinib: Successful Combination of Lorlatinib and Envafolimab in an ALK-Positive NSCLC Patient with Ultra-High PD-L1 Expression"],"prefix":"10.3390","volume":"33","author":[{"given":"Lu","family":"Ding","sequence":"first","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyizha","family":"Nuersulitan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanxiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2489-7791","authenticated-orcid":false,"given":"Minglei","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/j.ejca.2010.04.002","article-title":"The biology and treatment of EML4-ALK non-small cell lung cancer","volume":"46","author":"Sasaki","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nature05945","article-title":"Identification of the transforming EML4\u2013ALK fusion gene in non-small-cell lung cancer","volume":"448","author":"Soda","year":"2007","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.1200\/JCO.24.00581","article-title":"Lorlatinib versus crizotinib in patients with advanced ALK-positive non\u2013small cell lung cancer: 5-year outcomes from the phase III CROWN study","volume":"42","author":"Solomon","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.jtho.2025.02.021","article-title":"First-line lorlatinib versus crizotinib in Asian patients with advanced ALK-positive NSCLC: Five-year outcomes from the CROWN study","volume":"20","author":"Wu","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1158\/2159-8290.CD-16-0596","article-title":"Molecular mechanisms of resistance to first-and second-generation ALK inhibitors in ALK-rearranged lung cancer","volume":"6","author":"Gainor","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1007\/s00432-020-03444-y","article-title":"Clinicopathological and molecular characteristics associated with PD-L1 expression in non-small cell lung cancer: A large-scale, multi-center, real-world study in China","volume":"147","author":"Zheng","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1007\/s12539-019-00331-0","article-title":"PD-L1 expression and its regulation in lung adenocarcinoma with ALK translocation","volume":"11","author":"Ma","year":"2019","journal-title":"Interdiscip. Sci. Comput. Life Sci."},{"key":"ref_8","first-page":"100685","article-title":"Avelumab in combination with lorlatinib or crizotinib in patients with previously treated advanced NSCLC: Phase 1b\/2 results from the JAVELIN lung 101 trial","volume":"5","author":"Solomon","year":"2024","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.jtho.2018.02.022","article-title":"Phase 1\/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation\u2014Positive advanced non\u2013small cell lung cancer (CheckMate 370)","volume":"13","author":"Spigel","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S75","DOI":"10.1016\/j.jtho.2024.09.134","article-title":"MA06.07 Patterns of progression with lorlatinib and insights into subsequent anticancer therapy efficacy in advanced ALK+ NSCLC","volume":"19","author":"Mok","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8626","DOI":"10.1200\/JCO.2024.42.16_suppl.8626","article-title":"High PD-L1 expression among patients with ALK rearranged non\u2013small cell lung cancer and response to first line ALK tyrosine kinase inhibitors","volume":"42","author":"Nie","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"763","DOI":"10.3390\/cancers7020763","article-title":"Mechanisms of acquired resistance to ALK inhibitors and the rationale for treating ALK-positive lung cancer","volume":"7","author":"Isozaki","year":"2015","journal-title":"Cancers"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1158\/1078-0432.CCR-19-3906","article-title":"MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer","volume":"26","author":"Yoda","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_14","first-page":"100868","article-title":"The impact of PD-L1 expression status on the prognosis of ALK-positive lung cancer patients","volume":"42","author":"Wang","year":"2024","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1108514","DOI":"10.1080\/2162402X.2015.1108514","article-title":"EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1\u03b1 and STAT3","volume":"5","author":"Koh","year":"2016","journal-title":"OncoImmunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/annonc\/mdz167","article-title":"Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry","volume":"30","author":"Mazieres","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Oya, Y., Kuroda, H., Nakada, T., Takahashi, Y., Sakakura, N., and Hida, T. (2020). Efficacy of immune checkpoint inhibitor monotherapy for advanced non-small-cell lung cancer with ALK rearrangement. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072623"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.semcancer.2017.02.010","article-title":"The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells","volume":"45","author":"Ramachandran","year":"2017","journal-title":"Semin. Cancer Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.annonc.2022.12.009","article-title":"Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"34","author":"Hendriks","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"216140","DOI":"10.1016\/j.canlet.2023.216140","article-title":"Potent antitumor activity of ensartinib in MET exon 14 skipping-mutated non-small cell lung cancer","volume":"561","author":"Xia","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17004","DOI":"10.1038\/celldisc.2017.4","article-title":"Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade","volume":"3","author":"Zhang","year":"2017","journal-title":"Cell Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e009165","DOI":"10.1136\/jitc-2024-009165","article-title":"Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect","volume":"12","author":"Lu","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S1470-2045(17)30380-7","article-title":"Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: A secondary analysis of the KEYNOTE-001 phase 1 trial","volume":"18","author":"Shaverdian","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1667\/RADE-24-00040.1","article-title":"Abscopal effects, clastogenic effects and bystander effects: 70 years of non-targeted effects of radiation","volume":"202","author":"Lyng","year":"2024","journal-title":"Radiat. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Huang, Y.-F., Xie, W.-J., Fan, H.-Y., and Du, J. (2019). Comparative safety of PD-1\/PD-L1 inhibitors for cancer patients: Systematic review and network meta-analysis. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00972"}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/5\/258\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T04:18:04Z","timestamp":1777609084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/5\/258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":25,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["curroncol33050258"],"URL":"https:\/\/doi.org\/10.3390\/curroncol33050258","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]}}}