From Metabolic to Pathologic Complete Response: Case Report of Neoadjuvant Lorlatinib in Stage IIIB ALK-Positive NSCLC Combined with Uniportal VATS

From Metabolic to Pathologic Complete Response: Case Report of Neoadjuvant Lorlatinib in Stage IIIB ALK-Positive NSCLC Combined with Uniportal VATS | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report From Metabolic to Pathologic Complete Response: Case Report of Neoadjuvant Lorlatinib in Stage IIIB ALK-Positive NSCLC Combined with Uniportal VATS Ruifeng Li, Chudong Wang, Yuxuan Li, Jianyao Zhao, Man Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8711384/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract While stage IIIB non-small cell lung cancer (NSCLC) is generally considered unresectable, a subset of patients may benefit from neoadjuvant therapy following comprehensive evaluation. We report a 35-year-old non-smoking female diagnosed with stage IIIB (cT1bN2bM0) adenocarcinoma of the left lower lobe with multiple-station mediastinal lymph node metastasis. Based on a multidisciplinary evaluation of multimodality imaging and genomic features of ALK-positive, the patient with high tumor-burden yet no significant comorbidities received neoadjuvant lorlatinib. The patient achieved a complete metabolic response on restaging PET-CT after 10 weeks of lorlatinib, which led to a multidisciplinary decision to undergo uniportal VATS lobectomy. Pathological examination confirmed a pathological complete response (pCR). Following a 5-day hospitalization without complications, the patient remains disease-free at the 12-month follow-up. To our knowledge, this is the first reported case of combining neoadjuvant lorlatinib and uniportal VATS to achieve pCR predicted by complete metabolic response in stage IIIB ALK-positive NSCLC. Non-small cell lung cancer Neoadjuvant targeted therapy Pathological complete response Lorlatinib Case report Figures Figure 1 Figure 2 Figure 3 Introduction Approximately 30% of non-small cell lung cancer (NSCLC) cases are diagnosed at stage III, (1) with a subset harboring actionable driver mutations such as ALK fusions. The role of surgery in stage IIIB NSCLC remains controversial, necessitating comprehensive evaluation to identify patients who may benefit from multimodal strategies. In addition, the efficacy of ALK tyrosine kinase inhibitors (ALK-TKIs) in advanced NSCLC and the success of neoadjuvant EGFR inhibition provide a strong rationale for exploring neoadjuvant ALK-TKIs. Despite the extensive use of first- and second-generation ALK-TKIs, their long-term efficacy remains limited by acquired resistance. However, the use of third-generation ALK-TKIs, such as lorlatinib, in the neoadjuvant setting for ALK-positive NSCLC has not been widely reported and may delay the emergence of resistance. (2) Here, we present a rare case of a stage IIIB ALK-positive NSCLC patient who achieved a pathological complete response (pCR) after neoadjuvant lorlatinib, and attempt to utilize complete metabolic response (CMR) as a radiological biomarker to determine treatment duration, aiming to achieve an optimal balance between therapeutic outcomes and cost-effectiveness. Case Report A 35-year-old asymptomatic female without significant medical or family history presented with an incidentally discovered pulmonary nodule on routine physical examination. Computed tomography (CT) revealed a 1.8 × 1.3 cm solid nodule in the anteromedial basal segment (S7 + 8) of the left lower lobe, accompanied by enlarged ipsilateral hilar and mediastinal lymph nodes (Fig. 1 ). Histopathological examination of station 7 lymph nodes confirmed invasive adenocarcinoma, showing positive staining for TTF-1, Napsin A, cytokeratin (CK), and ALK protein (Fig. 2 B). Following multidisciplinary team discussion, a comprehensive evaluation was performed. Pulmonary function tests revealed normal lung ventilation. Positron emission tomography-CT (PET-CT) demonstrated increased fluorodeoxyglucose (FDG) uptake within the nodule (SUVmax 3.3) and pronounced fibroblast activation protein inhibitor (FAPI) uptake in the station 7 lymph nodes (SUVmax 11.0), suggesting malignancy with lymph node metastasis in the absence of distant metastasis (Fig. 2 A). According to the AJCC/UICC 9th edition staging system, the clinical stage was cT1bN2bM0 (stage IIIB). Multigene testing (Quantitative Real-time PCR) detected an ALK fusion in exons 19/20. After systematic assessment, the patient commenced neoadjuvant therapy with lorlatinib (100 mg once daily). Hypercholesterolemia emerged on day 15 and was managed with rosuvastatin without treatment interruption or dose reduction and no other adverse events were observed. A restaging PET-CT at week 10 demonstrated a partial response (PR): the primary lesion decreased to 1.4 × 0.8 × 0.6 cm without enlargement or increased FDG uptake in the previously involved lymph nodes, consistent with a CMR (Fig. 2 C). The post‑treatment clinical stage was ycT1N0M0. After a 10-week course of lorlatinib and 2-week treatment-free interval, uniportal video-assisted thoracoscopic surgery (VATS) left lower lobectomy with mediastinal lymphadenectomy was performed at week 12 (Fig. 3 ). Complete surgical resection (R0) was achieved with 20 ml intraoperative bleeding, and only mild adhesions required dissection during the procedure. Pathologic examination confirmed a pathological complete response (pCR), with the tumor bed and lymph nodes showing complete fibrosis and inflammatory replacement (Fig. 2 D). The patient was discharged on postoperative day 5 without complications and started on adjuvant lorlatinib (100 mg once daily) with a planned duration of 1 year. The surveillance plan involves thoracic CT every 3 months and 3-year disease-free survival tracking. At the 12-month postoperative follow-up, the patient showed no signs of recurrence or unanticipated events (Fig. 2 E). Figure 2 illustrates the timeline of the treatment. Discussion Although surgery is considered the primary treatment modality for NSCLC, curative resection is feasible in only 20–25% of patients at diagnosis. (3) Furthermore, evidence supporting the preoperative use of TKIs, mostly first- and second-generation agents, is limited and postoperative recurrence remains a challenge. Lorlatinib, a third-generation ALK-TKI with broad resistance mutation coverage and proven efficacy in the CROWN trial, (4),(5) prompted our consideration of its first-line use to mitigate refractory mutations and improve survival outcomes. Complete metabolic response (CMR), defined as 18F-FDG uptake indistinguishable from surrounding background, is an important quantitative indicator for treatment response and a validated prognostic tool in malignancies such as breast cancer and Hodgkin lymphoma. Informed by the achievement of CMR at 10 weeks, and data from prior trials (at least 9 weeks in NeoADAURA), we adopted a 10-week duration of neoadjuvant targeted therapy. Notably, in this case, histopathology remains the gold standard for confirming a pCR, while 18F-FDG PET-CT permits earlier response assessment. The 77.3% SUVmax reduction in primary tumor indicating the pCR is consistent with the recent studies. (6),(7) In addition, the targeted agents exhibit distinct toxicity profiles, including risks of bleeding and wound healing implications, which can pose technical challenges to subsequent surgery dissection. For instance, Long et al. reported that only 9 of 32 patients with locally advanced NSCLC were eligible for a minimally invasive approach. (8) However, in this case, the uniportal VATS was successfully completed with R0 resection, and only mild adhesions were noted with no air leak, conversion to thoracotomy, and other complications. The drainage tube was removed on postoperative day 3, and the patient was discharged on day 5. These data indicate that neoadjuvant lorlatinib may improve resectability through tumor downstaging and pCR without compromising perioperative safety or patient-reported outcomes, and the treatment aligns with Enhanced Recovery After Surgery principles. Conclusion Neoadjuvant lorlatinib may represent a promising and tolerable preoperative strategy for selected patients with stage IIIB ALK‑positive NSCLC, warranting evaluation in randomized controlled trials to define its efficacy, predictive biomarkers of optimal duration, and effects on long‑term survival and surgical outcomes. Abbreviations NSCLC Non-small cell lung cancer ALK Anaplastic Lymphoma Kinase EGFR Epidermal Growth Factor Receptor CK Cytokeratin TKI Tyrosine kinase inhibitors VATS Video-assisted thoracoscopic surgery PET-CT Positron emission tomography- Computed tomography PR Partial response pCR Pathological complete response CMR Complete metabolic response Declarations Ethics approval and consent to participate We obtained comprehensive informed consent from the patient. Ethical approval for this case report was waived by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University. Consent for publication All the author and the patient have consent for the publication. Data availability statement Not applicable. Funding None declared. Conflicts of interest/Competing interests None declared. Authors’ contributions Ruifeng Li : Conceptualization; Data curation; Writing - original draft; Writing - review & editing; Chudong Wang: Methodology;Writing - original draft; Project administration; Yuxuan Li: Resources; Data curation; Jianyao Zhao: Resources; Data curation; Man Zhang: Conceptualization; Data curation; Shuben Li: Conceptualization; Supervision; Writing - review & editing; All the authors reviewed approved the content of the manuscript. Acknowledgement Written informed consent was obtained from the patient for the publication of this case report. All adverse events were documented and reported in accordance with regulatory requirements to the national pharmacovigilance system. References Miao D, Zhao J, Han Y, Zhou J, Li X, Zhang T, et al. Management of locally advanced non-small cell lung cancer: State of the art and future directions. Cancer Commun (Lond). 2024;44(1):23-46. Nagasaka M, Ou SI. Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC. J Thorac Oncol. 2021;16(4):532-6. Liang Y, Wakelee HA. Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2013;2(5):403-10. 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):3400-9. Lu S, Zhou Q, Liu X, Du Y, Fan Y, Cheng Y, et al. Updated Efficacy and Safety of Lorlatinib in a Phase 2 Study in Chinese Patients With Previously Treated Advanced ALK-Positive Non-small Cell Lung Cancer. Clin Lung Cancer. 2024;25(7):e295-e303.e4. Zhuang F, Haoran E, Huang J, Wu J, Xu L, Zhang L, et al. Utility of (18)F-FDG PET/CT uptake values in predicting response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer. Lung Cancer. 2023;178:20-7. Seitlinger J, Salko O, Bulgarelli Maqueda L, Meng A, Têtu M, Desilets A, et al. Neoadjuvant chemo-immunotherapy in Non-Small Cell Lung Cancer: Can Positron Emission Tomography scan predict complete pathological response? Ann Thorac Surg. 2025. Jiang L, Huang J, Jiang S, Rong W, Shen Y, Li C, et al. The surgical perspective in neoadjuvant immunotherapy for resectable non-small cell lung cancer. Cancer Immunol Immunother. 2021;70(8):2313-21. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Mar, 2026 Reviews received at journal 22 Feb, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviews received at journal 16 Feb, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers invited by journal 16 Feb, 2026 Editor assigned by journal 31 Jan, 2026 Submission checks completed at journal 31 Jan, 2026 First submitted to journal 27 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8711384","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":592564535,"identity":"dde48bb9-ed87-46e1-98a1-388e9d11d915","order_by":0,"name":"Ruifeng Li","email":"","orcid":"","institution":"First Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruifeng","middleName":"","lastName":"Li","suffix":""},{"id":592564536,"identity":"ff587b15-d496-4095-b4fa-e270be9ac843","order_by":1,"name":"Chudong Wang","email":"","orcid":"","institution":"First Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chudong","middleName":"","lastName":"Wang","suffix":""},{"id":592564537,"identity":"c6dcb7a8-4b27-45e8-b863-d937fee82300","order_by":2,"name":"Yuxuan Li","email":"","orcid":"","institution":"First Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuxuan","middleName":"","lastName":"Li","suffix":""},{"id":592564538,"identity":"380e188b-bce8-494f-a16f-f098b470c50b","order_by":3,"name":"Jianyao Zhao","email":"","orcid":"","institution":"First Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jianyao","middleName":"","lastName":"Zhao","suffix":""},{"id":592564539,"identity":"517dc337-9b7c-49d3-affc-858856980396","order_by":4,"name":"Man Zhang","email":"","orcid":"","institution":"First Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Zhang","suffix":""},{"id":592564540,"identity":"122eddf5-ae0c-4f54-9844-0f54429af223","order_by":5,"name":"Shuben Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIie3RMQ6CMBSA4ZomuFRZayR4BQwJq1dpl06YODIw2GBgEGX1GI6OJCR1ee6MeAPdHFVWDcXNof/cL6+vRchk+sMsu2hK5sXEHkrZsCjWkzGFQXOLlDvJq8prQOmJi0I8PwD2vVqIyXWDe1wMXdR0lFp8DRBEfG0hO9uyboL34kUcLrM8qPnJQRQuR82UMminJAReBCzk0aWOsDfBPKVhsOIp7kNCv12fUCFQP0IVbx+ZkqqiDBTR7jIrkrL9ysVZyvsjil0723WTj8hvx00mk8n0tSfmkk0plDzBbgAAAABJRU5ErkJggg==","orcid":"","institution":"First Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shuben","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-01-27 14:09:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8711384/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8711384/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103166636,"identity":"19ccec75-e1e6-47d8-978a-05a36c3f84ad","added_by":"auto","created_at":"2026-02-22 12:40:46","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":368632,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline CT before the inititation of neoadjuvant lorlatinib. Chest CT\u003c/p\u003e\n\u003cp\u003erevealed a nodule in the left lower lobe with hilar and mediastinal lymphadenopathy.\u003c/p\u003e\n\u003cp\u003eCT, computed tomography.\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8711384/v1/a51f3974f08f5fb2761a5eae.jpeg"},{"id":103166639,"identity":"04abf348-3d64-4a45-b24c-9e44746bcb94","added_by":"auto","created_at":"2026-02-22 12:40:47","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":982223,"visible":true,"origin":"","legend":"\u003cp\u003eThe timeline for the neoadjuvant targeted therapy with radiographic images and pathology results. CT, computed tomography; PET, positron emission tomography; PR, partial response; MDT, multidisciplinary team; CMR, complete metabolic response; VATS, video-assisted thoracoscopic surgery; pCR, pathologic complete response; DFS, Disease-Free Survival.\u003c/p\u003e","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8711384/v1/9d1fca9f464fd315db2c830a.jpeg"},{"id":103166637,"identity":"a4676ab7-1f5b-4168-b327-a5726becc81d","added_by":"auto","created_at":"2026-02-22 12:40:46","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2401658,"visible":true,"origin":"","legend":"\u003cp\u003eIntraoperative view of uniportal video-assisted thoracoscopic surgery (VATS) left lower lobectomy. (A-C) Identification, dissection and transaction of the inferior pulmonary vein (IPV) and lower lobe bronchus (D) Ligation of minor vessels and exposure of the bronchial stump. Only mild adhesions and no air leak.\u003c/p\u003e","description":"","filename":"Figure3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8711384/v1/c87bffb9f88528915e171009.jpeg"},{"id":104397331,"identity":"5da9f887-70e6-4081-b4a0-88eed09a64e7","added_by":"auto","created_at":"2026-03-11 11:46:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5059008,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8711384/v1/91dc6901-a503-4987-9115-bb6dd08e6ee7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"From Metabolic to Pathologic Complete Response: Case Report of Neoadjuvant Lorlatinib in Stage IIIB ALK-Positive NSCLC Combined with Uniportal VATS","fulltext":[{"header":"Introduction","content":"\u003cp\u003eApproximately 30% of non-small cell lung cancer (NSCLC) cases are diagnosed at stage III,\u003csup\u003e(1)\u003c/sup\u003e with a subset harboring actionable driver mutations such as ALK fusions. The role of surgery in stage IIIB NSCLC remains controversial, necessitating comprehensive evaluation to identify patients who may benefit from multimodal strategies. In addition, the efficacy of ALK tyrosine kinase inhibitors (ALK-TKIs) in advanced NSCLC and the success of neoadjuvant EGFR inhibition provide a strong rationale for exploring neoadjuvant ALK-TKIs. Despite the extensive use of first- and second-generation ALK-TKIs, their long-term efficacy remains limited by acquired resistance. However, the use of third-generation ALK-TKIs, such as lorlatinib, in the neoadjuvant setting for ALK-positive NSCLC has not been widely reported and may delay the emergence of resistance.\u003csup\u003e(2)\u003c/sup\u003e Here, we present a rare case of a stage IIIB ALK-positive NSCLC patient who achieved a pathological complete response (pCR) after neoadjuvant lorlatinib, and attempt to utilize complete metabolic response (CMR) as a radiological biomarker to determine treatment duration, aiming to achieve an optimal balance between therapeutic outcomes and cost-effectiveness.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 35-year-old asymptomatic female without significant medical or family history presented with an incidentally discovered pulmonary nodule on routine physical examination. Computed tomography (CT) revealed a 1.8 \u0026times; 1.3 cm solid nodule in the anteromedial basal segment (S7\u0026thinsp;+\u0026thinsp;8) of the left lower lobe, accompanied by enlarged ipsilateral hilar and mediastinal lymph nodes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Histopathological examination of station 7 lymph nodes confirmed invasive adenocarcinoma, showing positive staining for TTF-1, Napsin A, cytokeratin (CK), and ALK protein (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFollowing multidisciplinary team discussion, a comprehensive evaluation was performed. Pulmonary function tests revealed normal lung ventilation. Positron emission tomography-CT (PET-CT) demonstrated increased fluorodeoxyglucose (FDG) uptake within the nodule (SUVmax 3.3) and pronounced fibroblast activation protein inhibitor (FAPI) uptake in the station 7 lymph nodes (SUVmax 11.0), suggesting malignancy with lymph node metastasis in the absence of distant metastasis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). According to the AJCC/UICC 9th edition staging system, the clinical stage was cT1bN2bM0 (stage IIIB). Multigene testing (Quantitative Real-time PCR) detected an ALK fusion in exons 19/20.\u003c/p\u003e \u003cp\u003eAfter systematic assessment, the patient commenced neoadjuvant therapy with lorlatinib (100 mg once daily). Hypercholesterolemia emerged on day 15 and was managed with rosuvastatin without treatment interruption or dose reduction and no other adverse events were observed. A restaging PET-CT at week 10 demonstrated a partial response (PR): the primary lesion decreased to 1.4 \u0026times; 0.8 \u0026times; 0.6 cm without enlargement or increased FDG uptake in the previously involved lymph nodes, consistent with a CMR (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). The post‑treatment clinical stage was ycT1N0M0.\u003c/p\u003e \u003cp\u003eAfter a 10-week course of lorlatinib and 2-week treatment-free interval, uniportal video-assisted thoracoscopic surgery (VATS) left lower lobectomy with mediastinal lymphadenectomy was performed at week 12 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Complete surgical resection (R0) was achieved with 20 ml intraoperative bleeding, and only mild adhesions required dissection during the procedure. Pathologic examination confirmed a pathological complete response (pCR), with the tumor bed and lymph nodes showing complete fibrosis and inflammatory replacement (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). The patient was discharged on postoperative day 5 without complications and started on adjuvant lorlatinib (100 mg once daily) with a planned duration of 1 year. The surveillance plan involves thoracic CT every 3 months and 3-year disease-free survival tracking. At the 12-month postoperative follow-up, the patient showed no signs of recurrence or unanticipated events (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the timeline of the treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough surgery is considered the primary treatment modality for NSCLC, curative resection is feasible in only 20\u0026ndash;25% of patients at diagnosis.\u003csup\u003e(3)\u003c/sup\u003e Furthermore, evidence supporting the preoperative use of TKIs, mostly first- and second-generation agents, is limited and postoperative recurrence remains a challenge. Lorlatinib, a third-generation ALK-TKI with broad resistance mutation coverage and proven efficacy in the CROWN trial,\u003csup\u003e(4),(5)\u003c/sup\u003e prompted our consideration of its first-line use to mitigate refractory mutations and improve survival outcomes.\u003c/p\u003e \u003cp\u003eComplete metabolic response (CMR), defined as 18F-FDG uptake indistinguishable from surrounding background, is an important quantitative indicator for treatment response and a validated prognostic tool in malignancies such as breast cancer and Hodgkin lymphoma. Informed by the achievement of CMR at 10 weeks, and data from prior trials (at least 9 weeks in NeoADAURA), we adopted a 10-week duration of neoadjuvant targeted therapy. Notably, in this case, histopathology remains the gold standard for confirming a pCR, while 18F-FDG PET-CT permits earlier response assessment. The 77.3% SUVmax reduction in primary tumor indicating the pCR is consistent with the recent studies.\u003csup\u003e(6),(7)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn addition, the targeted agents exhibit distinct toxicity profiles, including risks of bleeding and wound healing implications, which can pose technical challenges to subsequent surgery dissection. For instance, Long et al. reported that only 9 of 32 patients with locally advanced NSCLC were eligible for a minimally invasive approach.\u003csup\u003e(8)\u003c/sup\u003e However, in this case, the uniportal VATS was successfully completed with R0 resection, and only mild adhesions were noted with no air leak, conversion to thoracotomy, and other complications. The drainage tube was removed on postoperative day 3, and the patient was discharged on day 5. These data indicate that neoadjuvant lorlatinib may improve resectability through tumor downstaging and pCR without compromising perioperative safety or patient-reported outcomes, and the treatment aligns with Enhanced Recovery After Surgery principles.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNeoadjuvant lorlatinib may represent a promising and tolerable preoperative strategy for selected patients with stage IIIB ALK‑positive NSCLC, warranting evaluation in randomized controlled trials to define its efficacy, predictive biomarkers of optimal duration, and effects on long‑term survival and surgical outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNSCLC \u0026nbsp;Non-small cell lung cancer\u003c/p\u003e\n\u003cp\u003eALK \u0026nbsp;Anaplastic Lymphoma Kinase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEGFR \u0026nbsp;Epidermal Growth Factor Receptor\u003c/p\u003e\n\u003cp\u003eCK \u0026nbsp;Cytokeratin\u003c/p\u003e\n\u003cp\u003eTKI \u0026nbsp;Tyrosine kinase inhibitors\u003c/p\u003e\n\u003cp\u003eVATS \u0026nbsp;Video-assisted thoracoscopic surgery\u003c/p\u003e\n\u003cp\u003ePET-CT \u0026nbsp;Positron emission tomography- Computed tomography\u003c/p\u003e\n\u003cp\u003ePR \u0026nbsp; Partial response\u003c/p\u003e\n\u003cp\u003epCR \u0026nbsp;Pathological complete response\u003c/p\u003e\n\u003cp\u003eCMR \u0026nbsp;Complete metabolic response\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe obtained comprehensive informed consent from the patient. Ethical approval for this case report was waived by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the author and the patient have consent for the publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRuifeng Li : Conceptualization; Data curation; Writing - original draft; Writing - review \u0026amp; editing;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChudong Wang: Methodology;Writing - original draft; Project administration; Yuxuan Li: Resources; Data curation;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJianyao Zhao: Resources; Data curation;\u003c/p\u003e\n\u003cp\u003eMan Zhang: Conceptualization; Data curation;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShuben Li: Conceptualization; Supervision; Writing - review \u0026amp; editing;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll the authors reviewed approved the content of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of this case report. All adverse events were documented and reported in accordance with regulatory requirements to the national pharmacovigilance system.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMiao D, Zhao J, Han Y, Zhou J, Li X, Zhang T, et al. Management of locally advanced non-small cell lung cancer: State of the art and future directions. Cancer Commun (Lond). 2024;44(1):23-46.\u003c/li\u003e\n \u003cli\u003eNagasaka M, Ou SI. Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC. J Thorac Oncol. 2021;16(4):532-6.\u003c/li\u003e\n \u003cli\u003eLiang Y, Wakelee HA. Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2013;2(5):403-10.\u003c/li\u003e\n \u003cli\u003eSolomon 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):3400-9.\u003c/li\u003e\n \u003cli\u003eLu S, Zhou Q, Liu X, Du Y, Fan Y, Cheng Y, et al. Updated Efficacy and Safety of Lorlatinib in a Phase 2 Study in Chinese Patients With Previously Treated Advanced ALK-Positive Non-small Cell Lung Cancer. Clin Lung Cancer. 2024;25(7):e295-e303.e4.\u003c/li\u003e\n \u003cli\u003eZhuang F, Haoran E, Huang J, Wu J, Xu L, Zhang L, et al. Utility of (18)F-FDG PET/CT uptake values in predicting response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer. Lung Cancer. 2023;178:20-7.\u003c/li\u003e\n \u003cli\u003eSeitlinger J, Salko O, Bulgarelli Maqueda L, Meng A, T\u0026ecirc;tu M, Desilets A, et al. Neoadjuvant chemo-immunotherapy in Non-Small Cell Lung Cancer: Can Positron Emission Tomography scan predict complete pathological response? Ann Thorac Surg. 2025.\u003c/li\u003e\n \u003cli\u003eJiang L, Huang J, Jiang S, Rong W, Shen Y, Li C, et al. The surgical perspective in neoadjuvant immunotherapy for resectable non-small cell lung cancer. Cancer Immunol Immunother. 2021;70(8):2313-21.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Non-small cell lung cancer, Neoadjuvant targeted therapy, Pathological complete response, Lorlatinib, Case report","lastPublishedDoi":"10.21203/rs.3.rs-8711384/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8711384/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile stage IIIB non-small cell lung cancer (NSCLC) is generally considered unresectable, a subset of patients may benefit from neoadjuvant therapy following comprehensive evaluation. We report a 35-year-old non-smoking female diagnosed with stage IIIB (cT1bN2bM0) adenocarcinoma of the left lower lobe with multiple-station mediastinal lymph node metastasis. Based on a multidisciplinary evaluation of multimodality imaging and genomic features of ALK-positive, the patient with high tumor-burden yet no significant comorbidities received neoadjuvant lorlatinib. The patient achieved a complete metabolic response on restaging PET-CT after 10 weeks of lorlatinib, which led to a multidisciplinary decision to undergo uniportal VATS lobectomy. Pathological examination confirmed a pathological complete response (pCR). Following a 5-day hospitalization without complications, the patient remains disease-free at the 12-month follow-up. To our knowledge, this is the first reported case of combining neoadjuvant lorlatinib and uniportal VATS to achieve pCR predicted by complete metabolic response in stage IIIB ALK-positive NSCLC.\u003c/p\u003e","manuscriptTitle":"From Metabolic to Pathologic Complete Response: Case Report of Neoadjuvant Lorlatinib in Stage IIIB ALK-Positive NSCLC Combined with Uniportal VATS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 12:40:41","doi":"10.21203/rs.3.rs-8711384/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-16T07:53:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-23T03:32:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"90606757820033088369093618706234620869","date":"2026-02-17T07:28:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-17T04:18:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"122538589703881070036243442259621086208","date":"2026-02-17T02:08:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208379827415386642889522647935456544938","date":"2026-02-16T20:43:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-16T14:11:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-31T06:38:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-31T06:37:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2026-01-27T13:52:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9d14c62e-6b1d-428e-8ac5-f28f2ff95573","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-01T16:54:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 12:40:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8711384","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8711384","identity":"rs-8711384","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}