ALK-tyrosine kinase inhibitor resistance due to acquired MET amplification in ALK-fusion positive advanced NSCLC effectively treated by lorlatinib-vebreltinib combination: a case report and literature review

Introduction

Lung cancer stands as the most commonly diagnosed malignancy across the globe, representing approximately 12.4% of all newly-identified cancer cases and contributing to an alarming 18.7% of cancer-related fatalities worldwide (1). Non-small cell lung cancer (NSCLC), which accounts for 80–85% of all lung cancers, plays a significant role in targeted therapy (2). Anaplastic lymphoma kinase (ALK) gene fusion is a common type of genetic alteration in NSCLC, with an incidence rate of approximately 3–7%, primarily found in adenocarcinoma subtypes (3,4). ALK-tyrosine kinase inhibitors (TKIs) are a treatment option for patients with locally advanced or metastatic ALK-positive NSCLC. Compared with conventional chemotherapy, the first generation of ALK-TKIs (crizotinib), the second generation (ceritinib and alectinib), and the third generation (lorlatinib) have better curative effects (5-8). However, acquired resistance to ALK-TKIs is inevitable, and the mechanisms of resistance include secondary mutations in the ALK kinase domain, amplification of the ALK fusion gene, activation of bypass signaling and downstream pathways, and transformation to small cell lung cancer (SCLC) (9). Multiple bypass signaling mechanisms have been described in preclinical studies, including the activation of MNNG HOS transforming gene (MET), EGFR, SRC, and KRAS (10-12). MET is a particularly attractive target in this context, given the availability of potent MET-TKIs. MET activation has also been studied as a bypass signaling pathway in EGFR-mutant NSCLC, where MET amplification has been reported in 6–24% of cases that have become resistant to treatment (13,14). There have been reports of cases where alectinib-crizotinib combination therapy for intrinsic resistance to ALK-TKIs caused by de novo MET amplification (15). A study systematically elucidated the resistance mechanisms in 108 ALK-positive NSCLC patients who progressed after alectinib treatment, revealing that off-target MET and NF2 alterations are key drivers of early resistance. Among them, MET aberrations (including amplification, L1195F/Y1248H functional mutations, and kinase domain repeat KDD) were observed in 21% of first-line treated patients, with a median progression time of 7.2 months and a 6-month cumulative incidence reaching 45.5%, significantly earlier than ALK kinase domain mutations (median 10.0 months, 6-month cumulative incidence only 12.5%) (16). Nonetheless, further extensive research is imperative to validate whether MET is a clinically relevant driver of drug resistance in ALK-positive NSCLC and the corresponding therapeutic strategies. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0266/rc).

Case presentation

Diagnosis and initial treatment response

In November 2024, a 31-year-old man presented to Shandong Provincial Hospital with a 1-month history of coughing and expectoration. He had smoked one pack of cigarettes a day for 15 years. The patient reported no significant past, family, or psychosocial history. Physical examination revealed wet rales in the right lung. Chest computed tomography (CT) examination revealed cavitary lesions in the lower lobe of the right lung, as well as changes to the right lung bronchus. There was also evidence of multiple lymphadenopathies with necrosis in the right hilum and mediastinum (Figure 1). In addition, ultrasound imaging of the superficial lymph nodes revealed enlarged lymph nodes in both supraclavicular regions. To further confirm the diagnosis, a fiberoptic bronchoscopy was performed on 20 November 2024. A pathological biopsy was taken from diseased tissue in the right lung and bronchus. Hematoxylin and eosin (H&E) staining revealed cancer cells (Figure 2A). Immunohistochemical (IHC) markers (TTF1 +, Napsin A +, CK7 +, P53 mutant, Ki-67 60%, etc.) supported lung adenocarcinoma, with TTF1 (Figure 2B) and NapsinA (Figure 2C) positive. The programmed cell death ligand 1 (PD-L1) (clone 22C3, DAKO, Ventana-Link48) showed a tumor proportion score (TPS) of 70% (Figure 2D). Subsequent gene testing of the patient using the 5-mutation gene (EGFR/ALK/ROS1/MET/KRAS) detection kit in fluorescence polymerase chain reaction (PCR) method showed a positive result for the ALK fusion gene and no evidence of MET amplification. No obvious metastases were found in the patient’s brain-enhanced magnetic resonance imaging (MRI) scan, abdominal ultrasound, and whole-body bone scan. The patient was diagnosed with stage IIIC lung adenocarcinoma (cT3N3M0) with ALK fusion positivity. Therefore, the patient started oral third-generation ALK/ROS1 TKI lorlatinib at a dose of 100 mg once daily on 28 November 2024. The patient’s condition remained stable for the first 5 months of treatment.

Figure 1 Chest CT scans at different time points. (A,E) Chest enhanced CT scan of baseline (18 November 2024). (B,F) Chest CT scan after first-line treatment with lorlatinib showed shrinkage of the lesions (March 13, 2025). (C,G) Chest CT scan showing progression after 6 months of lorlatinib (13 September 2025). (D,H) Chest CT plain and enhanced images show that the pulmonary lesions shrank and remained stable after combination therapy with lorlatinib and vebreltinib (December 18, 2025). Red arrows indicate the lesions. CT, computed tomography.

Figure 2 Histopathological and immunohistochemical characterization of lung lesion biopsy specimen. (A) H&E staining showing cancer cells (×100). (B) Immunohistochemical staining for TTF1, demonstrating nuclear positivity in tumor cells (×100). (C) IHC staining for Napsin A, showing cytoplasmic granular positivity (×100). (D) IHC staining for PD‑L1 (clone 22C3, DAKO) performed on the Ventana‑Link48 platform, exhibiting a TPS of 70% (×100). H&E, hematoxylin and eosin; IHC, immunohistochemical; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score.

All procedures described in this case report were performed in accordance with the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University, and the Declaration of Helsinki and its subsequent amendments. All clinical data and information used in this report are de-identified, and patient was informed and provided written informed consent for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Disease progression and genetic mutation transformation

Subsequently, the patient developed progressive disease. He experienced intermittent symptoms and adverse reactions, including elevated transaminase levels, dyslipidemia and depression, as well as a brief episode of transient loss of consciousness that resolved spontaneously and was attributed to possible paraneoplastic syndrome after negative brain imaging. Subsequent Positron emission tomography-Computed tomography (PET/CT) imaging with fludeoxyglucose (FDG) revealed progression of the primary tumor and multiple metastases to the lungs, mediastinal, cervical, and subclavian lymph nodes, subcutis, muscles, and bilateral iliac/sacral bones (Figures 3,4). The treatment evaluation showed that the tumor had progressed (PD), and the stage was cT3N3M1c IVB. A puncture biopsy of subcutaneous nodules in the back was performed for the patient on June 17, 2025. H&E staining revealed poorly differentiated adenocarcinoma, suggesting distant metastasis (Figure 5A). IHC markers supported the diagnosis: TTF1 − (Figure 5B), CK7 + (Figure 5C), Napsin A − (Figure 5D), P53 wild-type, Ki-67 60%, etc. And PD-L1 (clone 22C3, DAKO, Ventana-Link48) showed a TPS of 90% (Figure 5E). Considering the patient’s medical history, metastatic lung cancer was considered. After that, the patient received a course of pemetrexed combined with carboplatin chemotherapy. A second genetic test was performed on a biopsy of the back subcutaneous nodule using high‑throughput next‑generation sequencing (NGS) on the ADxSEQ 200Plus platform (Amoen Biotechnology, Xiamen, China). The NGS panel used was the “Human Cancer Multi‑Gene Mutation Detection Kit” (Amoen Biotechnology), which covers 40 lung cancerrelated genes including ALK, MET, and TP53. The average sequencing depth was 1,247× (≥400× acceptable). This revealed a high‑level MET amplification with a copy number of 9.48 (classified as class I, positive), in addition to the original EML4‑ALK fusion (EML4 exon13‑ALK exon20, 2198 copies) and a TP53 p.(P151R) mutation (55.34% abundance). No other relevant genomic co‑alterations were detected. The microsatellite instability (MSI) status was microsatellite stable (MSS). The high MET copy number by NGS and the subsequent clinical response to vebreltinib support the functional relevance of this amplification.

Figure 3 Comparison of the patient’s PET/CT imaging in June and November 2025. (A) PET/CT performed on 10 June 2025 showed lymph node metastases from lung cancer as well as multiple distant metastases to skin, muscle, and bone. (B) PET/CT on 10 November 2025 showing suppressed tumor tissue activity in the primary lung lesion and lower activity in metastatic lesions such as distant subcutaneous nodules and bone than before. (C,D) Changes in lung lesions after treatment with lorlatinib in combination with vebreltinib. (E,F) Changes in skin and muscle metastatic lesions after treatment with lorlatinib in combination with vebreltinib. (G,H) Significant improvement in lymph node metastatic lesions. Red arrows indicate the pulmonary lesions and metastatic lesions. CT, computed tomography; PET, positron emission tomography.

Figure 4 PET/CT image showing multiple lymph node metastases in the right neck, right subclavian region, and other areas (10 June 2025). Red arrows indicate the transfer of the lesions. CT, computed tomography; PET, positron emission tomography.

Figure 5 Histopathological and immunohistochemical characteristics of subcutaneous nodules on the back. (A) H&E staining showing poorly differentiated adenocarcinoma (×100). (B) IHC for TTF1 (−) (×100). (C) IHC for CK7 (+) (×100). (D) IHC for Napsin A (−) (×100). (E) IHC for PD‑L1 (clone 22C3, DAKO) showing a TPS of 90% (positive) (×100). H&E, hematoxylin and eosin; IHC, immunohistochemical; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score.

Subsequent treatment regimen and treatment response

Lorlatinib was discontinued in July 2025 due to adverse reactions including elevated transaminases (grade 2), elevated lipid levels, and depression. Based on the clinical situation and the NGS results (which revealed acquired MET amplification), we concluded that the patient had developed resistance to ALK inhibitors, likely through activation of the MET pathway. At the time of progression, the patient had developed multiple adverse events related to prior lorlatinib, including elevated transaminases, hyperlipidemia, and depression. His Eastern Cooperative Oncology Group performance status (ECOG PS) had declined to 2–3. Although the ALK dependency was likely maintained, the clinical team decided to temporarily discontinue lorlatinib due to safety concerns and therefore switched to vebreltinib (a c‑Met inhibitor) administered in combination with a second cycle of chemotherapy and bevacizumab. However, during two cycles of follow-up, the patient’s tumor continued to grow and metastasized to the back and lower limbs, resulting in adverse reactions of back and lower limb muscle pain. The patient’s disease continued to progress even after one month of vebreltinib alone, suggesting that inhibition of a single pathway alone was not enough to stop the patient’s tumor progression. After the adverse reactions such as liver function and abnormal blood lipids improved, according to the results of two pathological biopsies and gene detection (right lung lesion and back subcutaneous nodule metastasis pathological biopsy and corresponding genetic test results), we decided to adopt the scheme of lorlatinib combined with vebreltinib to treat ALK fusion pathway and MET amplification pathway simultaneously. The patient started dual-drug targeted therapy in early September 2025. Given the patient’s previous adverse effects of hepatic impairment and elevated lipids on lorlatinib100 mg once daily, this time we used only half the dose (50 mg, once daily) and combined it with vebreltinib. In addition, intensity-modulated radiotherapy (IMRT) was used to treat distant metastatic lesions in the patients’ lower limbs. After two cycles of combined treatment, the patient’s condition had significantly improved. Both the primary lung lesions and the distant metastatic lesions had been effectively controlled. On 10 November 2025, repeat PET/CT (Figure 3) demonstrated a marked decrease in FDG uptake in the primary lung lesion and reduced metabolic activity in metastatic lesions (subcutaneous nodules and bones). Based on PET/CT findings and RECIST criteria (version 1.1), the overall response was assessed as partial remission (PR). This sequential approach-starting with MET inhibitor alone, followed by low-dose dual therapy after toxicities induced by lorlatinib subsided-led to a sustained PR, with no recurrence of serious adverse events. On 18 December 2025, the patient’s follow-up showed continued tumor control. The overall treatment process of this patient is shown in Figure 6. As illustrated in the treatment timeline, chemotherapy and bevacizumab served as short-term bridging therapy during lorlatinib-related adverse event recovery, while radiotherapy was locally directed only at bone metastases. Therefore, the sustained partial response is mainly attributed to dual ALK/MET inhibition, with only a minor contribution from the bridging therapy. In addition, considering the limitations of the PCR method and the problem of false negatives, we performed further IHC testing on the patient’s first biopsy sample to assess the expression level of the MET gene using a C-MET antibody reagent (clone D1C2, manufacturer: Xiamen AmoyDx Biotechnology Co., Ltd., Xiamen, China) on the Leica BOND-MAX detection platform, and detect MET amplification using fluorescence in situ hybridization (FISH) with the human c‑MET gene amplification detection kit (Xiamen AmoyDx Biotechnology Co., Ltd., Xiamen, China) (Figure 7). FISH revealed a MET/CEP7 ratio of 1.5 and a MET average copy number of 3.8 (negative per criteria: ratio <2.0 and copies <5.0). IHC demonstrated a H‑Score of 10 (90% of cells with 0+ staining, 10% with 1+ staining, no 2+ or 3+), interpreted as negative for MET protein overexpression. The results showed that MET expression was negative and no MET gene amplification had occurred. This further confirms that patients develop resistance after the first use of ALK inhibitors, leading to activation of the MET pathway. We will continue to monitor the patient’s condition and provide supportive care while closely tracking for possible acquired resistance mechanisms (e.g., through repeat biopsies) during ongoing treatment.

Figure 6 The patient’s overall treatment process (1 year). ALK, anaplastic lymphoma kinase.

Figure 7 MET gene test map of the patient’s primary lung lesion. (A) MET expression staining was performed using immunohistochemical methods (×200). (B) Plot of amplification results of MET gene detected by FISH technique. MET/CEP7 ratio =1.5 (OLYMPUS BX53, ×100). Red signals (Cy3) indicate MET probe (7q31), green signals (FITC) indicate chromosome 7 centromere probe (CEP7), and blue (DAPI) stains nuclei. DAPI, 4',6-diamidino-2-phenylindole; FISH, fluorescence in situ hybridization; FITC, fluorescein isothiocyanate.

Discussion

The ALK gene is one of the common oncogenic driver genes in NSCLC. Its pathogenic mechanism typically begins with rearrangements involving partner genes such as EML4, forming ALK fusion genes. The ALK fusion protein expressed by these fusion genes can continuously activate ALK kinase through dimerization, as well as via stabilization and cytoplasmic relocalization of the fusion protein (17), leading to abnormal activation of downstream signaling pathways such as RAS-MAPK, PI3K-AKT-mTOR, and JAK-STAT. This ultimately results in uncontrolled cell proliferation and differentiation, driving tumor development (18). In recent years, the application of TKIs has brought revolutionary progress in the treatment of ALK fusion-positive advanced NSCLC, significantly improving the prognosis of these metastatic patients (19). Among them, the third-generation ALK-TKI lorlatinib has shown particularly outstanding efficacy. A global phase II study (20) demonstrated that in patients who had received at least one prior ALK-TKI treatment, lorlatinib achieved an objective response rate (ORR) of 47% and a central nervous system response rate of 63%. In the subgroup of patients treated with at least one second-generation ALK-TKI, the ORR was 40%, with a median progression-free survival (PFS) of 6.9 months. The phase III CROWN study (21) further confirmed that lorlatinib as first-line treatment in previously untreated advanced ALK-positive NSCLC patients significantly outperformed crizotinib. The 5-year PFS rates were 63% [95% confidence interval (CI): 49–74%] and 7% (95% CI: 2–17%), respectively. In patients with baseline brain metastases, lorlatinib also showed significantly higher intracranial ORR (69% vs. 6%). Based on its excellent efficacy, lorlatinib has been recommended as the first-line standard treatment for advanced ALK fusion-positive NSCLC in the 2024 National Comprehensive Cancer Network (NCCN) clinical practice guidelines (22). Of course, local radiotherapy, immunotherapy, and other methods also play a role in the treatment of ALK fusion-positive NSCLC. Some studies have shown that multi-field intensity-modulated proton therapy (IMPT) for NSCLC has clinical advantages, and personalized diagnosis and treatment for patients are becoming increasingly important (23).

As a third generation ALK inhibitor, lorlatinib has become an important choice for ALK-mutant NSCLC because of its broad-spectrum inhibitory effect on mutations, strong penetration of the blood-brain barrier, and significantly prolonged survival period. However, its acquired resistance to lorlatinib, such as ALK complex mutations and bypass signaling activation, still needs to be addressed via further exploration and joint strategies (24). Recent studies on the resistance mechanisms of lorlatinib (25) indicate that approximately one-third of patients develop acquired resistance induced by ALK kinase domain mutations, whereas two-thirds develop ALK-independent resistance mechanisms such as bypass signaling activation or phenotypic switch. The MET is a potential therapeutic target in various cancers, including NSCLC. In NSCLC, MET pathway activation is believed to occur through a series of diverse mechanisms that affect cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests that MET activation serves as both a major oncogenic driver in subsets of lung cancer and a secondary driver of acquired targeted therapy resistance in other genomic subgroups (24). Research indicates that in ALK-positive NSCLC patients who develop resistance to ALK-TKIs, MET signaling pathway activation serves as one of the important ALK-independent resistance mechanisms, occurring in approximately 15–20% of cases and driven primarily by MET amplification (26). However, previous studies have focused on first and second-generation ALK inhibitors such as crizotinib, and there is a lack of literature on resistance to the third-generation ALK inhibitor lorlatinib and the impact of the MET mutation pathway. The therapeutic choices for individual patients remain challenging.

This case report details an NSCLC patient harboring an ALK fusion. Following first-line lorlatinib therapy, the tumor progressed and acquired resistance. A second biopsy revealed MET amplification as the underlying mechanism. Subsequent second‑line treatment with vebreltinib in combination with chemotherapy and bevacizumab failed to halt disease progression. After thorough systemic evaluation, a combination regimen of lorlatinib and vebreltinib was initiated, resulting in sustained PR, excellent treatment tolerance, and notable improvement in quality of life. Ideally, combined ALK and MET inhibition should be initiated as soon as acquired MET amplification is identified, as the tumor remains ALK‑dependent. However, in patients with significant cumulative toxicity from prior ALK‑TKI therapy, immediate dual therapy may not be feasible. Our case illustrates a pragmatic alternative: single‑agent MET inhibitor as a short‑term bridge, followed by reintroduction of a reduced‑dose ALK‑TKI once the patient’s condition improves. This strategy allowed us to achieve durable disease control while avoiding irreversible adverse events. Clinicians should weigh the biological rationale for dual therapy against the patient’s tolerability and quality of life. This is the first reported case of a NSCLC patient with MET amplification leading to ALK-TKI resistance being treated with the combination of lorlatinib and vebreltinib, achieving significant therapeutic effects. The discrepancy between the negative MET testing on the initial biopsy (PCR, FISH, IHC) and the subsequent detection of high‑level MET amplification (copy number 9.48) by NGS in a progressing metastasis can be explained by intratumoral heterogeneity and clonal evolution. It is likely that a minor subclone harboring MET amplification was either not sampled by the initial biopsy or fell below the detection limits of PCR, FISH, or IHC. Under the selective pressure of lorlatinib, this subclone expanded and became the dominant driver of resistance in the metastatic lesion. This case underscores the importance of repeat biopsy at progression and the use of sensitive, comprehensive methods such as NGS to capture acquired resistance mechanisms. In most cases, patients with ALK-TKI resistance who have high PD-L1 expression levels in tumor cells may benefit from immunotherapy-based treatments, often showing a better response to immunotherapy checkpoint inhibitors (27). Notably, in this case, the PD-L1 expression levels from two pathological tests were both high (70% and 90%). During the combination therapy, we reduced the dose of lorlatinib (from 100 to 50 mg once daily), yet the patient still benefited from the simultaneous blockade of both ALK and MET pathways. This strategy is in line with the therapeutic principles of precision, potency, and breaking through drug resistance, and the combination therapy effectively avoids tumor cells escaping inhibition by switching signaling pathways. This case fully demonstrates the key role of precision medicine in tumor treatment.

MET amplification represents a well-established bypass resistance mechanism in ALK-rearranged NSCLC. However, the biological and clinical implications of MET amplification differ substantially depending on whether it is present de novo (intrinsic) or emerges under treatment pressure (acquired). Urbanska et al. reported the first case of de novo MET amplification causing intrinsic resistance to second-generation ALK-TKIs; their patient harbored high-level MET amplification at baseline (median MET copy number 6.1–8.3 by FISH), progressed rapidly on first-line brigatinib, and subsequently achieved durable response with alectinib plus crizotinib (15). In contrast, acquired MET amplification is more common, occurring in approximately 15% of ALK-TKI-treated patients as a driver of secondary resistance (28). Importantly, most reported cases of acquired MET amplification have involved first- or second-generation ALK-TKIs (e.g., crizotinib, alectinib, ceritinib). Our case is distinct in that MET amplification was absent at baseline (confirmed by PCR, FISH, and IHC) but emerged as a high-level copy number gain (9.48 by NGS) after progression on lorlatinib—a third-generation ALK-TKI. This temporal distinction is clinically critical, as it informs both the expected timing of resistance and the optimal sequencing of combination therapy.

Beyond molecular alterations, phenotypic changes represent an increasingly recognized category of ALK-TKI resistance. In addition to transformation to SCLC (9), epithelial-mesenchymal transition (EMT) has been documented as a resistance mechanism in ALK-rearranged NSCLC. Research reported a case in which, after sequential treatment with multiple ALK-TKIs (crizotinib, ceritinib, alectinib) and subsequent progression, rebiopsy revealed EMT of newly occurred metastatic cells, which was associated with rapid disease progression and lack of response to continued ALK inhibition (29). Mechanistically, EMT may be driven by secondary ALK mutations (e.g., G1202R) activating the STAT3/Slug signaling pathway, as demonstrated in preclinical models (30). In our patient, no evidence of EMT or SCLC transformation was observed on repeat biopsy; instead, MET amplification emerged as the dominant resistance mechanism. Nevertheless, the possibility of phenotypic changes should be considered in cases of unexplained rapid progression.

Currently, the most straightforward therapeutic strategy for MET amplification that occurs after driver gene TKI resistance is to inhibit both the primary driver gene and the MET gene. This therapeutic idea has been fully validated in NSCLC patients who developed MET amplification after EGFR-TKI resistance. In a study of osimertinib plus savolitinib as first-line treatment for advanced NSCLC with EGFR mutations and MET abnormalities, the combination therapy (n=21) doubled the median PFS to 19.6 months compared to 9.3 months with osimertinib alone (n=23) at a median follow-up of 8.2 months (31). The TATTON study (32) evaluated the efficacy and safety of savolitinib combined with osimertinib in the treatment of advanced NSCLC patients with EGFR mutation positive and MET amplification who had previously received EGFR-TKIs treatment. The results showed that the combined treatment can offer patients another 5–12 months of PFS, especially for patients with MET copy number ≥10. These findings provide critical evidence for managing MET-driven resistance in EGFR-mutant NSCLC and offer important clinical guidance for addressing similarly mediated bypass resistance in ALK-targeted therapy. Meanwhile, studies have shown that patients with MET-driven ALK‑TKI resistance benefit from combination therapy targeting both ALK and MET (33). In this case, the patient initially achieved stable disease on lorlatinib. However, during subsequent treatment, disease progression with systemic metastases occurred, indicating acquired resistance. In addition, the patient experienced adverse events including impaired liver function and depression. Although MET amplification was later identified as a potential resistance mechanism, the patient’s poor baseline condition and significantly reduced tolerance raised substantial clinical concern regarding the suitability and safety of introducing a dual-targeted therapy regimen. MET signaling can be activated by a variety of mechanisms, including copy number gain, mutation, fusion, and ligand upregulation (34). The relationship between MET copy number and sensitivity to MET TKIs may be more complex in the context of acquired drug resistance. Specifically, in drug-resistant ALK-positive NSCLC that has not been fully inhibited by an ALK TKI, even low levels of MET amplification may be sufficient to restore proliferative signaling. MET amplification can act as a bypass resistance mechanism to ALK‑TKIs even at low levels, as it activates downstream pathways (e.g., PI3K/AKT, MAPK) and may be amplified functionally by cooccurring alterations (e.g., TP53 mutations) or transcriptional factors (e.g., TWIST1) (35). Moreover, the relationship between copy number and functional effect is non‑linear: lowlevel amplification can confer sensitivity to MET inhibition or drive resistance under selective pressure, especially when the primary target is not fully blocked (36).

Our case provides several novel insights. First, to our knowledge, this is the first report of acquired MET amplification emerging specifically after lorlatinib treatment and successfully managed with continued lorlatinib plus a MET inhibitor (vebreltinib). Previous reports of ALK/MET combination therapy have primarily involved alectinib plus crizotinib, often in the setting of intrinsic MET amplification (15) or acquired resistance to second-generation ALK-TKIs (37). Second, our case demonstrates that high-level MET amplification (copy number 9.48) can be reliably detected by NGS in progressing metastases, reinforcing the value of repeat biopsy and comprehensive genomic profiling at progression. Third, the favorable response to lorlatinib plus vebreltinib—despite a reduced lorlatinib dose due to prior adverse events—suggests that dose reduction may be feasible when combining these agents, without compromising efficacy. Together, these findings expand the understanding of MET-mediated resistance across ALK-TKI generations and support the clinical utility of ALK/MET dual inhibition for acquired MET amplification after lorlatinib.

Conclusions

We reported a case of intrinsic resistance to ALK-TKIs caused by MET amplification in a patient. MET amplification is an important resistance mechanism that cannot be overlooked in ALK-positive NSCLC patients undergoing targeted therapy. A dual-target inhibition strategy is currently the most theoretically grounded and clinically promising approach, whereas novel dual antibodies and bispecific antibody drug conjugates (ADC) offer more promising options for future treatment. In this case, the combination of lorlatinib and vebreltinib has been associated with significant clinical benefits, with no adverse events observed so far. This is the first reported case of using lorlatinib combined with vebreltinib to treat ALK-TKI-resistant MET amplification NSCLC and achieve significant efficacy. The treatment is still ongoing, and we are waiting for the results of long-term efficacy. Further clinical studies are needed to optimize this approach by combining ALK-TKIs with more potent MET-TKIs.

Acknowledgments

We would like to thank the patient and his family for their support of our work.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0266/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0266/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0266/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures described in this case report were performed in accordance with the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University, and the Declaration of Helsinki and its subsequent amendments. All clinical data and information used in this report are de-identified, and patient was informed and provided written informed consent for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)