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.

BACKGROUND: Molecular testing has become an essential part of managing non-small cell lung cancer (NSCLC). The detection of EGFR, BRAF, and MNNG HOS transforming gene (MET) mutations, and the analysis of anaplastic lymphoma kinase (ALK), ROS1, RET, and NTRK rearrangements have been incorporated into NSCLC diagnostic standards, and inhibitors of these kinases are used routinely in clinical practice. Although targeted therapies, represented by ALK-tyrosine kinase inhibitor (ALK-TKI), have significantly improved the prognosis of ALK-positive NSCLC patients, acquired resistance (such as MET amplification) remains a core challenge faced by clinicians. Currently, there is no standardized treatment regimen established in Chinese and international clinical guidelines for patients with ALK-TKI resistance caused by MET amplification. Although clinical practice has attempted to combine targeted drugs for MET amplification, such as crizotinib, with first and second-generation ALK-TKIs and observed preliminary efficacy, there is no published research on the combination of third-generation ALK-TKI lorlatinib with new MET inhibitors such as vebreltinib.

CASE DESCRIPTION: This report describes a patient with advanced NSCLC with multiple systemic metastases and ALK gene fusion, in whom MET amplification emerged as a resistance mechanism following disease progression on targeted therapy. The first-line treatment was lorlatinib, a third-generation ALK inhibitor, but the disease progressed rapidly. The second biopsy showed that MET amplification is the main mechanism of resistance to ALK-targeted therapy in the patient. Specifically, MET amplification was not present at baseline but appeared after lorlatinib treatment, confirming it as an acquired rather than intrinsic resistance mechanism. Due to complications, such as elevated transaminase (an indication of hepatotoxicity), hyperlipidemia, and depression, that occurred during the patient's first-line treatment, combined ALK- and MET-TKI targeted therapy was not administered. Subsequent second-line treatment with single-agent vebreltinib failed to halt disease progression. After thorough systemic evaluation, a combination regimen of lorlatinib and vebreltinib was initiated, resulting in sustained partial remission (PR), excellent treatment tolerance, and notable improvement in quality of life.

CONCLUSIONS: Our case report first successfully documented the use of third-generation ALK inhibitor (lorlatinib) in combination with novel MET inhibitor (vebreltinib) for the treatment of advanced NSCLC patients with ALK-TKI resistance due to MET amplification, enabling sustained clinical remission. This case highlights the importance of repeat biopsy to identify acquired resistance mechanisms arising from intratumoral heterogeneity in response to targeted therapy, which is critical for making clinical decisions and adjusting treatment plans for patients with NSCLC.