| Sumario: | Simple Summary: Targeted therapy has significantly improved outcomes for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC); however, the emergence of resistance remains an inevitable clinical challenge. Standard treatment after progression on third-generation ALK tyrosine kinase inhibitors (TKIs) is often restricted to chemotherapy, which may not be suitable or acceptable for all patients. We describe a patient with ALK-positive NSCLC and ultra-high PD-L1 expression whose disease progressed after first-line lorlatinib treatment. A repeat biopsy identified acquired MET amplification as a potential resistance mechanism. Given the limited standard options, the patient received a personalized combination of continued lorlatinib, envafolimab (an anti-PD-L1 antibody), and localized radiotherapy. This regimen induced a significant radiological response with a manageable safety profile. This case demonstrates that, in highly selected patients, a multi-modality strategy guided by repeat biopsy and biomarker profiling may provide meaningful clinical benefit after resistance to targeted therapies. 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 (≥50%) 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 ≥ 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.
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