Transformation of NSCLC to SCLC harboring EML4-ALK fusion with V1180L mutation after alectinib resistance and response to lorlatinib: A case report and literature review

Background: Histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) with anaplastic lymphoma kinase (ALK) positivity is extremely uncommon in ALK-positive NSCLC. To date, there have been limited reports regarding cases of SCLC transformation, and the optimal therapeutic strategies and prognosis for such patients remain unclear. This case is the first to describe the effectiveness of lorlatinib in treating a patient with SCLC that transformed from NSCLC harboring the ALK fusion V1180L mutation following acquired resistance to alectinib therapy. Case Description: We present a case of alectinib-induced transformation from ALK-positive NSCLC to SCLC with an ALK V1180L mutation after acquiring alectinib resistance. The patient achieved disease remission with lorlatinib treatment following ineffective chemotherapy. In April 2022, a 53-year-old male was diagnosed with ALKpositive advanced poorly differentiated adenocarcinoma with neuroendocrine differentiation in the left lower lobe of the lung. The diagnosis was accompanied by multiple bone metastases and brain metastases, categorizing the stage as cT3N2M1. Following 8 months of alectinib treatment, chest computed tomography (CT) and cranial magnetic resonance imaging (MRI) revealed disease progression. Pathological and genetic analyses indicated the transformation to pulmonary small cell carcinoma accompanied by ALK fusion V1180L mutation. After the administration of two cycles of EP chemotherapy with unsatisfactory response, oral lorlatinib therapy was initiated. A subsequent month of treatment resulted in notable reduction of the left lung lesion according to chest CT, as well as a significant decrease in intracranial lesions based on cranial MRI. After taking lorlatinib for 5 months, the lesions continue to shrink, and there is a noticeable improvement in the patient's quality of life. Currently, the patient remains in a state of sustained improvement. Conclusion: This study affirms the efficacy of lorlatinib in patients with ALK-positive SCLC transformation harboring the V1180L mutation. Furthermore, it underscores the imperative of conducting genetic testing in patients who transition to SCLC following ALK-TKI resistance, as targeted therapies may remain efficacious if a genetic driver is identified.