To the best of our knowledge, this is the first study to demonstrate the mechanism underlying the adaptive resistance to lorlatinib, which involves the HB-EGF/EGFR axis of the ALK-rearranged NSCLC cell line, and to identify the efficacy of combination therapy for EGFR and ALK aimed at tumor eradication in ALK-rearranged lung cancer. This evidence concerns the gene ALK and non-small cell lung carcinoma.