Case report: first-line lorlatinib in metastatic lung adenocarcinoma with a novel WIPF1-ALK and EML4-ALK dual fusion.

Background: The clinical management of non-small cell lung cancer (NSCLC) harboring rare anaplastic lymphoma kinase (ALK) fusion variants and complex molecular profiles remains challenging. Herein, we report, for the first time, a case of NSCLC with concurrent novel WAS/WASL interacting protein family member 1 (WIPF1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK double fusions, along with a concomitant TP53 mutation, which demonstrated marked sensitivity to lorlatinib in this genomically complex setting. Case Description: A 57-year-old Chinese female was diagnosed with stage IVA (T4N2M1a) lung adenocarcinoma. Comprehensive genomic profiling (CGP) identified dual ALK rearrangements: a novel WIPF1-ALK fusion as the predominant oncogenic driver [variant allele frequency (VAF) 7.81% in pleural effusion] and a minor EML4-ALK fusion component (VAF 0.64% in pleural effusion). The case was further complicated by a concurrent TP53 p.R110L mutation, representing a rare co-occurrence of dual ALK fusions with an additional resistance-associated genomic alteration. The efficacy of lorlatinib as first-line therapy achieved a partial response (PR). Notably, sustained disease control had been achieved for over 24 months in this patient. Conclusions: This report provides the first evidence of sustained efficacy of lorlatinib in a patient harboring the rare WIPF1-ALK fusion, a dual ALK rearrangement pattern, and a concurrent TP53 mutation. The achievement of over 24 months of disease control underscores lorlatinib's potent activity against these complex molecular profiles. Our findings highlight the importance of recognizing and targeting rare ALK fusion variants-even when coexisting with other ALK rearrangements and resistance-associated mutations and expand the therapeutic landscape of precision oncology for advanced NSCLC.