Effective management of lorlatinib-related adverse events, through close monitoring and timely intervention, is essential to enhance patient tolerance. Lorlatinib has progressively transformed the therapeutic landscape for patients with ALK + NSCLC.

P2, N=173, Active, not recruiting, Nuvation Bio Inc. | Trial completion date: Dec 2025 --> Jun 2027

After failure of gemcitabine/docetaxel chemotherapy, next-generation sequencing identified an IGFBP5-ALK fusion (breakpoint: IGFBP5 exon 1 - ALK exon 19), a TERT promoter mutation, and a homozygous CDKN2A/CDKN2B/MTAP deletion. This case highlights the first documented response to an ALK inhibitor in ALK-rearranged HG-ESS. The findings underscore the importance of comprehensive molecular profiling in identifying targetable alterations in rare sarcomas and support the use of iruplinalkib as an effective therapeutic option in this setting.

P=N/A, N=35, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=500 --> 35 | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Dec 2025 --> Jun 2026

P3, N=71, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

These results support the use of repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .

This study provides a comprehensive functional atlas of ALK tyrosine kinase domain variants under TKI selection, offering a valuable experimental framework for interpreting resistance-associated variants. Although derived from in vitro models and therefore context dependent, this resource complements existing clinical and genomic knowledge and may aid in the functional interpretation of ALK variants observed in ALK-driven cancers.

P=N/A, N=20, Recruiting, Peking University Shenzhen Hospital

P=N/A, N=10, Not yet recruiting, Peking University Shenzhen Hospital; Peking University Shenzhen Hospital

P=N/A, N=200, Not yet recruiting, Shandong First Medical University and Shandong Academy of Medical Sciences (Shandong Cancer Hospital ＆Institute); Shandong First Medical University

From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies.