ALK rearrangement

In non-small cell lung cancer (NSCLC), ALK gene rearrangements represent key oncogenic drivers, and ALK tyrosine kinase inhibitors (TKIs) such as crizotinib have significantly improved clinical outcomes...DATA AVAILABILITY: The raw RNA-seq reads and the processed gene expression matrix were deposited to the gene expression omnibus (accession number GSE284648). The data generated in this study are available from the author upon reasonable request.

The patient received first-line osimertinib combined with pemetrexed/cisplatin, achieving durable disease control for 17 months...Treatment was switched to alectinib, leading to significant tumor regression and partial response. This case illustrates that in triple-positive NSCLC, initial EGFR-TKI combined with chemotherapy can achieve long-term control, while dynamic molecular profiling at progression is essential for identifying resistance mechanisms. Sequential targeted therapy guided by NGS remains a cornerstone for precision management in this complex molecular subtype.

This case demonstrates an exceptionally durable response to first-line alectinib in an ALK-positive LUAD patient with a concurrent rare RET variant. It underscores the long-term efficacy and tolerability of alectinib and highlights the importance of comprehensive genomic profiling in guiding personalized targeted therapy for genetically complex NSCLC.

Our findings indicate that ALK-rearranged mesenchymal neoplasms with fibrosarcoma-like features, particularly those associated with elevated mitotic activity or tumor necrosis, should be classified as high grade in pathology reports. In addition, this case also demonstrated that neoadjuvant therapy may be a better treatment strategy compared to upfront surgery for ALK-rearranged mesenchymal neoplasms with a relatively high tumor burden.

Regimens co-targeting the MAPK pathway and ALK or ROS1 had limited efficacy in unselected patients with lorlatinib-resistant NSCLC, underscoring the need for more effective and biomarker-informed treatment strategies.

Since the approval of crizotinib, several next-generation ALK inhibitors have been introduced, offering improved treatment outcomes. The phase III eXalt3 study, a global randomized open-label trial, compared the efficacy of ensartinib, a second-generation ALK inhibitor, with crizotinib in patients with advanced ALK-rearranged NSCLC who had not received prior ALK-targeted therapy. With superior systemic and intracranial efficacy, ensartinib stands as a promising option in precision oncology. Ongoing research into improved ALK inhibitors and novel therapeutic strategies, including immune-based approaches, is expected to further improve patient outcomes.

P2, N=80, Recruiting, Stanford University | Trial primary completion date: Dec 2025 --> Dec 2026

ALK overexpression by immunohistochemistry and confirmatory molecular testing, when necessary, plays a critical diagnostic role. The expanding spectrum of ALK-rearranged cutaneous tumors underscores the value of an integrated diagnostic approach to ensure accurate diagnosis and guide clinical management.

PRMT5 inhibitor activity is independent of TKI exposure, driver alteration, and SDMA expression and enhanced by addition of TKI. These findings support clinical evaluation of PRMT5 inhibitor + TKI combinations for advanced NSCLC.

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.

This case supports considering IMT in pediatric pelvic masses and reinforces that complete surgical resection remains the primary treatment. Although ALK gene rearrangement was not associated with therapeutic intervention in the present case, its identification remains diagnostically relevant and may provide important insights into management decisions in selected clinical scenarios, such as recurrence or unresectable disease.

P3, N=390, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2026 --> Feb 2027 | Trial primary completion date: Oct 2026 --> Dec 2025