ALK fusion

P2, N=46, Not yet recruiting, Massachusetts General Hospital

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.

Reflex NGS at diagnosis in resected Stage 0-IA LUAD is feasible, rapid, and reveals a high rate of actionable alterations, which may support its integration in the future into early-stage diagnostic workflows.

Among patients who received next-generation ALK TKIs as first-line therapy, continuation of next-generation ALK TKI with PT/Pem led to longer PFS and OS than PT/Pem alone, with no unanticipated toxicities. The modest efficacy of PT/Pem-based regimens overall underscores the need for more effective therapies for TKI-refractory ALK+ NSCLC.

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.

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.

P2, N=18, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027

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

Compared to results from established architectures such as Inception-v3 on the same WSIs, our model demonstrated significantly improved performance for most features. With further optimization, our model could support triaging for molecular testing and inform precision treatment strategies for NS-LUAD patients.

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.