Alecensa (alectinib)

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.

Here, we report a case of an ALK-positive lung adenocarcinoma patient who developed resistance following sequential treatment with the ALK-TKI alectinib and lorlatinib, accompanied by histological transformation to LCNEC and concurrent genetic alterations including TP53 deletion, CDKN2A deletion, and MYC amplification. This case expands the spectrum of ALK-TKI resistance mechanisms and highlights the potential value of exploring combinatorial approaches incorporating immunotherapy, antiangiogenic therapy, and chemotherapy for the management of such cases.

The patient received whole-brain radiotherapy (30 Gy in 10 fractions), cisplatin-pemetrexed chemotherapy, and sequential targeted therapy with alectinib and lorlatinib. During three years of follow-up, MRI showed complete resolution of all lesions, and the patient remained neurologically intact and systemically stable. This case underscores the rarity of non-enhancing brain metastases in ALK-positive NSCLC and highlights the importance of recognizing this atypical imaging presentation for timely diagnosis and management.

Genomic metrics showed tumor mutational burden (TMB) of 0.94/Mb, microsatellite stability, and CNV burden of 2.1%. He underwent near total resection followed by alectinib; to our knowledge, this is the first reported young pediatric (<10 years old) CNS IMT with this fusion.

Multigene testing is underutilized in this population. While many targeted therapies carry a high risk of pneumonitis, sotorasib appeared relatively safe. Despite the risks, identifying and treating actionable oncogenic drivers may improve survival.

ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required.

In the Th-MYCN/ALKF1174L neuroblastoma mouse model, combination therapy induced complete tumor regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treating aggressive malignancies such as high-risk neuroblastoma, exploiting the untapped polypharmacology of alectinib as an RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.

This case underscores the critical importance of retesting for resistant mechanisms, such as EML4-ALK fusion, in patients with EGFR-mutant lung adenocarcinoma who experience rapid progression on EGFR-tyrosine kinase inhibitor (TKI) therapy. Early identification of such co-alterations and an immediate switch to alectinib can lead to rapid and sustained clinical improvement.

The patient was initially treated with alectinib, but experienced rapid disease progression. After repeat genetic testing, therapy was switched to lorlatinib, which again resulted in early progression...To our knowledge, this is the first reported case of ivonescimab use in such a patient. This case offers a potential reference for the management of ALK fusion-positive lung adenocarcinoma resistant to ALK tyrosine kinase inhibitors (ALK-TKIs).

Off-label combination therapy to treat targeted therapy resistance in advanced NSCLC is feasible in routine clinical practice. Additional real-world evidence is needed to clarify best practices with this emerging approach.

Stability studies for 40 % ALB ASD formulation were conducted at room temperature (25 ± 2 ˚C/ 60 ± 5 % RH) and accelerated conditions (40 ± 2 ˚C/ 75 ± 5 % RH), and results showed stability up to 6 months, as demonstrated by drug content, DSC, PXRD, and dissolution. The observed increase in solubility and dissolution in bio-relevant media suggests potential for improved in vivo absorption, especially in the fed-state.These findings support the use of solid dispersion as a strategy to enhance the bioavailability of ALB.