ALK amplification

We report the first case of ALK-RCC with concurrent ALK amplification and fusion. This article presents the clinical data, morphology, immunohistochemistry, and molecular characteristics of this case, with the aim of enhancing the clinical and pathological understanding of ALK-RCC among clinicians and pathologists.

ORNi-PCR followed by ddPCR/real-time PCR enables highly sensitive and accurate detection of ALK mutations by liquid biopsy. Although the clinical data are limited, our results show that these methods are potentially useful for identifying ALK-TKI-resistant NSCLC at the early recurrent phase.

Yet, to our knowledge, we present herein the first case of ALK + NSCLC rapidly progressing on 1 st line Brigatinib treatment due to de novo MET- amplification. The recognition of this mechanism of ALK-TKI resistance by FISH, especially in NGS-negative cases, should be considered before initiating 1 st line treatment. This is of clinical importance, as effective combined therapy with ALK-TKI and MET-inhibitor is feasible.

Some atypical fusion partners were observed in white and BAA that were not observed in other races. These data emphasize the importance of testing lung cancer patients with assays that allow for unbiased fusion detection and identification of novel fusion partners across racially diverse populations to better understand racial and ethnic differences in ALK-rearranged lung cancers.

Hepatocellular carcinoma (HCC) currently lacks effective therapies, leaving a critical need for new treatment options. Additional studies identified that the apoptosis-inducing effect of lorlatinib was mediated via GGN and NRG4. These findings establish ALK inhibitors as promising HCC treatments, either alone or in combination with immunotherapies or senolytic agents.

P1, N=65, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1b, N=44, Terminated, Pfizer | Active, not recruiting --> Terminated; Termination of further treatment on the study due to the availability of commercial supply or a rollover study (NCT05160922) that will allow active subjects to continue receiving treatment.

Although the sample size of patients receiving targeted therapies was limited, the study highlighted improved overall survival and progression-free survival rates compared to earlier trials, suggesting advancements in systemic lung metastasis treatment. The study suggests that as more targeted therapies emerge, the prospects for increased overall survival and progression-free survival in lung brain metastasis patients will likely improve.

MET-amplified, ALK + NSCLC often presents with high-level and heterogeneous amplification in tissue, seldom overlaps with ALK mutations, and frequently co-occurs with alterations associated with aggressive tumor biology.

Conclusions The combination of GGTT and osimertinib improves TTF and OS in EGFR mutation positive NSCLC patients failing osimertinib. Future prospective comparative study is warranted.

HGSOC harbouring activating ALK mutations might be associated with a better survival, while ALK overexpression and ALK amplification does not impact the prognosis.

In Cohort 1 (n=21), 15 (71%) pts had progressed on alectinib, 5 (24%) on ceritinib and 1 (5%) on ensartinib. In Cohort 2 (n=18), pts had progressed on crizotinib followed by alectinib (n=9, 50%), ceritinib (n=4, 22%) or brigatinib (n=3, 17%); 2 (11%) pts progressed on crizotinib, then ceritinib followed by alectinib...Of 5 pts with ALK resistance mutations (I1171N, V1180L, L1196M, G1202R, and E1210K) who subsequently received lorlatinib, repeat ctDNA NGS after 2 months demonstrated clearance of ALK resistance mutation(s) in 4/5 (80%) pts (i.e. undetectable on repeat testing)... Resistance mechanisms to ALK inhibitors are heterogenous, including both ALK dependent and independent pathways. DDR and cell cycle gene alterations were commonly detected and may represent previously unreported acquired resistance alterations. Comprehensive ctDNA NGS analysis at progression may help detect novel resistance alterations in patients on ALK inhibitors.