EML4-ALK fusion

We report a case showing that lorlatinib is effective in treating EML4-ALK-positive low-grade serous ovarian cancer (LGSO) with intracranial metastasis. This may be the first clinical evidence of LGSO benefit from ALK inhibitors, to provide evidence for the use of ALK inhibitors in more ovarian cancer patients with EML4-ALK fusion and promoting new ideas for the study of EML4-ALK targets in ovarian cancer.

This is the first report of a NSCLC patient with a novel SV2B-ALK, EML4-ALK double-fusion benefiting from alectinib. Alectinib may be an effective therapeutic option for both primary and metastatic lesions including brain metastases in the late-line setting in NSCLC patients with double-ALK fusion.

Of total cohort, 18 patients (72.0 %) underwent intrathecal pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence interval, 3.3-11.6) from the initiation of ITP to death...Our results highlight CSF cfDNA NGS's potential in LM resistance understanding and ITP efficacy prediction. MET CNG positively impacts survival for ITP recipients, whereas the coexistence of EGFR T790M and EGFR-independent resistance mechanisms leads to poor outcomes.

Between January 2020 and February 2024, we identified four patients with either EML4-ALK fusions (2/4) or EGFR mutations (2/4) who underwent treatment with brigatinib or osimertinib before surgery. This case series highlights the potential of targeted therapies for resectable NSCLC in the neoadjuvant setting. Further research is required to confirm their benefits, assess their safety and efficacy, and determine optimal timing and sequencing.

P2; Active, not recruiting --> Completed

Interlaboratory studies using the EML4-ALK RMs and potential RMP showed that participating laboratories can produce consistent copy concentrations of fusion variant and ALK-ref as well as the ratio of EML4-ALK/ALK-ref. The established potential RMP with high specificity and accuracy can be used to characterize the EML4-ALK RMs, and the potential RMP and RM are useful to establish the traceability of EML4-ALK fusion measurement to improve the comparability and consistency in clinical tests.

Based on the genomic analysis, we treated the patient with brigatinib, an ALK inhibitor. We describe here a patient with LCNEC who responded significantly to brigatinib without serious adverse events.

Despite two cycles of adjuvant chemotherapy consisting of carboplatin and gemcitabine, CT revealed that the pleural effusion had increased from it before chemotherapy, and the shortness of breath worsened...Treatment with alectinib, a second-generation ALK-tyrosine kinase inhibitor, led to a partial response of 18 months' duration, and the shortness of breath improved...Variations in the drug response among EML4-ALK fusion variants highlight the importance of understanding their molecular structure. Further investigation is warranted to refine fusion gene detection methods and assess the therapeutic implications of rare fusion variants.

V3 patients had poor outcomes regardless of PD-L1 status, while V1 patients with PD-L1 negativity had better outcomes. These biomarkers offer key insights into treatment outcomes for ALK-positive patients.

The patient was treated with lorlatinib as the first-line treatment. This case is the first to describe the effectiveness of lorlatinib in treating an advanced high-grade PMEC with EML4-ALK fusion V2 mutation patient.

Consistently, combination of the ALK TKI alectinib with the MET TKI capmatinib and/or the integrin inhibitor cilengitide was significantly more efficacious than single agent treatment in suppressing tumor growth using an in vivo EML4-ALK -dependent allograft mouse model of NSCLC. In summary, these findings emphasize the complexity of resistance-associated crosstalk between CAFs and cancer cells, which can involve multiple concurrent signaling pathways, and illustrate how comprehensive elucidation of paracrine and juxtacrine resistance mechanisms can inform on more effective therapeutic approaches.

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.