EML4-ALK rearrangement

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.

Conclusion  Oncogenic driver mutations are present in Indian NSCLC patients. Molecular testing should be performed for all patients of advanced NSCLC to identify those that can benefit from newer generation of targeted or immunotherapies.

Median prior therapy lines was 3 (range 2-5); all pts previously received Crizotinib, two pts received also Alectinib and 1 Ceritinib as TKI treatment. Lorlatinib represents a safe and effective salvage therapy for ALK+ Lymphoma patients failing first line TKI treatment. The obtainment of CR at M1 seems to represent a pivotal prognostic factor. Lorlatinib also offers a promising bridging regimen to salvage ASCT especially for ALK+ BCL patients, with high response rates and no additional toxicities, .

Notably, (+)-8l significantly suppressed tumor growth in the H1975 cell-inoculated xenograft model (20 mg/kg/d, TGI: 96.11%), PC9 cell-inoculated xenograft model (20 mg/kg/d, TGI: 96.61%) and EML4 ALK-Baf3 cell-inoculated xenograft model (30 mg/kg/d, TGI: 80.86%). These results highlight the differentiated potential of (+)-8l to inhibit ALK rearrangement and EGFR mutation in NSCLC.

However, large clinical trials must be conducted in the future to determine the treatment course and efficacy of the neoadjuvant alectinib modality. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022376804.

This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.

The most frequent ALK TKIs were alectinib (n= 87, 58%) and crizotinib (n= 56, 38%). Conclusions In a population including multiple tumor types, NGS and IHC were highly concordant in ALK fusion detection. ALK TKI benefit may be observed in cases with discordant testing, in which only one assay detects a putative ALK fusion.

PC-9_v3a-gef and PC-9_v3b-gef cells were resistant to gefitinib and ALK inhibitors alone, but ALK inhibitors enhanced gefitinib-induced cytotoxicity. Furthermore, combination treatment with osimertinib and ceritinib caused a decrease in liver tumor size of the patient with liver metastases. Our data suggest that combination treatment with EGFR and ALK inhibitors can be a therapeutic strategy for treating NSCLC with concomitant EGFR mutation and EML4-ALK rearrangement.

Results In 1st line, ORR with ALKi was 63.6% [crizotinib: 60.7%, ceritinib: 70%, alectinib: 66.6%, p=0.508] and that with chemotherapy was 26.1%. Patients who received ALKi in second or later lines fared much better in comparison to chemotherapy. Use of ALKi in any lines of therapy resulted in significantly prolonged OS.

He was started on Alectinib 600mg twice daily with zoledronic acid from Aug 2017. Molecular testing and looking for ALK resistance mutation helps to choose Lorlatinib, the only sensitive TKI which targets (G1202R). This is an evolving precision based therapy, improves outcome in lung cancer.