ALK I1171T

We found that F1174 and R1275Q-related anaplastic lymphoma kinase mutations are the most common pathogenic mutations in neuroblastoma. Anaplastic lymphoma kinase mutation status did not show any heterogeneity, and the mutations were correlated with intermediate- or high-risk groups.

Our findings suggest that real-time quantitative monitoring of ALK resistance mutations during the response period could provide a time course of changes while acquiring resistance mutations. This information would be beneficial for designing an appropriate treatment strategy.

Its role in populations who have shown resistance to Alectinib and Crizotinib after initial response has not been evidenced by a large randomized controlled trial. Brigatinib therapy resulted in rapid improvement for our patient with previously treated ALK mutation NSCLC and severe acute respiratory therapy due to aggressive lymphangitic spread. The long-term response for this patient remains unknown and the broader applicability of these results will have to await further reporting and randomized trials.

He achieved complete remission after 2 cycles with multi-agent chemotherapy (dexamethasone, ifosfamide, methotrexate, cytarabine, etoposide, cyclophosphamide, doxorubicin and brentuximab)...He had progressive disease after 3 weeks and was changed to combination chemotherapy with brentuximab and nivolumab with the addition of alectinib, a second generation ALK inhibitor. He again had progressive disease within 3 weeks and received therapy with ifosfamide, carboplatin and etoposide with a mixed response...Based on preclinical studies and limited clinical studies demonstrating that ALKI1171T mutations are resistant to crizotinib and alectinib but may maintain sensitivity to ceritinib, the patient started ceritinib in combination with brentuximab... Testing for the presence of ALK rearrangements via IHC is standard in pediatric ALCL but cannot solely predict sensitivity to specific inhibitors. Consideration should be made for upfront ALK gene sequencing as this may drive therapeutic decisions regarding which inhibitor is most likely to result in a clinical response.

This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.

This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.

Of these, 52 received first-line alectinib treatment (1L) and 56 received alectinib after crizotinib resistance (2L). Also, NF2-mutant patients only had a median PFS of 4 months, significantly poorer than those without (HR 11.1, 95CI 2.17-50; p<0.001). Conclusions By analyzing different mutational profiles of ALK-rearranged patients after alectinib treatment, we proposed MET and NF2 as putative mechanisms that conferred resistance to early resistance of first-line alectinib, which shone light on future tailored treatment for ALK-positive NSCLCs.

ALK rearrangements are detected in approximately 4% of patients with advanced non-small cell lung cancer (NSCLC), and the tyrosine kinase inhibitors (TKIs) crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib have been approved by the FDA for the treatment of ALK-positive NSCLC. The dPCR method was highly sensitive in detecting gene mutations with low allele frequency. It was also found to be able to monitor variable resistance mutations over time during ALK-TKI treatment. In addition, we found that the appearance of G1202R did not always indicate clinical acquisition of resistance that required drug modification.

The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

One patient was deemed as sensitive to carboplatin but tumor showed to be resistant...The patient started alectinib but showed progression after 12 months...Treatment was switched to brigatinib with no response...The In vitro results demonstrated no activity of lorlatinib but a strong response to crizotinib... We present clinical evidence that PDOs are an alternative tool in oncogenic addicted tumors helping to guide treatment decisions and increasing a more personalized sequential treatment approach.

We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.

After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment...In conclusion, resistance to ALK-TKIs based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. The appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.