ALK I1171

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

V3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.

Furthermore, the US simulation results elucidate that the pathways through which lorlatinib dissociates vary across mutant systems, and the distinct environments during the dissociation process culminate in diverse resistance mechanisms. Collectively, these insights provide important clues for the design of novel inhibitors to combat resistance.

ALK inhibitors first-line crizotinib, second-line ceritinib, and alectinib are effective against NSCLC patients with these rearrangements. Based on the Y1278-C1097 H-bond and E1167-K1150 salt bridge interaction, I1171N strongly promotes the constitutively active kinase independent of ATP. This structural mechanism study will aid in understanding the oncogenic activity of ALK and the basis for improving the ALK inhibitors.

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.

Legal entity responsible for the study Fondazione Policlinico Universitario A Gemelli – IRCCS. In post-lorlatinib NGS-assay, 2 pts had ALK-compound mutations, while 4 pts had newly off-target alterations (CDKN2A/B CDKN2B loss, NF1 deletion, DNMT3A/ARID1A/CHECK2 M+). Conclusions Implementation of longitudinal genomic assessment is required in order to provide an extensive overview of resistance mechanisms and clinical outcomes according to current ALK-inhibitors treatment sequences.

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.

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 treatment may provide a new therapeutic strategy for ALK TKIs resistant patients, especially in position 1171 of ALK exon20.

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.