ALK C1156Y

We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

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.

The model is a non-small cell lung cancer harboring EML4-ALK fusion and ALK C1156Y/G1269A mutation, sensitive to the 3rd generation ALK TKI lorlatinib... We demonstrated potential targetable features of DTP cells. A combination of targeted therapies with DTP drug candidates could represent a therapeutic opportunity to improve the depth of response and delay the emergence of resistance in patients.

Another pt with the G1202R mutation following alectinib treatment had tumor shrinkage of 27.9%. APG-2449 has a favorable safety and PK profile and was well tolerated in 84 subjects. Preliminary efficacy was observed in pts whose disease was resistant to second-generation TKIs, especially among those with brain metastases, and in TKI-naïve pts. Biomarker data indicated potential target engagement on FAK and immunomodulatory effects of APG-2449.

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.

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.

The patient was therefore given an endobronchial cryotherapy and ALK inhibitor crizotinib. The patient was therefore received alectinib, and the tumor exhibited partly response. Overall, it is very rare that two types of pulmonary tumors exist in one patient driven by two distinct ALK fusions, which emphasizes the necessity of gene sequencing in clinical decision-making and individualized therapy.

This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.

Table: 1195P * ALK fusion+ pts received prior alectinib (median 3 prior TKI); EGFR T790M+ pts received prior osimertinib (median 2 prior TKI).**concurrent aberrations (G1202R+C1156Y; MET amp+ T790M; FGFR1 amp + CDK4 amp; C797S + BRAF; EGFR amp+CCND2 amp) Legal entity responsible for the study: The authors. Funding: Princess Margaret Cancer Foundation; Guardant Health. Clinical trial identification: NCT03576937.

Consistent with previous reports, ensartinib showed high clinical efficacy. Longitudinal ctDNA analysis could be a powerful tool in predicting treatment outcomes and revealing resistant mechanisms of ensartinib. We observed G1269A, G1202R and E1210K as the major resistant mutations to ensartinib.

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.