ALK resistance mutations (muts) developed in different ALK fusion types.

Abstract

e14741 Background: Patients (pts) treated with ALK inhibitors (ALKi) inevitably develops resistance. Diverse mutations (muts) confer resistance to ALKis, which may be related to the diverse types of ALK fusion. The objective of this study is to see whether the resistance mechanisms developed during ALKi therapy are ALK fusion types dependent. Methods: The mutation profiles of 38 pts with known ALK fusion partners and positions, who ordered NGS test in our institution after progressed on ≥ 1 ALKis, were analyzed. Results: Resistant muts in ALK kinase domain ( ALK resistant muts) were detected in 53% (20/38) of the resistant pts. 100% (1/1) of the EML4-ALK V5’ variant (V5’), 81% (13/16) of the EML4-ALK V3 variant (V3), 60% (3/5) of the non- EML4-ALK, 23% (3/13) of EML4-ALK V1 variant (V1), and 0% (0/3) of the EML4-ALK V2 variant (V2) had ALK resistant muts. ALK G1202R was detected in 29% of the pts. 100% (1/1) of the V5’, 50% (8/16) of the V3, 20% (1/5, HIP1-ALK) of the non- EML4-ALK, and none of the V1 (0/13) and V2 (0/3) had G1202R. Amplification and gain of function muts in oncogenes and loss of function muts in tumor suppressor gene were detected in 16% (6/38) of the pts, namely 4 V1, 1 V2, and 1 V3. On average, pts treated with 3rd generation ALKis had significantly more muts in ALK (7.5 vs. 3.6, p = 0.0008) and in all targeted regions (9.1 vs. 4.3, p = 0.0005) than pts treated with only 1st and 2nd generation ALKis. Conclusions: The type of resistance mechanisms developed during ALKi therapy may depend on the ALK fusion type of the pt. ALK resistant muts, especially G1202R, developed most frequently in V3/V5’, followed by non- EML4-ALK, and V1/V2, while amplification and grain of function muts in oncogenes and loss of function muts in tumor suppressor genes developed more often in V1/V2 than in V3/V5’. The 3rd generation ALKi may increase the genomic alterations in treated pts.