1288P - Clinical impact and landscape of heterogeneous ALK resistance mutations (muts) after comprehensive genomic profiling (CGP)

Background

ALK rearrangements are established drivers and validated molecular targets in NSCLC, with five approved targeted therapies in the US. Tumors inevitably develop resistance, and there are several therapeutic approaches aimed at overcoming secondary ALK resistance muts. We sought to describe the genomic and treatment landscape of ALK resistance muts detected by CGP.

Methods

CGP results from 2,714 tissue and 302 liquid circulating tumor DNA samples from ALK-rearrangement positive (ALK+) NSCLC samples were queried for ALK muts (T1151M/R, L1152R, C1156Y, I1171N/T/S/H/V, F1174X, V1180L, R1192P, L1196M, L1198F, G1202X, D1203N, S1206Y, E1210K, G1269A) associated with acquired resistance (ALK AR) to 1^st-3^rd generation ALK tyrosine kinase inhibitors (TKIs). The Flatiron Health-Foundation Medicine clinico-genomic database, a nationwide (US-based) de-identified EHR-derived database linked to CGP data, was queried for post-TKI AR and treatment patterns for patients with CGP specimens collected >30 days after TKI start.

Results

ALK AR were detected in 190 (17%) tissue and 56 (18.5%) liquid ALK+ samples. The most common were G1202R (43.9%), L1196M (14.6%), and I1171N (14.2%); 20% of tissue and 50% of liquid samples harbored multiple ALK AR muts. Other ALK muts (G1123A, T1151insT, I1171M, G1202del, I1268V, E1129V, L1196Q) were detected in 9 samples also harboring known ALK AR. 9 patients with ALK AR also had potential off target resistance (AXL, BRAF, MAP2K1, MET, NF2, NRAS). Of 90 ALK+ patients with a post-TKI CGP sample, 29 had on-target ALK AR, 13 had off-target putative resistance (BRAF, MET, NF2, PIK3CA), and 1 had both. Of 71 patients with a documented therapy after ALK TKI, 55 (77%) initiated therapy after CGP report receipt. 21/55 patients had ALK AR, 17 of which received another ALK TKI, 2 immune checkpoint inhibitor (ICPI)-based regimens, 1 clinical study drug, and 1 chemo-based regimen. Of 8/55 patients with off-target resistance, 5 received an ALK TKI, 2 ICPI-based regimens, and 1 chemo-based regimen.

Conclusions

These results suggest that AR mechanisms beyond well characterized ALK point muts are prevalent after ALK-TKI therapy and detection with CGP may potentially influence treatment decisions for these patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine, Inc.

Disclosure

P. Hofman: Financial Interests, Advisory Role: Sanofi, Amgen, Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, Janssen, Pierre Fabre, Thermo-Fisher Scientist, Qiagen, Diaceutics, Novartis, Biodena, Biocartis, Eli Lilly; Financial Interests, Speaker, Consultant, Advisor: AbbVie, Sanofi, Amgen, Roche, Bristol Myers Squibb, AstraZeneca, Qiagen, Pfizer, Janssen, Thermo-Fisher Scientist, Biodena, Diaceutics, Biocartis, Daiichi Sankyo, Eli Lilly, Bayer, Novartis, Pierre Fabre; Financial Interests, Funding: Amgen, Thermo-Fisher Scientist, Biodena, Roche. C.F.B. Tambaoan: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine, Inc.; Financial Interests, Institutional, Stocks/Shares: Roche. A.B. Schrock, R. Madison, J. Lee, R. Huang: Financial Interests, Institutional, Stocks or ownership: Roche; Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine, Inc. G. Erb: Financial Interests, Institutional, Full or part-time Employment: Roche.