1363P - Genomic heterogeneity of ALK rearrangements and acquired resistance pathways in ALK+ Advanced non-small cell lung cancer (NSCLC) treated with upfront alectinib: Preliminary results of GALILEO project

Background

Longitudinal genomic evaluation of ALK+ ANSCLC patients treated with 1L alectinib is poorly explored in clinical practice.

Methods

GALILEO (Genomic ALteratIons and cLonal EvOlution in ALK+ NSCLC) is national observational prospective cohort study on ALK+ ANSCLC pts treated with new generation ALK-TKIs. Comprehensive genomic profiling was performed on pre-treatment FFPE tissue of ALK+ ANSCLC identified by using FISH and/or IHC. At the time of progression, DNA-based NGS was repeated on newly obtained tissue (if feasible) or blood ctDNA (FM1 CDx/Liquid®).

Results

In this preliminary analysis, 30 ALK+ ANSCLC pts who started 1L alectinib by Dec 2020 were evaluable. In pre-treatment samples, NGS identified 26 (86.6%) EML4-ALK fusion (V1: 9, V2: 2; V3: 11; NOS: 4), 6 (20%) non canonical fusions (1 alone, 5 conc. with EML4-ALK), 8 (30%) ALK Internal/Intrachromosomal rearrangements (4 intron 19, 2 exon 19, 1 intron 18, 1 C2orf44; 2 alone, 6 conc. with ALK-fusions); in one case, any ALK-alteration was detected. As the data cut-off (median FU: 37 mo.), 14 pts had radiological progression (PD). Among 11 alectinib-responder pts (CR/PR or SD > 6 mo.), 4 patients presented de-novo ALK-SNV [G1202R (50%); E1210K (25%); I1171N/T (25%)], 4 pts had no ALK-SNV (DNMT3A M+: 3 pts; SEDTD2 M+: 2 pts, TP53 M+: 2 pts), 1 pt had oncogene-switch (EGFR); 2 pts failed ctDNA-NGS (low purity). Among 8 pts who received 2L lorlatinib, we observed 3 PR in ALK SNV+ pts, 2 SD ≥6 mo. and 3 PD in pts without ALK-SNV. 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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Policlinico Universitario A Gemelli – IRCCS.

Funding

Grant award: "Roche per la Medicina di Precisione - 2020"; Roche Italia - Fondazione GIMBE.

Disclosure

All authors have declared no conflicts of interest.