BIOM-01 - Genomic alterations in ALK fusion-positive non-small cell lung cancer (NSCLC) patients with brain metastases

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Poster Presenter(s)

Jordan E. Eichholz, BS

Memorial Sloan Kettering Cancer Center
New York, United States

Author(s)

EM

Emily Miao, PharmD

Memorial Sloan Kettering Cancer Center
New York, United States
EL

Emily Lebow, MD

Memorial Sloan Kettering Cancer Center
New York, United States
HW

Henry Walch, MS

Memorial Sloan Kettering Cancer Center
New York, United States
JF

Jessica Flynn, MS

Memorial Sloan Kettering Cancer Center
New York, United States
ZZ

Zhigang Zhang, PHD

Memorial Sloan Kettering Cancer Center
New York, United States
HH

Harper Hubbeling, MD

Memorial Sloan Kettering Cancer Center
New York, United States
KB

Kathryn Beal, MD

Memorial Sloan Kettering Cancer Center
New York, United States
Nelson S. Moss, MD

Memorial Sloan Kettering Cancer Center
New York, United States
KY

Kenny Yu, MBBS, PhD

Memorial Sloan Kettering Cancer Center
New York, United States
JY

Jonathan Yang, MD, PhD

Memorial Sloan Kettering Cancer Center
New York, United States
AM

Alicia Meng, MD

Memorial Sloan Kettering Cancer Center
New York, United States
DK

Daniel Kelly, MS

Memorial Sloan Kettering Cancer Center
New York, United States
TB

Thomas Boerner, MD, MSc

Memorial Sloan Kettering Cancer Center
New York, United States
DG

Daniel Gomez, MD, MBA

Memorial Sloan Kettering Cancer Center
New York, United States
AR

Andreas Rimner, MD

Memorial Sloan Kettering Cancer Center
New York, United States
NS

Nikolaus Schultz, PhD

Memorial Sloan Kettering Cancer Center
New York, United States
AD

Alexander Drilon, MD

Memorial Sloan Kettering Cancer Center
New York, United States
Brandon S. Imber, MD, MA

Memorial Sloan Kettering Cancer Center
New York, United States
LP

Luke Pike, MD, DPhil

Memorial Sloan Kettering Cancer Center
New York, United States

Purpose: Brain metastases (BM) are common in patients with anaplastic lymphoma kinase fusion-positive NSCLC (ALK+ NSCLC). We characterized the genomics of patients with ALK+ NSCLC BM treated with alectinib with or without local therapy to identify correlations of co-mutations with CNS-specific outcomes.

Methods: We retrospectively reviewed ALK+ NSCLC patients with BMs who received alectinib for the definitive treatment of BM from 1/2012 and 5/2021. Genomic characteristics of 27 specimens from 27 patients were assessed with MSK-IMPACT, a 505-gene next-generation sequencing (NGS)-based tumor sequencing assay with >700x coverage. Intracranial progression-free survival (iPFS) and overall survival (OS) from BM diagnosis were analyzed using standard statistical methods.

Results: The median age at BM diagnosis was 57 years (range 25-83). Median iPFS was 1.94 years (95%CI: 1.58- not reached) and median OS was 6.08 years (95%CI: 1.7– not reached). All patients received alectinib for the treatment of brain metastases (78% as 1st-line TKI) and 22% received local therapy. The most frequently altered co- alterations were CDKN2A (48%), TP53 (22%), MAP2K4 (15%), SMARCA4 (11%), CREBBP (11%), and ATM (7%). CDKN2A alterations were more common in patients with intracranial progression (64% vs 31%). MAP2K4 alterations were enriched in metastatic samples (p = 0.028, q = 0.113). SMARCA4 co- alterations were associated with inferior OS (HR: 8.76, 95%CI = 1.74-44.2, p= 0.009) and trended toward association with iPFS but was insignificant (HR: 3.25, 95%CI = 0.83-12.4, p=0.089). We identified missense ALK alterations in CSF from a patient who acquired resistance to alectinib and had leptomeningeal progression (G1269A, I1171T, L1108P).

Conclusion: 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.