Abstract
Characterization of diverse targetable alterations in ERBB2 and ERBB3 in 93,465 non-small cell lung cancers (NSCLC).
Author
person
Dazhi Liu
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Dazhi Liu, Rachel B Keller, Andreas M Heilmann, Justin Allen, Geoffrey R. Oxnard, Lyudmila Bazhenova, Alexa Betzig Schrock, Bob T. Li
Full text
Authors
person
Dazhi Liu
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Dazhi Liu, Rachel B Keller, Andreas M Heilmann, Justin Allen, Geoffrey R. Oxnard, Lyudmila Bazhenova, Alexa Betzig Schrock, Bob T. Li
Organizations
Memorial Sloan Kettering Cancer Center, New York, NY, Foundation Medicine, Inc., Cambridge, MA, University Of California San Diego, Moores Cancer Center, San Diego, CA
Abstract Disclosures
Research Funding
Pharmaceutical/Biotech Company
Foundation Medicine, Inc.
Background:
Recently, fam-trastuzumab deruxtecan-nxki was approved for NSCLC with selected activating
ERBB2
(HER2) mutations. Patritumab deruxtecan, a novel HER3 directed antibody drug conjugate, exhibits
in vitro
activity against HER3 mutations. We present a comprehensive landscape of
ERBB2
/
ERBB3
alterations (alt) that may predict sensitivity to HER2/HER3 targeted therapies in development.
Methods:
We queried an institutional database (Foundation Medicine) of tissue or liquid comprehensive genomic profiling (CGP) results from 93,465 patients with NSCLC (85,704 tissue and 7,761 liquid samples).
ERBB2
amp was defined as ≥ sample ploidy +3. Activating/likely activating alts were called using annotations including presence in COSMIC, functional knowledge of the gene affected, internal insights, and characterization in the literature. ctDNA tumor fraction (TF) on FoundationOneLiquid CDx was estimated using a composite algorithm.
Results:
Activating/likely activating alt in
ERBB2
and
ERBB3
were detected in 3.9% (n = 3337) and 0.8% (n = 696) of NSCLC tissue samples, respectively (
ERBB2
: 2.0% amp, 1.7% mutations [mut; SNVs or indels], 0.001% rearrangements [RE], and 0.2% multiple;
ERBB3
: 0.5% amp, 0.3% mut, and 0.004% multiple). Age at diagnosis, sex, and predicted ancestry were similar among patients with
ERBB2
alt and
ERBB2
wt tumors.
ERBB2
alt were more frequently observed in non-squamous NSCLC (4.3% vs 2.3% in SCC), largely driven by differential
ERBB2
mut frequencies (2.0% vs 0.4%).
ERBB2
mut were most common in the kinase domain (KD; 70%, 56% of which were exon 20 insertions [ex20ins]), followed by the extracellular domain (ECD; 20%) and transmembrane domain (TMD; 6%), while
ERBB3
mut were most common in the ECD (88%, most commonly V104L/M and G284R).
ERBB2
RE or splice mut affecting exon 16 were detected in 23 cases (0.03%). While
ERBB2
alt were mutually exclusive with other oncogenic drivers (
KRAS
,
ALK
,
BRAF
,
EGFR
,
MET
,
ROS1
,
RET;
each p < 0.05),
ERBB3
alt were found to co-occur with both
ERBB2
(8.5% vs 3.9%
ERBB2
wt, p < 0.001) and
MET
(8.6% vs 5.2%
ERBB2
wt, p < 0.001) alt. A similar distribution of
ERBB2
alt (1.6% amp, 2.4% mut, 0.4% multiple) was detected in liquid samples with elevated TF (≥10%; n = 1458); across all liquid samples,
ERBB2
mut frequency was comparable to tissue (1.5%) but frequency of amp was 0.5%. In our study, 26% of
ERBB2
mut tissue samples had activating/likely activating mut not included in the DESTINY-Lung01 trial, most notably 100% of both TMD mut (n = 99) and exon 16 alt (n = 25), as well as 35% of ECD mut (117/331) and 14% of KD mut (162/1145, including 6% of ex20ins).
Conclusions:
Diverse
ERBB2
and
ERBB3
alt in NSCLC may predict sensitivity to anti-HER2/3 therapies, but not all classes of alts are detected/reported by all profiling assays. Utilization of comprehensive testing to guide biomarker definitions, treatment selection, and clinical trial enrollment is imperative.
3 organizations
2 drugs
3 targets
Organization
Memorial Sloan Kettering Cancer CenterOrganization
Foundation Medicine, Inc., Cambridge, MATarget
ERBB3Target
ERBB3 (HER3)Target
ERBB2 (HER2)