Abstract
Characterization of diverse targetable ERBB2 alterations in 512,993 patients with solid tumors.
Author
person
Dazhi Liu
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Dazhi Liu, Rachel B Keller-Evans, Alexa B. Schrock, Alexander E. Drilon, Justin Jee, Bob T. Li
Full text
Authors
person
Dazhi Liu
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Dazhi Liu, Rachel B Keller-Evans, Alexa B. Schrock, Alexander E. Drilon, Justin Jee, Bob T. Li
Organizations
Memorial Sloan Kettering Cancer Center, New York, NY, Foundation Medicine, Inc., Boston, MA, Foundation Medicine, Inc., Cambridge, MA
Abstract Disclosures
Research Funding
No funding sources reported
Background:
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated activity against a range of HER2-expressing and HER2-mutant (mut) solid tumors. We present an extensive landscape of
ERBB2
alterations (alt) that may predict sensitivity to HER2-targeted therapies in development with a focus on mutations and cancer types without approved indications.
Methods:
We queried institutional databases (MSKCC and Foundation Medicine, Inc.) of comprehensive genomic profiling (CGP) performed on solid tumor tissue samples using either MSK-IMPACT (N=83,332; MSK) or FoundationOne/FoundationOne CDx (N=429,661; FMI) and on patient-matched liquid biopsies using FoundationOne Liquid CDx (N=1,922). ctDNA tumor fraction (ctDNA TF) on FoundationOne Liquid CDx was estimated using a composite algorithm. Clinicopathological characteristics and treatment outcomes were annotated for MSK-IMPACT samples.
Results:
ERBB2
activating alt were detected in 6.6% (n=28,508) and 5.0% (n=4,133) of tumors in the FMI and MSK cohorts, respectively. In FMI tissue samples,
ERBB2
alt were most prevalent in gastroesophageal (GEC; 18.1%), bladder (18.0%), salivary gland (14.1%), breast (12.7%), and uterine (12.1%) cancers. The cancer types with the largest number of
ERBB2
mut tumors, specifically, included NSCLC (n=1,618, 1.9%), breast (n=1,565, 3.5%), colorectal (CRC; n=1,221, 2.3%), bladder (n=855, 8.8%), and GEC (n=660, 3.4%). Across these 5 cancers,
ERBB2
mut were most commonly located in the kinase domain (KD; 58%), followed by the extracellular domain (ECD; 28%) and transmembrane domain (TMD; 2%). Rare splice site mut and in-frame deletions resulting in exon 16 loss (Ex16Alt) were also observed (n=76, <0.1%).
ERBB2
mut were found to be mutually exclusive with other RTK/MAPK driver oncogenes including:
EGFR
,
KRAS
,
ALK
,
MET
,
BRAF
, and
RET
in NSCLC;
FGFR1
in breast cancer;
BRAF
in CRC; and
FGFR3
in bladder cancer. In patient-matched liquid biopsy samples, sensitivity for detecting
ERBB2
amplifications (amp; 33.3%, 43/129) was lower than for detecting
ERBB2
mut (72.3%, 47/65) across select cancers. However, sensitivity for detection of both alts was improved in liquid samples with elevated ctDNA TF (≥1%), increasing to 52.6% (40/76) for amp and 97.3% (36/37) for mut. In the MSK cohort, 110 of 986 (11.2%) patients with
ERBB2
mut non-NSCLC tumors received one or more HER2-targeted therapies, including ADCs. Clinical responses to HER2-targeted therapies were observed in patients harboring KD mut (n=10), ECD mut (n=6), TMD mut (V659E, n=1), and in 1 patient with a V697L mut.
Conclusions:
CGP detects diverse
ERBB2
activating alt at a high incidence in solid tumor types beyond NSCLC. These represent patient populations who may benefit from HER2-directed therapies. Trials of novel HER2-targeted agents are necessary to refine our understanding of the biological dependency of HER2 alterations.
2 organizations
Organization
Memorial Sloan Kettering Cancer CenterOrganization
Foundation Medicine, Inc., Cambridge, MA