172P - HER2 expression across solid tumors and real-world implications for use of fam-trastuzumab deruxtecan-nxki (T-Dxd)

Background

On April 5, 2024, FDA granted accelerated approval to T-Dxd for adult patients with metastatic HER2-positive Immunohistochemistry (IHC) 3+ relapsed/refractory solid tumors. However, the real-world expression of HER2 across solid tumors and its implications in clinical practice are unknown.

Methods

Solid tumor specimens from UAB sent to Caris Life Sciences were analyzed for HER2 status. HER2 (ERBB2) copy number amplification (amp) was determined by comparing sample's average depth and sequencing depth of each exon to a pre-calibrated reference. Copy number (CN) > 6 was classified as positive, while CN ≥ 6 with low statistical confidence was labeled as intermediate. HER2 variants (SNV/INDELs) were categorized based on ACMG standards. IHC assays were performed using FDA-approved companion diagnostic tests: HER2/neu (PATHWAY anti-HER-2/neu (4B5), Ventana). IHC results adhere to ASCO/CAP scoring criteria: 0 (no expression), 1+, 2+, or 3. Data from these test reports were extracted and analyzed using descriptive statistics.

Results

We analyzed 653 cases across 24 cancer types: colorectal carcinoma (30.3%, n=198), uterine neoplasms (21.3%, n=139), metastatic breast carcinoma (10.1%, n=66), cholangiocarcinoma (8.6%, n=56) & ovarian/fallopian carcinomas (6.9%, n=45). Tumors with highest proportion of HER2 IHC 3+ in our cohort were salivary gland tumors (16.7%, n=1), esophageal/esophagogastric junction carcinoma (10.3%, n=3), breast carcinoma (9.1%, n=6), ovarian/fallopian carcinomas (6.7%, n=3) & cholangiocarcinoma (3.6%, n=2). HER2 IHC scores were 3.1% IHC 3+ (n=20), 13.2% IHC 2+ (n=86) & 19.8% IHC 1+ (n=129). CNV analysis revealed 3.1% (n=20) with positive amp & 3.5% (n=23) intermediate. Moreover, 3.1% (n=20) harbored pathogenic HER2 mutations. HER2 amp & overexpression varied notably among tumor types. In the positive CNV amp cohort, 75% showed IHC 3+ status, whereas, only 8.7% in the intermediate group. Interestingly, in cases with pathogenic HER2 mutations, only 5% had IHC 3+.

Conclusions

Our study highlights the variable expression and significance of HER2 testing across multiple solid tumor types, reinforcing the importance of HER2 testing to optimize the utilization of T-Dxd in the real-world setting.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Desai: Financial Interests, Personal, Advisory Board: Sanofi, Amgen, AstraZeneca, Janssen, Foundation Medicine. All other authors have declared no conflicts of interest.