3473 - Real-World Landscape of c-MET Expression in HPV Negative Head and Neck Squamous Cell Carcinoma (HNSCC)

Purpose/Objective(s):

HGF/c-Met signaling axis is a key regulator of tissue regeneration. In HNSCC, dysregulated HGF/c-Met signaling has been linked to aggressive tumor biology and poor prognosis, particularly in p16-negative disease. A Phase 3 clinical study with Ficlatuzumab, an anti-HGF monoclonal antibody, is ongoing in HPV negative HNSCC patients (NCT06064877). To better understand c-Met expression in the target patient population, real world p16-negative HNSCC biopsy samples were evaluated and compared with a range of clinical parameters.

Materials/Methods:

The HNSCC FFPE tumor biopsies (from a biobank) were screened for p16 status, a surrogate of HPV negativity. Biopsies, from primary tumors (PT, n=48) or lymph nodes (LN, n=48), were evaluated for c-Met protein expression (Ventana SP44 RxDx IHC assay), and MET transcript levels (nCounter PanCancer IO360 panel). Biopsy samples were also analyzed to verify HPV status (nCounter HPV panel). The data were analyzed using summary statistics.

Results:

Tumor biopsies were from HNSCC patients aged 32 years to 91 years (median 62.5 years); 72.9% male and 27.1% female; 13.5 % Caucasian, 36.5% Asian and 50% unknown ethnicity. Primary tumor biopsies were from oropharynx (65%), hypopharynx (13%), oral cavity (13%), larynx (4%), and others (6%).

MET RNA was expressed in 98.9%, and 95.7% had a positive H-score by IHC. Median expression was comparable using RNA between PT and LN with median 191.8 copies in PT (IQR 134.8-267.4) and 157.7 copies for LN (IQR 85.9-221.0), and for protein with median H-score 85 for both PT (IQR 50-101) and LN (IQR 30-152). c-Met protein expression increased slightly from stage I biopsies (median H-score 50, IQR 50-85) to Stage II biopsies (median H-score 85, IQR 28.5-107.5), but no increases were observed with subsequent progression. MET RNA expression was similar across all disease stages.

Sex did not impact the expression profile. A moderate positive correlation was observed between the RNA and protein expression of c-Met (Pearson correlation coefficient = 0.435, p-value < 0.001).

All biopsies were screened for p16 negativity by IHC, but 1.06% cases were positive for HPV16 early genes (E6 and E7), in line with published literature. With a small sample size, the impact of HPV16 positivity on c-Met expression could not be assessed.

Conclusion:

Here, we show >95% c-Met positivity in p16-negative HNSCC tumor samples. Two orthogonal methods for evaluation of c-Met expression exhibited a positive correlation. c-Met expression increased during early disease progression, but the upward trend did not continue with advancing stage. A limited dataset was used for this study, and results should be interpreted in the appropriate context. Validation in a larger real-world setting would help understand the mechanistic role of HGF/c-Met signaling in HNSCC.