Abstract 559: Expression of molecular targets for antibody-drug conjugates in patients with NSCLC and RET fusions
Authors: Marinello Arianna , Ghigna Maria Rosa , Gazzah Anas , Godefroy Karine , Lacroix Ludovic , Vasseur Damien , Remon-Masip Jordi , Barlesi Fabrice , Planchard David , Scoazec Jean-Yves , Besse Benjamin , Aldea Mihaela 
Published: June 2023

Abstract
Background RET fusions are found in 1-2% of patients (pts) with advanced non-small cell lung cancer (NSCLC). RET inhibitors are highly effective, but resistance eventually occurs. Antibody-drug conjugates (ADC) are promising treatments in NSCLC, that could be employed at time of resistance. Data on the membranous expression of ADC targets, such as EGFR/HER2/HER3 and the possible impact of novel therapeutic agents in RET+ NSCLC are lacking.
Methods We conducted a single-center observational study, collecting tissue specimens from 19 patients (pts) affected by RET+ NSCLC. The expression of EGFR/HER2/HER3 proteins on the cellular membrane was evaluated by immunohistochemistry (IHC). EGFR expression was assessed by using the DAKO EGFR pharmDx kit (Dako, Glostrup, Denmark); HER2 staining (4B5 clone by Roche clone) was evaluated using ASCO/CAP guidelines in scale from 0 to 3+; HER3 staining (D22C5 clone by Cell Signaling) was categorized by intensity as 0, 1+, 2+, and 3+, according to the same criteria used for HER2 evaluation. All IHC analyses were performed at Gustave Roussy.
Results Out of 19 pts, 18 were evaluable for EGFR expression, 18 for HER2, 17 for HER3. All analyses were conducted on archival tissue samples from tumor biopsies performed predominantly in treatment-naïve pts (17/19). Pts had adenocarcinoma in 5/19 cases, KIF5B fusion partner in 13/19 cases. Median PD-L1 expression in evaluable pts was 15% (IQR 1- 60.00). EGFR expression was high, moderate, and low in 4 (22%), 2 (11%) and 5 (27%) cases, respectively. HER3 expression was 2+ in 4 (24%) cases, 1+ in 5 (29%) pts and 0 in the other 47%. None had HER2 membranous expression. EGFR expression was more frequently found in pts with uncommon fusion partners (6/11 vs 0/7, p=0.038) and non-adenocarcinoma histology (5/11 vs 0/7, p=0.10). HER3 expression evaluated at 2+ were identified in 3 cases with KIF5B-RET fusion and adenocarcinoma and 1 case with ANKRD26-RET fusion and undifferentiated histology. PD-L1 expression did not show significant difference between pts with positive vs negative EGFR or HER3 staining (p=1).
Conclusions EGFR and HER3 had variable expression in RET+ NSCLC, deserving further exploration for novel treatment strategies. HER2 expression was not found in our RET cohort.
Citation Format: Arianna Marinello, Maria Rosa Ghigna, Anas Gazzah, Karine Godefroy, Ludovic Lacroix, Damien Vasseur, Jordi Remon-Masip, Fabrice Barlesi, David Planchard, Jean-Yves Scoazec, Benjamin Besse, Mihaela Aldea. Expression of molecular targets for antibody-drug conjugates in patients with NSCLC and RET fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 559.