Abstract 5134: Immunohistochemistry expression of membrane targets for novel therapeutic agents in RET-rearranged NSCLC
Authors: Marinello Arianna , Ghigna Maria Rosa , Zrafi Wael Salem , Mandarano Martina , Monnet Isabelle , Genova Carlo , Russo Alessandro , Terrisse Safae , Metro Giulio , Remon Jordi , Gazzah Anas , Barlesi Fabrice , Planchard David , Scoazec Jean-Yves , Besse Benjamin , Aldea Mihaela 
Published: March 2024

Background: RET fusions are found in 1-2% of patients (pts) with advanced non-small cell lung cancer (aNSCLC). RET inhibitors (RETi) are effective, but resistance occurs. Scarce data are available on treatment after progression (PD) to RETi. Antibody-drug conjugates and bispecific antibodies are promising therapies in NSCLC, possibly employed at resistance. Data on the expression of membrane targets and the impact of novel agents are lacking.

Methods: This is a multicentric retrospective study of 6 European centers. We collected archival tissue samples from pts with RET+ aNSCLC, treated or not with RETi. Membrane expression of cMET/TROP2/HER2/HER3/EGFR was centrally evaluated by immunohistochemistry (IHC). Expression was scored from 0 to 3+. cMET was assessed with EP1454Y clone, TROP2 with EPR20043, HER2 with 4B5, HER3 with D22C5, EGFR with DAKO EGFR pharmDx kit. IHC 2+ and 3+ were considered as high expression. cMET FISH testing was performed on cMET 3+ cases with available tissue. PFS was calculated from RETi start to PD or death, OS from diagnosis to death/last follow up in pts treated with RETi.

Results: 52 pts were included. Median age was 65 years, 63% were female, 92% had adenocarcinoma, median PD-L1 expression was 10% (IQR 0-62.5). All samples were collected before RETi start. IHC 2/3+ scores were observed in 80% of evaluable cases (25/31) with TROP2, 60% (30/50) with cMET, 39% with HER3 (19/48), 31% with EGFR (15/48), and 4% (2/48) with HER2. 31 patients had more than 1 highly expressed target, mostly TROP2/cMET (n=17) and cMET/HER3 (n=13). FISH testing was negative for MET amplifications (N=5). PFS and OS of pts with low vs high target expression are presented in the Table.

Conclusion: cMET and TROP2 were frequently expressed in RET+ aNSCLC, EGFR and HER3 were present in a lower proportion, HER2 was rarely found. These markers were not associated with a prognostic or predictive impact on RETi outcomes. The activity of novel therapeutic agents should be evaluated in this setting.

PFS and OS of pts with low versus high target expression. Marker cMET TROP2 HER2 HER3 EGFR Treated with RETi, n Total=38 low=17 high=21 Total=22 low=4 high=18 Total=36 low=34 high=2 Total=37 low=24 high=13 Total=36 low=27 high=9 PFS of low vs high, median in months 12.88 vs 15.05 (HR 0.90, 95%CI 0.34-2.05, p=0.77) 3.99 vs 6.06 (HR 2.44, 95%CI 0.54-11.3, p=0.10) 13.96 vs 10.10 (HR 0.57, 95%CI 0.91-3.63, p=0.445) 7.55 vs 17.12 (HR 1.54, 95%CI 0.65-3.67, p=0.356) 12.88 vs 13.96 (HR 1.29, 95% CI 0.47-3.52, p=0.64) OS of low vs high, median in months 38.75 vs 51.6 (HR 1.29, 95%CI 0.53-3.14, p=0.55) 22.17 vs 51.6 (HR 2.09, 95%CI 0.50-8.71, p=0.19) NE 51.5 vs 62.6 (HR 1.31, 95%CI 0.50-3.46, p=0.59) 51.6 vs 62.45 (HR 0.97, 95% CI 0.32-2.96, p=0.96)

Citation Format: Arianna Marinello, Maria Rosa Ghigna, Wael Salem Zrafi, Martina Mandarano, Isabelle Monnet, Carlo Genova, Alessandro Russo, Safae Terrisse, Giulio Metro, Jordi Remon, Anas Gazzah, Fabrice Barlesi, David Planchard, Jean-Yves Scoazec, Benjamin Besse, Mihaela Aldea. Immunohistochemistry expression of membrane targets for novel therapeutic agents in RET-rearranged NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5134.