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Multicenter Study
. 2025 Jul 1;11(7):762-770.
doi: 10.1001/jamaoncol.2025.1293.

Expression of Membrane Targets for Therapeutics in RET-Positive Non-Small Cell Lung Cancer

Arianna Marinello  1 , Maria Rosa Ghigna  2 , Julia K Rotow  3 , Tolulope Adeyelu  4 , Giulio Metro  5 , Mariana Brandão  6 , Florian Guisier  7 , Isabelle Monnet  8 , Hortense Gaultier de Saint Basile  9 , Carlo Genova  10 , Judith Raimbourg  11 , Safae Terrisse  12 , Karine Godefroy  13 , Luca Toschi  14 , Martina Mandarano  15 , Hélène Doubre  16 , Alessandro Russo  17 , Alexander Valent  2 , Abdul Rafeh Naqash  18 , Ayesha Aijaz  18 , Anas Gazzah  1 , Jordi Remon  1 , Ari Vanderwalde  4 , Andrew Elliott  4 , Balazs Halmos  19 , Fabrice Barlesi  1   20 , David Planchard  1   20 , Pasi A Jänne  3 , Benjamin Besse  1   20 , Mihaela Aldea  1   3   20
Affiliations
Multicenter Study

Expression of Membrane Targets for Therapeutics in RET-Positive Non-Small Cell Lung Cancer

Arianna Marinello et al. JAMA Oncol. .

Abstract

Importance: Patients with advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC) who experience disease progression following treatment with RET inhibitors (RETis) have limited treatment options. Identifying membrane protein targets may support the assessment of novel therapies, such as antibody-drug conjugates and bispecific antibodies.

Objective: To evaluate membrane target expression in RET+ NSCLC.

Design, setting, and participants: This multicenter cohort study used centralized immunohistochemistry (IHC) on archival tissue samples and whole transcriptome sequencing (WTS) in an independent cohort. Tissue samples were collected from 12 European centers, and WTS was performed on globally sourced patient samples submitted for molecular profiling. This study included samples from patients with RET+ NSCLC and RET-wild-type (RET-wt) adenocarcinoma controls that were analyzed by IHC and 203 RET+ and 19 579 RET-wt samples analyzed by WTS.

Exposures: Membrane protein expression of MET, ERBB2 (formerly HER2), epidermal growth factor receptor (EGFR), human epidermal growth factor 3 (HER3), and trophoblastic cell surface antigen 2 (TROP2) was evaluated using IHC, with samples scored on a scale of 0 to 3. Scores of 2 or greater were considered positive. Target expression as analyzed by WTS was expressed as median transcript per million scores.

Main outcomes and measures: Biomarker positivity, coexpression of biomarkers, dynamic changes in paired biopsies, and clinical correlates with survival outcomes.

Results: A total of 189 patients were included in the study (among 81 patients with RET+ NSCLC, the median [IQR] age was 62 [55-70] years, and there were 49 female individuals [60%]). In 93 samples from 81 patients with RET+ NSCLC, positive IHC scores were observed for MET in 51 of 86 (59%), ERBB2 in 3 of 84 (3.6%), EGFR in 24 of 84 (29%), HER3 in 31 of 82 (38%), and TROP2 in 59 of 65 (91%). Compared with RET-wt adenocarcinoma (n = 112), RET+ tumors showed higher MET (59% vs 43%; P = .03) and lower ERBB2 expression (3.6% vs 15%; P = .01). The WTS analysis from the independent cohort confirmed these results. Of 61 evaluable samples, 59 of 61 (97%) had at least 1 positive biomarker, 60 of 77 (78%) when excluding TROP2. MET/EGFR coexpression occurred in 17 of 79 evaluable samples (21.5%). Dynamic change in biomarker expression was observed in paired biopsy specimens. No significant survival differences based on target expression emerged in patients treated with RETi in the IHC and the WTS cohorts.

Conclusions and relevance: The results of this cohort study suggest that RET+ NSCLC tumors frequently express MET and TROP2, with MET positivity enriched vs RET-wt controls. Coexpression and biomarker dynamics highlight the need for membrane target screening and novel therapeutic strategies for this population.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rotow reported personal fees from Genentech, AstraZeneca, Summit Therapeutics, G1 Therapeutics, BioAtla, Guardant, Johnson and Johnson, Takeda, Jazz, Amgen, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, Merus, Boehringer Ingelheim, Novocure, and Gilead and institutional research funding from Bicycle Therapeutics, BioAtla, Blueprint, Daiichi-Sankyo, Enliven, EpimAb, LoxoOncology, ORIC, RedCloud , Summit Therapeutics, Black Diamond, Regeneron, ImmunityBio, Altor Bioscience, and Duality outside the submitted work. Dr Adeyelu reported personal fees from Caris Life Sciences outside the submitted work. Dr Brandão reported nonfinancial support from Roch, AstraZeneca, and Sanofi; advisory board service for Janssen, Boeringher, MSD, and AstraZeneca; grants from AstraZeneca, Pierre Fabre, Merus, and BMS outside the submitted work. Dr Guisier reported personal fees from Lilly, Roche, Takeda, AstraZeneca, BMS, MSD, Viatris, Pfizer, Regeneron, Janssen, and Sanofi; grants from Roche, Takeda, and Pfizer; and nonfinancial support from MSD, Janssen, AstraZeneca, and BMS outside the submitted work. Dr Monnet reported travel fees from Takeda, MSD, Pfizer, Oxyvie, and Regeneron outside the submitted work. Dr Gaultier de Saint Basile reported nonfinancial support from Amgen, Novartis, and Janssen outside the submitted work. Dr Genova reported personal fees from Amgen, AstraZeneca, BMS, MSD, Novartis, Roche, Eli Lilly, Regeneron, and Takeda as well as grants from the Italian Ministry of Health and FONICAP/LILT outside the submitted work. Dr Raimbourg reported personal fees from Pierre Fabre, MSD, Amgen, BMS, and Janssen and nonfinancial Daichii Sankyo from AstraZeneca outside the submitted work. Dr Toschi reported personal fees from Pfizer, Daiichi Sankyo, Beigene, Regeneron, Sanofi, Roche, Pfizer, and AstraZeneca outside the submitted work. Dr Doubre reported nonfinancial support from Pfizer, Roche, Amgen, Leo Pharma, Bristol Myers Squibb, and Novartis outside the submitted work. Dr Russo reported personal fees from AstraZeneca, MSD, Novartis, Pfizer, BMS, Takeda, Amgen, Regeneron, Daiichi Sankyo, Merck, Roche, and Johnson & Johnson outside the submitted work. Dr Naqash reported honoraria from Foundation Med, Astellas, NGMBiosiencesa, grants from Medlive, and travel support from Jazz Pharma outside the submitted work. Dr Nagash reported trial funding from Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunocore, Phanes Therapeutics, and Kymera Therapeutics; editorial compensation from JCO Precision Oncology; travel fees from SITC/AACR/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/ Caris Life Sciences/ ASCO/Jazz Pharmaceuticals; advisory board service for Foundation Med, Astellas, NGMBiosciences; honoraria from BinayTara Foundation, Foundation Med, and Medlive; and grant support from the SWOG Hope Foundation outside the submitted work. Dr Remon reported being the Secretary of EORTC LCG outside the submitted work. Dr Vanderwalde reported employment with Caris Life Sciences during the conduct of the study and employment with Ari VanderWalde outside the submitted work. Dr Elliott reported personal fees from Caris Life Sciences during the conduct of the study. Dr Halmos reported grants from BMS, Takeda, Amgen, AbbVie, Daiichi, Janssen, Pfizer, Boehringer Ingelheim, Merck, AstraZeneca, Arrivent, Forward Pharma, Black Diamond, Advaxis, and GSK and personal fees from Nuvalent, Apollomics, Genentech, AstraZeneca, BMS, Takeda, Amgen, AbbVie, Daiichi, Janssen, Pfizer, Boehringer Ingelheim, and Merck outside the submitted work. Dr Barlesi reported institutional fees from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Summit Therapeutics, and Takeda outside the submitted work. Dr Planchard reported personal fees from AstraZeneca, AbbVie, Bristol Myers Squibb, Bohringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-Fabre, Takeda, ArriVent , Mirati, Seagen, and GSK and ; work as principal or coinvestigator in trials for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, AbbVie, Janssen, Pierre-Fabre, Takeda, ArriVent, Mirati, and Seagen; and travel fees from AstraZeneca, Roche, Novartis, and Pfizer outside the submitted work. Dr Janne reported personal fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Chugai Pharmaceuticals, Eli Lilly Pharmaceuticals, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi Oncology, Takeda Oncology, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, MOnte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics, Blueprint Medicines, Dizal Pharma, and Glaxo Smith Kline; grants from Daiichi Sankyo, AstraZeneca, Takeda Oncology, Revolution Medicines, and Eli Lilly; and a patent for EGFR mutations licensed to LabCorp outside the submitted work. Dr Besse reported advisory board service for AbbVie, Biontech SE, Beijing Avistone Biotechnology; Bristol Myers Sqibb CureVac AG, Pharmamar, Regeneron, and Sanofi Sventis during the conduct of the study as well as research support from Conseil, AbbVie, Bristol Myers Sqibb, CureVac AG, Eli Lilly, Ellipses pharma Ltd, F.Hoffmann-La Roche Ltd, Foghorn Therapeutics Inc, Genmab, Immunocore, Owkin, and Sanofi Aventis; steering committee service for AstraZeneca, Amgen, Beigene, CureVac AG, GENMAB A/S, Janssen, MSD, Ose Immunotherapeutics, Pharmamar, Sanofi, and Takeda; and speaker fees from AbbVie, AstraZeneca, Bristol Myers Sqibb, Daichii Sankyo, Lilly, MSD, Ose Immunotherapeutics, Sanofi Aventis, and Servier outside the submitted work. Dr Aldea reported grants from Amgen, AstraZeneca, Sandoz, and Owkin outside the submitted work. No other disclosures were reported.

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