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

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 19579 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.