Dynamic changes in target protein expression following treatment in NSCLC: Simultaneous evaluation of MET, TROP2, HER2, B7-H4, and MDM2 expression in paired biopsies.

8591 Background: Antibody-drug conjugates and bispecific antibodies targeting non-small cell lung cancer (NSCLC) tumor surface antigens are under development, but the impact of prior treatments on target protein expression remains unclear. This study evaluates changes in the expression of multiple therapeutic target proteins in the same patient before and after treatments. Methods: Patients diagnosed with NSCLC underwent rebiopsy after treatments at the National Cancer Center Hospital between 2014 and 2023 were eligible. Tissues were obtained by surgery, bronchoscopy, or needle biopsy with an interval of at least 100 days of systemic anti-cancer therapy. We investigated clinicopathological features in paired specimens focusing on tumor-associated surface proteins potentially related to novel drug development such as MET, TROP2, HER2, B7-H4, and MDM2. TROP2, B7-H4, and MDM2 were evaluated using the H-score. HER2 was evaluated on a scale from 0 to 3+, as previously reported. For MET, a scoring system was adopted in which overexpression (OE) was defined as IHC 3+ positive cells representing 25% or more of the cells. Results: A total of 51 cases were included in this study. The median age was 64 years. Of the patients, 27 (57%) were male, 33 (65%) were smokers, and 45 (88%) had lung adenocarcinoma. EGFR 24 cases (47%)/ALK 8 cases (16%)/BRAF 1 case (2%)/ROS1 1 case (2%) were identified among 34 cases with actionable genetic alterations (AGAs). The proportion of MET OE before and after treatment was 33.3%/45.1% overall. In subgroup analyses, the proportions were 38.2%/47.1% (AGA positive), 23.5%/41.2% (AGA negative), 36.0%/52.0% (PD-L1 positive), and 30.8%/38.5% (PD-L1 negative). For HER2 positive (2+, 3+) cases, the overall proportions were 20.9%/11.6%, while subgroup proportions were 15.2%/12.1%, 40.0%/10.0%, 20.0%/15.0%, and 21.7%/8.7%, respectively. The proportion of patients who experienced change in protein expression after previous treatment was as follows: MET, 31.4%; TROP2, 29.4%; HER2, 27.9%; B7-H4, 0.0%; MDM2, 51.0%. Conclusions: MET, TROP2, HER2, and MDM2 showed expression changes before and after treatment in approximately 30% of patients. There were differences in the rate of change depending on whether AGA was present, with a higher rate of change in AGA negative patients. Based on these findings, rebiopsy after treatment is recommended when considering therapies targeting tumor surface protein antigens. Percentage change in MET, TROP2, HER2, B7-H4, and MDM2 following previous treatment. MET (%) TROP2 (%) HER2 (%) B7-H4 (%) MDM2 (%) Proportion changing (n=51) 31.4 29.4 27.9 0.0 51.0 AGA positive (n=34) 32.4 20.6 21.2 0.0 52.9 Elevated 20.6 17.6 9.1 0.0 32.3 Decreased 11.8 3.0 12.1 0.0 20.6 AGA negative (n=17) 29.4 47.1 50.0 0.0 47.1 Elevated 23.5 47.1 10.0 0.0 17.6 Decreased 5.9 0.0 40.0 0.0 29.4 AGA; actionable gene alternation.