Minsuk Kwon

Biliary tract cancers (BTCs) are associated with poor outcomes despite recent incorporation of immune checkpoint inhibitors into first-line chemotherapy. Human epidermal growth factor receptor 2 (HER2) overexpression or amplification defines a therapeutically targetable subset of BTC but its integration into first-line chemoimmunotherapy has not been prospectively evaluated. This multi-institutional, open-label, phase 1b/2 HERBOT study (KCSG-HB23-05) aimed to evaluate first-line HER2-targeted quadruplet regimen consisting of trastuzumab, nivolumab, gemcitabine and cisplatin in participants with HER2-positive advanced BTC. Here the primary endpoint was met with an objective response rate of 55% (95% confidence interval (CI) 38.5–70.7; one complete response and 21 partial responses among 40 participants) and a disease control rate of 95% (95% CI 83.5–99.4); the median duration of response was 12.6 months (95% CI 5.7–not reached). With a median follow-up of 17.0 months, the median progression-free survival was 10.6 months (95% CI 7.8–17.4) and median overall survival was not reached. Two participants (5.0%) underwent curative-intent conversion surgery. Common grade ≥3 treatment-related adverse events included neutropenia (57.5%), anemia (30.0%) and thrombocytopenia (22.5%). Preplanned artificial-intelligence-powered whole-slide image analyses suggested that tumors with higher proportions of HER2 3+ cells were associated with greater clinical benefit. These findings suggest that upfront HER2-targeted therapeutic intensification in BTC may represent a promising direction for future first-line treatment strategies, with relevance to ongoing phase 3 studies. ClinicalTrials.gov identifier: NCT05749900.

Background: Metastatic melanoma in East Asian populations is enriched for acral and mucosal subtypes and harbors a distinct molecular landscape compared with Western cutaneous melanoma. However, data on the efficacy of first-line immune checkpoint inhibitor (ICI) therapy and on the impact of molecular characteristics on treatment effect in this population remain limited. We aimed to characterize the genomic landscape of an East Asian metastatic melanoma cohort and to evaluate the predictive values of molecular markers for first-line ICI therapy. Methods: This study included 135 patients with metastatic melanoma who received first-line ICI at Samsung Medical Center between January 2022 and December 2025. Of these, 108 with paired next-generation sequencing (NGS) data were included in the molecular analysis. Survival outcomes were estimated by the Kaplan–Meier method, and the prognostic value of molecular subtype was assessed using univariable and multivariable Cox proportional hazards models. Results: Mucosal melanoma was the most common primary site (58, 43.0%), followed by acral melanoma (31, 23.0%) and cutaneous melanoma (25, 18.5%); 4 (3.0%) had uveal melanoma and 17 (12.6%) had melanoma of other or unknown primary origin. The overall objective response rate to first-line ICI was 37.8% (51 of 135), and median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI] 4.0–9.6). Using the hierarchical classification, 108 patients were classified into five molecular subtypes: BRAF-altered (n = 17, 15.7%), RAS-altered (n = 17, 15.7%), KIT-altered (n = 15, 13.9%), and NF1-altered (n = 7, 6.5%), and quadruple–wild-type (n = 52, 48.1%). TMB-high status (10.2%) showed no significant association with outcomes. Molecular subtype was significantly associated with PFS (log-rank p = 0.009). After multivariable adjustment, BRAF fusion (hazard ratio [HR] 5.05, 95% CI 1.70–14.98, p = 0.003) and KIT-altered status (HR 2.91, 95% CI 1.46–5.77, p = 0.002) emerged as independent adverse prognostic factors, whereas BRAF V600 single-nucleotide variants did not differ significantly from quadruple–wild-type. Conclusions: In this East Asian metastatic melanoma cohort, BRAF fusion and KIT alterations were independent adverse prognostic factors for first-line ICI. These findings suggest that BRAF fusion and KIT-altered tumors may represent distinct subgroups that warrant further investigation.

PURPOSE: Activating mutations in GNAQ and GNA11 are recognized oncogenic drivers in uveal melanoma (UM); however, their prevalence across various cancers and their genomic context remain inadequately characterized. This study aimed to elucidate the genomic landscape of these mutations across a range of metastatic solid tumors. MATERIALS AND METHODS: We conducted a pan-cancer analysis involving 5,416 patients with metastatic solid tumors who had undergone next-generation sequencing. Our evaluation encompassed mutational distribution, hotspot identification, tumor mutational burden (TMB), microsatellite instability (MSI), and coalterations. RESULTS: Mutations in GNAQ (n = 10) or GNA11 (n = 16) were detected in 26 patients (0.48%). Aside from UM, these mutations were most frequently observed in colorectal cancer (38.5%), melanoma (15.4%), gastric cancer (11.5%), and neuroendocrine tumors (7.7%). A notable subset exhibited an immunogenic profile, with 42.3% classified as TMB-High (≥10 Mut/Mb) and 19.2% as MSI-High. This immunogenic subgroup was primarily associated with nonhotspot mutations (eg, p.Gln88His, p.Ala231Val), suggesting that these may represent bystander events in hypermutated tumors. Conversely, canonical hotspots (Q209, R183) were predominantly identified in TMB-Low/microsatellite stable tumors, such as UM. Notable coalterations included NOTCH3 (80%), FAT1 (70%), and TP53 (37.5%-40%). Exploratory survival analysis suggested favorable OS in the immunogenic subgroup, supported by cases with durable ICI benefit including a treatment-free remission exceeding 21 months. CONCLUSION: This real-world analysis demonstrates that GNAQ and GNA11 mutations are not exclusive to UM, occurring across diverse solid tumors, particularly colorectal cancer. The strong association between nonhotspot mutations and high TMB/MSI status defines a distinct immunogenic subgroup, underscoring the need to differentiate canonical hotspot drivers from bystander mutations when selecting targeted pathway inhibitors versus immune checkpoint blockade.

Purpose: This study evaluated the clinical outcomes and prognostic factors in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) treated with upfront FOLFIRINOX followed by local-regional therapy (LRT), surgical resection (SR), and radiotherapy (RT). We aimed to identify specific patient subgroups for which RT may serve as a reasonable alternative to SR for local tumor control.Methods: We retrospectively analyzed 116 patients (SR group, n= 70; RT group, n= 46) at a single center between 2015 and 2020. Survival outcomes were compared based on LRT modalities, focusing on identifying subgroups in which RT provided an efficacy comparable to that of SR.Results: Among 116 patients, the SR group achieved a significantly higher 5-year overall survival (OS) than the RT group (27.1% vs. 8.7%, P< 0.0001), despite similar progression-free survival (P= 0.23). Significant prognostic factors for OS included carbohydrate antigen 19-9 (CA19-9) response in BRPC (P= 0.02) and radiologic partial response in LAPC (P= 0.05). Subgroup analysis revealed that, while SR provided a survival advantage in CA19-9 responders, no significant difference in OS was observed between SR and RT in CA19-9 non-responders (P= 0.37).Conclusion: Although surgery remains the gold standard, RT may be considered a justifiable local alternative for CA19-9 non-responders and surgically ineligible patients with LAPC, yielding comparable outcomes in these specific, biologically unfavorable subgroups.

Background: Deletion of the MTAP gene at chromosome 9p21.3 defines a therapeutically actionable molecular subset of cancers due to synthetic lethal vulnerability to PRMT5 and MAT2A inhibition. The real-world prevalence and genomic context of MTAP deletion in diverse solid tumors remain incompletely characterized. Methods: We retrospectively analyzed 579 solid tumor specimens subjected to next-generation sequencing-based copy-number profiling. The prevalence of MTAP deletion and its co-occurrence with CDKN2A and CDKN2B were evaluated, and genomic deletion patterns across chromosome 9 were systematically assessed. Results: MTAP deletion was detected in 14 cases (2.4%, 95% confidence interval [CI], 1.45–4.02%), with enrichment in sarcoma, pancreatic cancer, and urothelial carcinoma. Concurrent CDKN2A loss was observed in 92.9% of MTAP-deleted tumors, and 64.3% showed additional CDKN2B loss, indicating a coordinated focal deletion event at 9p21.3. Statistical analyses confirmed strong genomic associations between MTAP and neighboring tumor suppressor genes. Across the full cohort, deletion frequency peaked at the 9p21 locus, and among MTAP-deleted tumors, co-deletion frequency decreased with increasing genomic distance. All MTAP-deleted tumors were microsatellite stable and low tumor mutational burden (TMB-low). Conclusions: Our findings demonstrate that MTAP deletion is an infrequent but genomically coherent event in solid tumors, characterized by a canonical 9p21 co-deletion pattern. This real-world analysis underscores the importance of comprehensive genomic profiling to identify patients who may benefit from emerging MTAP-directed therapies.

PURPOSE: This study aimed to characterize the genomic landscape of Korean gastric cancer and evaluate associations among oncogenic alterations, established biomarkers, demographics, and treatment outcomes. METHODS: A total of 1,283 patients with gastric cancer who underwent tumor-only targeted sequencing as part of practice and received palliative treatment between January 2017 and August 2025 at the Samsung Medical Center were included. RESULTS: Among 1,283 patients (median [IQR] age, 61 [52-68] years; 827 males [64.46%]), TP53 (51.91%), ARID1A (19.02%), ERBB2 (12%), KRAS (10.29%), and PIK3CA (9.12%) were the most frequently altered genes. Epstein-Barr virus–positive tumors exhibited enrichment of BCOR , PIK3CA , and ARID1A alterations and reduced TP53 mutations (false discovery rate [FDR] adjusted P < .01). Human epidermal growth factor receptor 2–positive tumors were characterized by coamplification of ERBB2 , CCNE1 , and MYC (FDR adjusted P < .001), whereas PD-L1 positivity was associated with KRAS and CDKN2A alterations (FDR-adjusted P < .05). Among patients treated with first-line nivolumab plus chemotherapy (n = 269), those with high tumor mutational burden (TMB; ≥10 mutations per megabase) had improved overall survival ( v the low TMB subgroup; hazard ratio [HR], 0.48 [95% CI, 0.25 to 0.93]; P = .03), particularly when combined with PD-L1 positivity ( v all other biomarker-defined subgroups; HR, 0.33 [95% CI, 0.14 to 0.76]; P = .006). Moreover, as TMB levels increased, patients derived greater survival benefit from nivolumab plus chemotherapy versus chemotherapy alone, even among those with microsatellite-stable tumors. Across treatment regimens, FGFR2 and MET alterations were linked to poorer outcomes, whereas PIK3CA mutations were observed in patients with longer overall survival after first-line chemotherapy. CONCLUSION: Our findings provide a comprehensive genomic landscape of Korean gastric cancer and underscore the clinical relevance of integrating genomic and established biomarkers to advance precision oncology.

Background/Objectives: For patients with advanced or metastatic clear cell renal cell carcinoma (RCC), combinations of immune checkpoint inhibitors (ICIs) and VEGFR-targeted tyrosine kinase inhibitors (TKIs) are standard first-line therapies. However, the clinical benefit of these regimens in patients with favorable IMDC risk remains unclear. Methods: We retrospectively analyzed 147 patients with favorable-risk metastatic RCC treated with first-line systemic therapy at the Samsung Medical Center between 2019 and 2023. Treatment regimens included TKI monotherapy (n = 110) or ICI–TKI combinations (n = 37). Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated using Kaplan–Meier and Cox regression analyses. Results: At a median follow-up of 46.3 months, the overall median PFS was 20.1 months (95% CI, 14.5–25.7). Median PFS was 26.2 months with ICI–TKI combinations versus 17.0 months with TKI monotherapy (HR 1.32; 95% CI, 0.82–2.12; p = 0.25). In multivariate analysis, TKI monotherapy (HR 14.01; p = 0.002) and liver metastasis (HR 9.17; p < 0.001) were independent predictors of shorter PFS. ORR was significantly higher with combination therapy (68% vs. 46%; p = 0.01). Median OS was not reached in either group, with 3-year OS rates of 89% and 84%, respectively. Conclusions: The findings suggest that even within the favorable-risk population, clinical heterogeneity influences treatment outcomes, emphasizing the need for individualized therapy selection and refined prognostic models.

Purpose:Clinical trials have shown limited efficacy of anti–PD-1 treatment for glioblastoma (GBM). In this study, we examined the expression of TGFβ type I receptor (TGFβRI) in GBM-infiltrating CD8+ T cells and the characteristics of TGFβRI+CD8+ T cells. We examined the ex vivo effects of the co-blockade of PD-1 and TGFβ on the functions of GBM-infiltrating CD8+ T cells.Experimental Design:Using flow cytometry, we examined the phenotypes of tumor-infiltrating CD8+ T cells from newly diagnosed patients with GBM. We performed single-cell RNA/T-cell receptor sequencing to characterize the tumor-infiltrating TGFβRI+CD8+ T cells. We also examined the effects of co-blockade of PD-1 and TGFβ on the functions of tumor-infiltrating CD8+ T cells in ex vivo assays.Results:GBM-infiltrating CD8+ T cells expressed significantly increased levels of TGFβRI compared with peripheral blood CD8+ T cells. Among tumor-infiltrating CD8+ T cells, TGFβRI+CD8+ T cells exhibited increased expression of immune checkpoint inhibitory receptors, and tumor antigen–specific cells were enriched in TGFβRI+CD8+ T cells. Single-cell profiling revealed that tumor-infiltrating TGFBR1+CD8+ T cells demonstrated more clonal expansion and upregulation of T-cell receptor signaling genes compared with TGFBR1−CD8+ T cells. In vitro, anti-CD3 stimulation upregulated TGFβRI expression on CD8+ T cells. Patients with GBM with a high frequency of TGFβRI+CD8+ T cells presented with increased TGFβ signaling intensity. Importantly, combined blockade of PD-1 and TGFβ significantly enhanced the functions of tumor-infiltrating CD8+ T cells ex vivo.Conclusions:Our findings provide a basis for further investigation of the co-blockade of PD-1 and TGFβ for the treatment of patients with GBM.