Jung Sun Kim

Background: Although a phase 3 trial did not demonstrate a survival benefit for gemcitabine, cisplatin, and nab-paclitaxel (Gem/Cis/Nab-P) in advanced biliary tract cancer (BTC), favorable outcomes were observed in specific patient subgroups, notably those with locally advanced disease or gallbladder carcinoma (GBC). This study aimed to assess the prognostic value of FDG PET/CT-derived parameters in advanced BTC patients treated with the Gem/Cis/Nab-P regimen, thereby identifying potential PET/CT imaging biomarkers that may aid in predicting survival benefit. Patients and Methods: We conducted a retrospective analysis of 125 advanced BTC patients who underwent pretreatment FDG PET/CT followed by Gem/Cis/Nab-P therapy. From the PET/CT images, maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of primary tumors were quantified. The influence of these parameters on prognostic outcomes was determined. Results: Multivariate survival analysis identified TLG as an independent significant prognostic factor for both progression-free survival (PFS) and overall survival (OS) ( P <0.05). In subgroup analyses stratified by disease stage and TLG, patients with locally advanced disease and low TLG achieved the most favorable survival outcomes (median PFS, 18.4 months; median OS, not reached). Among tumor subtypes, TLG effectively differentiated PFS and OS in GBC patients, with the low TLG group exhibiting a median PFS of 11.7 months. Conclusions: TLG on pretreatment FDG PET/CT served as an independent prognostic biomarker for PFS and OS in advanced BTC. Locally advanced disease and low TLG, as well as GBC with low TLG, might be predictive of enhanced survival benefit from Gem/Cis/Nab-P therapy.

Background/Aims: Immune checkpoint inhibitors (ICIs) have transformed advanced HCC treatment. The benefit of sequential immunotherapy after prior ICI failure remains unclear. Given the expanded use of atezolizumab plus bevacizumab (Ate/Bev) over the past 5 years, we explored the real‐world outcomes of nivolumab plus ipilimumab (Nivo/Ipi) in patients with advanced HCC, with more focus on those previously exposed to Ate/Bev. Methods: Patients treated with Nivo/Ipi for advanced HCC from six referral hospitals in Korea, Hong Kong, Taiwan and Singapore were included. Patients with prior non–Ate/Bev ICI or Child–Pugh B–C were excluded. Outcomes were compared between the ICI‐naïve and Ate/Bev‐experienced groups. Results: Among 116 patients with advanced HCC treated with Nivo/Ipi, 57 were ICI‐naïve and 59 had prior Ate/Bev exposure. Overall objective response rate was 31.2%, higher in the ICI‐naïve group (42.6% vs. 20.0%, p = 0.01). However, the median duration of response was comparable between groups (24.8 vs. 23.7 months; p = 0.71), suggesting durable benefits regardless of prior Ate/Bev therapy. Median progression‐free survival (PFS) and overall survival (OS) were 2.5 and 11.3 months, respectively, with longer PFS (5.3 vs. 1.6 months; p < 0.01) and OS (16.2 vs. 7.8 months; p = 0.06) in the ICI‐naïve. Immune‐related adverse events (irAEs), especially thyroid dysfunction, were associated with longer PFS and OS. Notably, most Nivo/Ipi responders post‐Ate/Bev (8/11) had irAEs during Nivo/Ipi treatment, whereas no irAEs occurred during prior Ate/Bev. Nivo/Ipi responders post‐Ate/Bev revealed a high tumour mutational burden (5.71–12.75 mutations/Mb). Conclusion: Nivo/Ipi demonstrated meaningful clinical activity in patients with advanced HCC, even after Ate/Bev failure.

Background & Aims: Nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) had promising efficacy in phase II trials for advanced biliary tract cancer (BTC) but failed to demonstrate superiority in phase III. We investigated Gem/Cis/nab-P efficacy and identified molecular subgroups with clinical benefit. Approach & Results: This prospective observational cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received Gem/Cis/nab-P from July 2021 to December 2022. Of these, 108 were included in genomic and transcriptomic analyses of pretreatment tumor samples that met quality control criteria. Among 119 patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% extrahepatic cholangiocarcinoma, and 23.5% gallbladder cancer. Most patients had metastatic disease (68.9%). At a median follow-up of 23.7 months, the median progression-free survival was 8.3 months and median overall survival 19.8 months. Grade ≥3 treatment-related adverse events occurred in 70 patients (58.8%), and dose reduction was required in 99.2%. Frequent genetic alterations were TP53 (53.7%), KRAS (29.6%), and CDKN2A (20.4%), with TP53 mutations being significantly associated with worse outcomes. Transcriptomic analysis identified four molecular subtypes: cholangiocyte-like, stromal, metabolic, and inflammatory-proliferative. The cholangiocyte-like subtype, marked by increased cholangiocyte markers, had the most favorable prognosis. Stromal and metabolic subtypes showed moderate outcomes, characterized by a fibroblast-rich stroma with activated angiogenesis and enriched metabolic pathways, respectively. The inflammatory-proliferative subtype had the worst prognosis, with cell cycle and inflammatory activation, and an exhausted immune microenvironment. Conclusions: This study demonstrated the clinical activity of Gem/Cis/nab-P in advanced BTC and highlighted that biology-driven patient stratification based on genomic and transcriptomic features may provide important prognostic information.

Background: This study aimed to assess prognostic significance of FDG PET/CT parameters in predicting progression-free survival (PFS) and overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab therapy. Patients and Methods: We retrospectively enrolled 78 patients with HCC who underwent FDG PET/CT before atezolizumab plus bevacizumab therapy and identified intrahepatic target tumor lesions on pretreatment imaging studies. From PET/CT images, we measured SUVmax, tumor-to-normal liver uptake ratio, metabolic tumor volume, and total lesion glycolysis (TLG) for intrahepatic tumor lesions, as well as SUVmax for extrahepatic metastatic lesions (extrahepatic SUVmax). Results: In comparisons of PET/CT parameters, patients with progressive disease demonstrated significantly higher TLG values than those achieving complete or partial response (P < 0.05). In the multivariate survival analysis, TLG independently predicted both PFS (P = 0.019) and OS (P = 0.003). Metabolic tumor volume was significantly associated with OS alone (P = 0.010), and extrahepatic SUVmax was significantly associated with only PFS (P = 0.045). Patients with high TLG values experienced poorer PFS and OS than those with low TLG values (P < 0.05). Conclusions: TLG in intrahepatic HCC lesions was significantly associated with treatment response and served as an independent prognostic factor for PFS and OS. TLG could be a potential imaging biomarker for predicting clinical outcomes in patients with HCC receiving atezolizumab plus bevacizumab therapy.

Purpose Since 2020, atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year.Materials and Methods This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group.Results Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden < 25%, Eastern Cooperative Oncology Group 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p < 0.001; median time to onset [mTTO], 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO, 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO, 4.2 months), and proteinuria (69.6% vs. 38.4%, p < 0.001; mTTO, 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87.0% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment.Conclusion The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.