4154 Background: Advanced gallbladder cancer (GBC) carries a dismal prognosis, with a real-world median overall survival (OS) of 6.8 months. We hypothesized that adding losartan to standard chemotherapy could improve outcomes by modulating the fibrotic tumor microenvironment (TME). Methods: This was a single-arm phase II study conducted at two academic centers between July 2022 and April 2024. Adult patients with histologically confirmed, unresectable or metastatic gallbladder cancer or cholangiocarcinoma received six cycles of gemcitabine and cisplatin with concurrent oral losartan. The primary endpoint was overall survival (OS). Exploratory analysis by whole-exome sequencing (WES) was done on 18 patients. Results: Thirty patients were enrolled. Clinical characteristics are depicted in Table. Median OS was 10.3 months (range 0.5–38.7), with 6-month and 12-month OS rates of 68% and 36%, respectively. Median PFS was 5 months. An objective response was observed in 88% of patients, including five complete responses. Patients with ECOG performance status 2 and those with cholelithiasis had inferior survival. Losartan was well tolerated. Genomic analysis revealed a clear discretion between cohorts (median PFS >, <=6 months). Responders exhibited a "TME-favorable" signature, characterized by genes associated with anti-inflammatory properties, regulated angiogenesis, and cellular stress response. This group was uniquely enriched for variants in ATRX, CHEK2, DNMT3A, EZH2, IDH1, SMARCA4 , and TSC2. Conversely, non-responders (NR) showed a pro-inflammatory profile and oncogenic mutations in the angiogenesis pathway ( AKT2, BRAF, MET, NRAS, SMAD4 ), potentially mediating resistance to losartan-induced vascular normalization. Both groups shared core GBC drivers, including TP53, KRAS, ARID1A , and ERBB2. Conclusions: Losartan improves survival in GBC patients with a specific molecular buildup. The presence of anti-inflammatory genomic signatures and specific variants like SMARCA4 and ATRX may serve as predictive biomarkers for TME-targeted therapy, whereas pro-inflammatory profiles and primary angiogenesis mutations identify a resistant phenotype. Clinical trial information: CTRI/2023/02/049523. Baseline clinical features (n=30). Clinical features n % Age in years Median (range ) 59 (31-75) Gender Male Female 1119 3664 ECOG PS * 1 2 219 7030 Gallstones 12 41 Cholecystectomy 10 34 Jaundice at baseline Present Absent 822 2674 Site Gallbladder Cholangiocarcinoma Intra-hepatic Extra-hepatic distal CBD ** 2613 87310 Weight in Kgs Mean (range ) 58 (41-82) History of weight loss present 15 52 Co-morbidities Diabetes mellitus Hypertension Hypothyroidism 781 23263 Angiotensin receptor blocker Losartan Telmisartan 282 946 ERBB2 positive Received Trastuzumab 22 6100 Immunotherapy(Durvalumab) 5 17 * PS: Performance status, ** CBD: Common bile duct.
Patel et al. (Wed,) studied this question.
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