Citations

Abstract Molecular profiling reveals that up to 40% of advanced biliary tract cancers (BTCs) harbor actionable genomic alterations amenable to matched targeted therapies. However, conventional trial designs typically evaluate these agents in pretreated populations, resulting in approvals for later-line use. Notably, 25–44% of patients with advanced BTC may become ineligible for treatment after first-line therapy due to disease progression or functional decline, thus the real-world survival outcomes with matched therapies remains poorly characterized. This international collaborative study includes data from Mayo Clinic, Duke Cancer Institute, and National Cancer Center East (Japan), as well as a combined dataset from the SCRUM-Japan GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2 projects. We assessed overall survival (OS) of patients based on the presence of actionable alterations and the receipt of matched therapy. To adjust for confounding, we applied propensity score weighting with inverse probability of treatment and multivariate Cox regression modeling, controlling for age, sex, tumor location, prior resection, and mutational subgroup. Among 1,049 patients that were analyzed, 358 (34.1%) harbored actionable alterations, with 160 (44.7%) receiving matched targeted therapy. The matched group (patients with actionable tumors who received a matched therapy) were significantly associated with longer median OS (23.3 months; 95% CI: 19.5–30.4) compared to the unmatched group (14.7 months; 95% CI: 12.8–17.9) and those with non-actionable tumors (17.1 months; 95% CI: 15.5–18.7; HR 0.57, 95% CI: 0.46–0.71; p < 0.0001). The unmatched group also was associated with the lowest three-year OS rate (13% vs. 35% in matched and 19% in actionable groups, respectively; p<0.0001). On multivariable analysis with patients who received ≥2 lines of therapy, receipt of matched therapy remained an independent predictor of improved OS (HR 0.62; 95% CI 0.43–0.90). These findings support the early integration of targeted therapies in BTC management and underscore the need to overcome systemic barriers to treatment access.

4119 Background: TP53 mutations are frequent genetic alterations in cancers and also prevalent in biliary tract cancer (BTC). In non-small cell lung cancer, TP53 mutations have been reported to enhance immune checkpoint inhibitor (ICI) efficacy and improve outcomes. However, their impact on BTC remains unclear. This study investigated the clinico-molecular characteristics, prognosis, and ICI efficacy in TP53 -mutated BTC. Methods: Patient data were collected from the SCRUM-Japan GOZILA and MONSTAR-SCREEN-1/2 databases (Japan) and the Duke university and Mayo clinic databases (U.S.), which included patients receiving first-line ICI therapy. Comparisons between TP53 wild-type (WT) and mutation groups were performed in the Japanese cohort. Subsequently, analyses were expanded to include U.S. patients, focusing on comparisons between non-ICI and ICI groups. Tumor Immune Dysfunction and Exclusion (TIDE) scores were calculated using MONSTAR-SCREEN-2 whole transcriptome sequencing (WTS) data to evaluate ICI responsiveness, and gene set enrichment analysis (GSEA) explored pathways associated with TP53 mutations. Results: In the Japanese cohort (n=594), TP53 mutations were identified in 311 patients (52.4%). KRAS , ERBB2 , CDKN2A , and SMAD4 alterations were more frequent in the TP53 mutation group, while IDH1, BAP1 , and FGFR2 fusions were more common in the WT group. Multivariable analysis showed TP53 mutations were independent prognostic factors for poor outcomes (progression-free survival [PFS]: HR 1.37, 95% CI: 1.11–1.69, P=0.003; overall survival [OS]: HR 1.36, 95% CI: 1.06–1.75, P=0.017). Incorporating the U.S. cohort (n=625; non-ICI: 548; ICI: 77), no significant differences in overall response rate (ORR) or disease control rate (DCR) were observed in the non-ICI group between the groups. However, in the ICI group, TP53 mutations tended to show higher ORR (21.1% vs. 38.5%, P=0.16) and DCR (47.4% vs. 66.7%, P=0.14). In the non-ICI group, TP53 mutations were associated with worse PFS (HR 1.46, median PFS: 7.4 vs. 5.3 months, P<0.001), whereas, in the ICI group, no significant difference was observed; however, a trend toward better PFS was seen in the TP53 mutation group (median PFS: 5.0 vs. 6.4 months, P=0.163). TIDE scores were significantly lower in the TP53 mutation group, indicating higher ICI responsiveness. GSEA revealed enrichment of oxidative phosphorylation and hypoxia pathways. Conclusions: TP53 mutations are independent prognostic factors for poor outcomes in BTC. However, patients with TP53 mutations may derive greater benefits from ICIs, underscoring the importance of tailored therapeutic strategies in TP53- mutated BTC.

PURPOSE Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various malignancies. However, the high cost of these therapies limits access for much of the global population. This systematic review aims to evaluate the efficacy of low-dose ICIs compared with standard doses in different malignancies, addressing financial and access barriers in global cancer care. METHODS We conducted a systematic review of studies comparing the efficacy of low-dose versus standard-dose ICI regimens in advanced solid tumors. A comprehensive search was performed across multiple electronic databases, including retrospective and prospective studies. Excluded were animal studies, editorials, conference papers, book chapters, and other immunotherapy modalities. Outcomes assessed included overall survival (OS), progression-free survival, and objective response rate. Results were summarized descriptively due to study heterogeneity. RESULTS From 1,010 screened articles, four studies with 435 Asian patients were included, covering a variety of solid tumors. All included studies were with a low quality of evidence and a high risk of bias due to retrospective design. Two studies used weight-based dosing (pembrolizumab <2 mg/kg and nivolumab <2.15 mg/kg), showing similar OS to standard dosing in non–small cell lung cancer (NSCLC) and renal cell carcinoma, respectively. Flat dose regimens in two studies (nivolumab 20 mg or 100 mg once every 3 weeks and pembrolizumab 100 mg once every 3 weeks) also demonstrated comparable OS in NSCLC. CONCLUSION Low-dose ICIs may offer equivalent clinical benefits to standard dosing, potentially reducing costs and expanding access in developing countries. Although awaiting more representative randomized clinical trials, weight-based ICI regimens could be a viable alternative in low- and middle-income countries.

Abstract Biliary tract cancer (BTC) remains among the most challenging malignancies with a poor prognosis and limited treatment options, particularly in pretreated patients. As most patients experience disease progression after first-line treatment, effective second-line and subsequent treatments are required. Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. Moreover, most clinical trials demonstrated modest efficacy of molecular-targeted agents for molecularly unselected pretreated advanced BTC. Patients with advanced BTC carry a relatively high druggable genetic alteration rate and have shown promising responses to molecular-matched therapies targeting gene alterations such as FGFR2 fusions/rearrangements, IDH1 mutation, and HER2 overexpression/amplification. Additionally, tumor-agnostic approaches, including BRAF V600E, NTRK fusion, and RET fusion, have expanded the treatment options for some patients. Immune checkpoint inhibitors have shown limited efficacy as mono- or combination therapy in patients with pretreated advanced BTC. Therefore, developmental efforts have shifted to immune checkpoint inhibitor and other combinations such as vascular endothelial growth factor receptor inhibitors or radiation. In addition to refining combination strategies to enhance the therapeutic potential of immune checkpoint inhibitor, future research should focus on elucidating the tumor microenvironment. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.

243 Background: HER2-amplified aCRC is associated with poor prognosis despite new anti-HER2 regimens. Insight on biomarkers that predict response to these therapies is limited. This study aims to evaluate whether baseline alterations in oncogenic drivers along the HER2 pathway predict response to anti-HER2 therapy in HER2-amplified aCRC. Methods: In this international multi-center study involving Mayo Clinic, Duke Cancer Institute and National Cancer Center Hospital East (Japan), we collected baseline genomic alterations from tissue or blood samples using next-generation sequencing (NGS) prior to anti-HER2 therapy initiation. We defined PIK3CA, RAS, RAF, MAP2K, and MET as oncogenic drivers of resistance within the HER2 pathway. Overall survival (OS) was evaluated with the Kaplan-Meier method and a log-rank test was used to compare median OS (mOS) between pts with and without alterations in the above genes. A chi-square test (significance level 0.05) was performed to compare overall response rate (ORR) and disease control rate (DCR). Results: We identified 39 pts with HER2-amplified aCRC and baseline NGS. Median age was 57 (range 30-77), 54% were male. Baseline alterations in HER2 pathway oncogenic drivers were identified in 17 pts (43.5%). 18 (46%) received monoclonal antibodies (mAbs) plus tyrosine kinase inhibitors, 12 (30%) received dual mAbs and 7 (18%) received trastuzumab deruxtecan. The mOS was 41.9 months (mos) (95%CI 23.7-60.1) for other alterations vs 24.2 mos (95%CI 14.1-34.3) in pts with HER2 pathway alterations (p = 0.1). ORR was 47% vs 41% (p = 0.7) and DCR 82% vs 73% (p = 0.4), for pts with HER2 pathway alterations and without HER2 pathway alterations, respectively. 4 pts receiving trastuzumab/tucatinib had complete response, none of which had HER2 pathway alterations. Conclusions: Pts with baseline alterations in oncogenic drivers of the HER2 pathway had clinically worse outcomes compared to pts without such alterations despite receiving HER2-targeted therapy, though results lacked statistical significance. Larger studies are needed to confirm the lack of benefit from anti-HER2 therapy in this subgroup.

634 Background: CAT is the second leading cause of cancer-related death, yet the genetic underpinnings of VTE risk in BTC remain underexplored. The evaluation of CAT risk is based on Khorana score (KS), which is limited to clinical parameters. Incorporation of a genomic signature in CAT risk assessment may allow for individualized risk assessment. Methods: We collected data from consecutive patients (pts) with BTC treated at Mayo Clinic Hospitals (Phoenix, Rochester, Jacksonville) between 1998-2024. Genomic profiling was conducted on FFPEs and blood samples through next-generation sequencing (NGS) (NextSeq, Tempus xT CDx, FoundationOne CDx). Association between CAT and clinic-pathologic features (age, gender, race, ethnicity, BMI, tumor site (TS), surgery, stage, radiotherapy, systemic therapy, history of thromboembolism (hVTE)) were assessed with multivariate Cox regression (p<0.05). A separate Cox regression adjusting for age, hVTE, radiotherapy, systemic therapy, metastatic disease stratified for TS was used for gene associations. Benjamini–Hochberg method was applied (q<0.1) based on previous publications. Median overall survival (mOS) was calculated from the date of diagnosis to the date of death or last follow-up. Results: 740 adult pts were included, median age 62 years (IQR: 56-71), male/female (51%/49%), median BMI 26.6 (IQR: 22.8-31.1) with intrahepatic (496, 67%) and extrahepatic BTC (173, 23%), gallbladder cancer (71, 10%). 244 (33%) had metastatic disease. 216 (29%) experienced CAT. For those with CAT, 31 (14%) scored 1, 9 (4%) scored 2 and 1 (<1%) scored 3 on KS. mOS was 33 months (mos) (95% CI 28.9-38.4) vs. 55 mos (95% CI 25.1-39.1) (p=0.2) for pts with and without CAT, respectively. hVTE was associated with CAT (HR 3.14, 95% CI 1.98-4.98, p<0.001) along with systemic therapy (HR 1.19, 95% CI 1.11-2.89, p<0.01) and metastatic disease (HR 1.65, 95% CI 1.11-2.44, p<0.01). 305 pts (41%) underwent NGS. The most common altered genes were TP53 (126, 41%), KRAS (64, 21%), CDKN2A (63, 21%). The most common altered currently targetable genes were FGFR2 (43, 14%), IDH1 (30, 10%) and HER2/ERBB2 (16, 5%). MYC (4, 1%) (HR 11.60, 95% CI 3.04-44.25, p<0.001, q=0.058) and HER2/ERBB2 (HR 2.45, 95% CI 1.26-4.77, p=0.008, q=0.087) alterations were significantly associated with an increased risk of CAT. MYC alterations were all copy number gains (100%). The most frequent HER2/ERBB2 alterations were copy number gains (10, 62%). FGFR2 fusions (31, 10%) were linked to a lower CAT risk (HR 0.46, 95%CI 0.22-0.93, p=0.032, q=0.075) with FGFR2-BICC1 being the most frequent (5,16%). Conclusions: MYC and HER2/ERBB2 alterations are novel predictive biomarkers for an increased risk of CAT in BTC, while FGFR2 fusions confer lower risk. The knowledge of mutational status lends insight into guidance for anticoagulant prophylaxis management for this subgroup and integration with KS.

628 Background: Biliary tract cancers (BTC) are aggressive malignancies with poor survival outcomes and limited treatment options. This study compared the epidemiological and molecular differences of advanced BTC patients through a global collaboration involving the Mayo Clinic and National Cancer Center Hospital East. Methods: We included patients with advanced BTC who underwent comprehensive tumor molecular profiling who received at least 30 days of systemic therapy. Patients were grouped based on specific alterations. Overall survival (OS) was calculated from the start of first-line therapy until death and compared among subgroups using Cox regression models. Results: 332 (36%) out of 932 patients had at least one actionable mutation : somatic BRCA1/2 mutations N=106, FGFR2 fusions N=61, HER2 amplifications N=65, KRAS G12C/D mutations N=46, IDH1 mutations N=38, and TMB >10 mut/Mb N=16. BRCA1/2 -mutated BTC were more commonly found in older Asian males with intrahepatic tumors and often presented with peritoneal and liver metastases upon initial diagnosis. FGFR2 fusions were more prevalent in younger White females with intrahepatic tumors, while HER2 amplifications were mainly seen in Asian females with gallbladder tumors. KRAS mutations were primarily observed in Asian males, and IDH1 mutations were common in White males with intrahepatic tumors, frequently presenting with liver metastasis. Survival outcomes varied significantly based on the alteration type: patients with FGFR2 fusions had the longest median OS (mOS) at 23.3 months (mo) (95%CI 18.4-34.9), followed by those with IDH1 mutations (19.3 mo; 95% CI 17.4-NE) and TMB >10 mut/Mb (17.8 mo; 95% CI 13.6-NE). BRCA mutations had a mOS of 16 mo (95% CI 14.6-19.8), while HER2 amplifications and KRAS mutations had mOS of 15.5 (95% CI 11.9-20.2) and 11.6 mo (95% CI 10.0-20.9), respectively. Conclusions: These findings underscore the heterogeneity in clinical and genomic characteristics among BTC patients, highlighting the importance of tailored therapeutic approaches. Baseline patient characteristics stratified by mutation status. KRAS G12C/D (N=46) BRCA 1/2 (N=106) IDH1 (N=38) HER2 amplification(N=65) FGFR2 fusion(N=61) TMB>10 mut/Mb(N=16) P-value Median Age, year 67 68 64 66 52 73 <0.001 Female, n (%) 19 (41) 34 (32) 18(47) 34 (52) 45(74) 6 (38) <0.001 Race, n (%) <0.001 Asian 31 (67) 97 (92) 13 (34) 51 (79) 10 (16) 6 (38) White 14 (30) 8 (8) 24 (63) 13 (20) 48 (79) 10 (63) Primary tumor location, n (%) <0.001 Intrahepatic 28 (68) 45 (45) 33 (100) 19 (31) 54(95) 10 (67) Extrahepatic 9 (22) 27(27) 0 (0) 10 (16) 2 (4) 4 (27) Gallbladder 4 (10) 28 (28) 0 (0) 32 (53) 1 (2) 1 (7) Sites of Metastasis at diagnosis, n (%) Abdominal Wall / Peritoneal 9 (24) 15 (19) 4(13) 7 (12) 6 (10) 4 (27) 0.309 Bone 33 (92) 70 (90) 26 (87) 2 (3) 9(15) 0 (0) 0.212 Liver 20 (49) 52 (61) 28 (82) 45 (73) 45 (76) 6 (38) 0.001 Lung 26 (70) 65 (82) 22 (69) 36 (58) 27(45) 11 (69) 0.006