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ABSTRACT Background Over the years, prognostic indexes have been developed to help clinicians stratify patients with biliary tract cancers (BTC) into risk groups. This study aims to identify a new prognostic index for patients with BTC treated with cisplatin, gemcitabine and durvalumab (CGD) in the first‐line setting. Patients and Methods The study population consisted of patients with BTC from 11 Eastern and Western Countries. Using multivariate analysis for overall survival (OS), we identified 5 baseline statistically significant variables: stage, carcinoembryonic antigen (CEA) levels, albumin levels, gamma glutamyl transferase (GGT) levels, neutrophil‐to‐lymphocyte ratio (NLR). Metastatic disease is a prognostic factor with a superior weight considering the HR of 3.62, while all the others can be considered prognostic factors with equivalent weight as the HRs are quite similar (HRs between 1.55 and 1.92). Based on these reasons, we developed a prognostic model called the MAGIC‐D index by assigning a score of 2 for metastatic disease, and a score of 1 for CEA increased levels, albumin decreased levels, GGT increased levels, NLR ≥ 3. Patients were stratified into three risk groups as follows: low‐risk group (Score from 0 to 2), intermediate‐risk group (Score from 3 to 4) and high‐risk group (Score from 5 to 6). At the first data cutoff (April 2024), these data were available for 319 patients that composed the training cohort used for the analysis. At the second data cutoff (May 2025), 79 patients were further enrolled and composed the validation cohort. Results Median progression‐free survival was 11.7 months in low‐risk group (20.7%), 8.7 months in intermediate‐risk group (46.4%) and 5.4 months in high‐risk group (32.9%) [low‐risk hazard ratio (HR): 0.27, intermediate‐risk HR: 0.55, high‐risk HR: 1, p < 0.0001]. Median OS was 18.4 months in low‐risk group,15.9 months in intermediate‐risk group and 7.8 months in high‐risk group (low‐risk HR: 0.17, intermediate‐risk HR: 0.43, high‐risk HR: 1, p < 0.0001). There was no difference in overall response rate (low‐risk: 31.8%, intermediate‐risk: 36.5% and high‐risk: 25.7%; p = 0.0718), while disease control rate was significantly different across the three risk groups (low‐risk: 83.3%, intermediate‐risk: 70.9% and high‐risk: 60.9%; p < 0.0001) as well as the rate of patients receiving a second‐line therapy (low‐risk: 54.5%, intermediate‐risk: 48.6% and high‐risk: 25.7%; p = 0.0061). Finally, the prognostic role in terms of OS and PFS of the MAGIC‐D index was confirmed in a validation cohort of 79 patients. Conclusion The MAGIC‐D index is an easy‐to‐use tool able to stratify patients with BTC with different prognoses undergoing first‐line therapy with CGD.

AbstractStandard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

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.

Abstract Background In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial. Methods The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or &gt;6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS). Results A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG &gt; 6 vs. CGD &gt; 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]. Conclusion Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.

379 Background: A single priming dose of T (anti-CTLA-4) added to D (anti-PD-L1) in the STRIDE (Single T Regular Interval D) regimen, formerly T300+D, showed encouraging clinical activity and limited toxicity in a phase 2 uHCC study (Study 22, NCT02519348), suggesting single exposure to T is sufficient to improve upon D activity. HIMALAYA (NCT03298451) evaluated the efficacy and safety of STRIDE or D vs sorafenib (S) in uHCC. Methods: HIMALAYA is an open-label, multicenter, phase 3 study, in which pts with uHCC and no prior systemic therapy were initially randomized to STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg every 4 weeks [Q4W]), D (1500 mg Q4W), S (400 mg twice daily), or T 75 mg Q4W (4 doses) plus D 1500 mg Q4W (T75+D). Recruitment to T75+D ceased after a planned analysis of Study 22 showed T75+D did not meaningfully differ from D. The primary objective was overall survival (OS) for STRIDE vs S. The secondary objective was OS noninferiority (NI) of D to S (NI margin: 1.08). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR; RECIST v.1.1), duration of response (DoR), and safety. Results: In total, 1171 pts were randomized to STRIDE (N=393), D (N=389), or S (N=389). At data cutoff (DCO), the primary objective was met: OS was significantly improved for STRIDE vs S (hazard ratio [HR], 0.78; 96% confidence interval [CI], 0.65–0.92; p=0.0035; Table). D met the objective of OS NI to S (HR, 0.86; 96% CI, 0.73–1.03). ORRs were higher for STRIDE (20.1%) and D (17.0%) than for S (5.1%). No new safety signals were identified. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8% (STRIDE), 12.9% (D), and 36.9% (S) of pts. Grade 3/4 hepatic TRAEs occurred in 5.9% (STRIDE), 5.2% (D), and 4.5% (S) of pts. No TRAE of esophageal varices hemorrhage occurred. Rates of TRAEs leading to discontinuation were 8.2% (STRIDE), 4.1% (D), and 11.0% (S). Conclusions: HIMALAYA was the first large phase 3 trial with a diverse, representative uHCC population and extensive long-term follow-up to assess both mono- and combination immunotherapy. D was noninferior to S with favorable safety. The combination of a single priming dose of T plus D in STRIDE displayed superior efficacy and a favorable benefit-risk profile vs S. STRIDE is a proposed, novel, first-line standard of care systemic therapy for uHCC. Clinical trial information: NCT03298451. [Table: see text]

348 Background: The proportion of females in medicine is increasing (approx. 50% in medical school/workforce), but disparities in female authorship in oncology research publications exist; female corresponding authorship reportedly ranges from 7.2-39.1% in oncology clinical trials (Ludmir et al 2019). This study aimed to describe and assess factors associated with female first and senior authorship in later phase systemic clinical trials in BTC and to identify any changes over time. Methods: Embase/Medline were used to identify final primary trial publications in BTC (2000-2020) (excluding phase I (PI) (expected to move to later phase), mixed tumour site trials, reviews, editorials and trial-in-progress publications). Gender was determined by inspection of names, google search and author communication. Chi-square tests and log regression were used to assess factors associated with female first and senior authorship, including changes over time (STATA16). Results: Of 501 publications, 163 met inclusion criteria; 80% single-arm PII and 15% and 5% randomised PII and PIII respectively; 73% enrolled ≤50 patients. Tumour primary sites were all BTC: 86%, cholangiocarcinoma: 8%, gallbladder cancer: 6%; 80% involved chemotherapy, 13% targeted therapy and 5% localised/systemic combinations; 65% were in first-line (1L) advanced setting, 17% post 1L, 13% advanced non-specified and 5% neo-adjuvant/adjuvant. Forty-eight percent received industry funding and 65% met primary end-point. Sixty-four percent were published post ABC-02 (Valle et al 2010). Publication impact factor (IF) was ≤5 in 50% and >20 in 12%. Median number of authors in all publications was 11. Geographic location of all first and senior authors were Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Median individual trial female author representation was 25%; there were no female authors in 12% of trials. Overall, female first and senior author representation was 21% and 11%, respectively. Median position of first female author was second. In publications with IF ≤20 and >20, there were 22% and 16% female first and 13% and 0% female senior authors, respectively. The phase of trial, journal IF, industry funding, or whether met primary end-point did not impact female first or senior author representation (all P>.05). There were more female senior authors associated with “other” geographic locations (40% in 10 trials) (P=.016) vs Asia (7%), Europe (8%) and USA (14%). There were no significant changes in female first or senior author representation over time (‘00-05: 21%/18%, ‘06-10: 27%/5%, ‘11-15: 15%/15%, ‘16-20: 22%/9%, P=.738, and P=.508 respectively). Conclusions: Female first and senior author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed.