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378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)

Abstract Disclosure: M. Kakakhel: None. S. Fatima: None. H. Ahmad: None. A. Ibrahim: None. W. Rahman: None. R. Haider: None. H. Jawad: None. A. Qadeer: None. M. Khawar: None. F. Ahmed: None. J. Ikram: None. R. Kirchoff: None. Background: Across the world, type 1 diabetes mellitus (T1DM) is a major health problem for teenagers and young people. This study aims to examine the incidence and prevalence of T1DM by gender in the 15-39 age range between 1990 and 2021. Methods: We analyzed data from the Global Burden of Disease (GBD) to evaluate incidence and prevalence rates of T1DM in each gender from 1990 to 2021. The Annual Percentage Change (APC) and The Annual Average Percentage Change (AAPC) was used to assess trends, with p-values determining the statistical significance. Results: From 1990 to 2021, the global prevalence of T1DM was found to be increased steadily for both genders, with the highest rates recorded in 2021: 247.32 per 100,000 for females and 246.47 per 100,000 for males. Incidence rates in 2021 showed a contrasting pattern, with males exhibiting higher rates (7.18 per 100,000) compared to females (5.98 per 100,000). AAPC analysis showed that males exhibit a faster rise in both prevalence and incidence compared to females over the study period. The difference in AAPC between males and females is more pronounced for prevalence (+0.3748%) compared to incidence (+0.1956%), with all AAPC values being statistically significant (p &lt; 0.000001). Following the APC analysis, other significant trends were revealed. Male incidence experienced the greatest increase during 2015-2021, with an APC of +1.9033% (p &lt; 0.000001), whereas female incidence increased most between 2011 and 2014 (APC = +1.3050%; p &lt; 0.000001). In contrast, the most significant decline in incidence was observed in females during 1990-1992, with an APC of +0.1665% (p = 0.006799), which was the lowest increase in the dataset. For prevalence, males exhibited the highest increase during 2015-2021, with an APC of +1.3938% (p &lt; 0.000001), whereas females had their peak increase during 2006-2009, with an APC of +0.8957% (p &lt; 0.000001). The slowest increase in prevalence for females occurred during 2014-2019, with an APC of +0.4591% (p &lt; 0.000001). Conclusion: The prevalence and incidence of T1DM among people aged 15-39 increased significantly between 1990 and 2021, with a greater increase in males. This highlights the need for gender-specific strategies in T1DM prevention and management, and research into the factors driving these disparities. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Kakakhel: None. S. Fatima: None. H. Ahmad: None. M. Khan: None. A. Rai: None. A. Qadeer: None. R. Haider: None. M. Khawar: None. U. Habib: None. H. Jawad: None. J. Ikram: None. F. Ahmed: None. R. Kirchoff: None. Introduction: Type 1 Diabetes Mellitus (T1DM) is a disease that affects people all over the world. This condition causes significant morbidity, as measured by Disability-Adjusted Life Years (DALYs) and mortality rates, and its severity varies worldwide. The purpose of this study is to examine trends in T1DM-related death rates and DALYs across 26 geographical areas from 1990 to 2021 in order to provide a current picture of the disease's consequences and identify regional differences. Methods: This study examined DALYs and mortality rates per 100,000 people in individuals aged 15-39 years using data from the Global Burden of Disease Study from 1990 to 2021. Trends were assessed using the Average Annual Percentage Change (AAPC), with p-values used to define statistical significance. The study examined 26 regions with varied socioeconomic development indices (SDI). Using confidence intervals to account for data uncertainty, DALYs and mortality were examined to investigate the disease burden across time. Results: In 1990, the Middle SDI region had the highest DALYs at 298,352 (95% CI: 256,144 -349,670), which reached 382,857 (95% CI: 213,704-317,664) by 2021 (AAPC = 0.15, P-value &lt; 0.000001). The region with the highest DALYs in 2021 was the Low-Middle SDI, with 419,772 (95% CI: 344,307- 495,496) cases (AAPC = -2.93, P-value = &lt;0.000001). From 1990 to 2021, Oceania consistently had the lowest DALYs of 1,895 (95% CI: 1,264-2,577) and 4,210(95% CI: 3,011-5,724), respectively (AAPC= 0.15, P-value = 0.0004). Mortality rates in 1990 were highest in the Middle SDI area with 3,758 deaths (95% CI: 3,343-4,332) (AAPC= -1.23, P-value = &lt;0.000001), but by 2021, South Asia had the highest mortality rate at 5,189(95% CI: 4,272-6,087) (AAPC= -0.49). Oceania had the lowest mortality rate of 25 deaths (95% CI 145-35) (AAPC = 0.193, P-value = &lt;0.0004) in 1990, whereas Australasia had the lowest mortality rate of 28 deaths (95% CI 26-29) in 2021 (AAPC = -0.93, P-value = &lt;0.000001). Conclusion: From 1990 to 2021, the global burden of type 1 diabetes—as indicated by DALYs and death rates—underwent a substantial shift, with significant rises in several regions. DALYs were highest in the Middle SDI region in 1990 but have migrated to the Low-Middle SDI region by 2021, reflecting shifting healthcare issues and demographics. Mortality rates followed a similar pattern, with South Asia and the Low-Middle SDI regions experiencing the highest rates in 2021. Over both time periods, however, Oceania and Australasia consistently had the lowest DALYs and death rates. These findings emphasise the critical need for targeted interventions in high-burden areas. Addressing these differences is crucial for decreasing the global burden of T1DM. Presentation: Sunday, July 13, 2025

Abstract Disclosure: H. Ahmad: None. S. Fatima: None. M. Kakakhel: None. I. khan: None. A. Raza: None. Z. Khan: None. R. Haider: None. A. Qadeer: None. M. Khawar: None. F. Ullah: None. H. Jawad: None. J. Ikram: None. F. Ahmed: None. R.W. Kirchoff: None. Background: Type 1 diabetes mellitus (T1DM) is an autoimmune condition, characterized by the destruction of pancreatic beta cells, resulting in lifelong dependency on insulin. It is a significant health burden in adolescents and young adults, with long-term complications affecting quality of life and survival. We aim to explore sex-stratified trends in mortality and disability-adjusted life years (DALYs) due to T1DM from 1990 to 2021. Methods: We obtained sex-stratified data for adolescents and young adults (15-39 years) with T1DM from the Global Burden of Disease (GBD) from 1990 to 2021. The mortality rates were age-standardized and expressed per 100,000 deaths. Trends were analyzed as annual percentage change (APC) and average APC (AAPC) using Joinpoint Regression. Results: From 1990 to 2021, deaths due to T1DM in adolescent and young adult males increased globally from 7,123 to 9,244 per annum, with age-standardized mortality rates (ASMRs) decreasing from 0.64 to 0.61 and standardized DALYs rising from 49.56 to 51. In females, deaths rose from 6,160 to 6,892, with ASMRs declining from 0.57 to 0.47 and DALYs declining from 47.12 to 43.11. Despite the apparent rise in deaths, ASMRs exhibited a significant decline in both sexes, with an AAPC of -0.16% (95% CI: -0.20 to -0.12) in males and -0.62% (-0.68 to -0.55) in females, four times that of in males. The DALYs showed a significant decline in females with an AAPC of -0.31% (-0.35 to -0.26) but a significant increase in males with an AAPC of 0.09% (0.04 to 0.12). Males showed the greatest APC increase in ASMRs of 1.34% from 1990 to 1994, while females showed the greatest APC increase of 0.45% from 1990 to 2000, three times less and over twice the period seen in males. This was followed by the greatest APC decline of -1.14% in females from 2001 to 2011, and a non-significant decline of -0.14% till 2021. Males experienced the greatest decline of -1.14% from 2000 to 2013. It then increased significantly from 2013 to 2018 (APC: 0.73%), followed by a significant decline of -0.62% till 2021, almost four times that in females. DALYs showed a similar trend in females with the greatest increase of 0.45% from 1990 to 2000, followed by the greatest decrease of -1.14% till 2011, and then a non-significant decline of -0.14 till 2021. Males showed the greatest increase of 1.24% from 1990 to 1994 and the greatest decrease of 0.63% from 2000 to 2013, followed by a much smaller decline. Conclusion: Although ASMRs declined, the recent decline in ASMRs in females is becoming less pronounced highlighting the importance of ongoing monitoring and improvement strategies. The disparity in DALYs between males and females also demands the need for targeted interventions addressing male-specific challenges to reduce the burden of T1DM. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A. Zhang: None. J. Kapoor: None. C. Deveney: None. A.G. Cope: None. M.M. Walther-Antonio: None. N. Chia: None. C.W. Pattanayak: None. M.J. Tetel: None. The vaginal microbiome (VM) consists of the microorganisms and their metabolites residing in the vaginal tract and is critical for maintaining female reproductive health. The Lactobacillus species predominate most VMs and produce lactic acid, which has been cited as a key protector of vaginal health. Alterations in the finely balanced vaginal microbiome can cause infections, such as bacterial vaginosis, and may contribute to the development of endometrial and ovarian cancer. While it is well-established that stress and the gut microbiome impact each other via the gut-brain axis, the influence of stress, hormones, and lifestyle factors on the VM composition remains poorly understood. We investigated the relationship between stress, hormones (menstruation, hormonal contraception), lifestyle factors (diet, exercise, sleep), and the VM composition. In this 10-week study, healthy, young female volunteers (n=62) provided daily vaginal and fecal swabs, weekly stress ratings, daily data on sleep and activity (via FitBit) and diet information. High-throughput 16S rRNA sequencing was used to identify the vaginal microbial composition of each sample. Types of hormonal birth control were none (n=30), local progestin (n=9), systemic progestin-only (n=7), or systemic estrogens and progestin combined (n=16). Consistent with our previous study, vaginal microbial diversity, as measured by the Shannon index, varied by type of hormonal birth control, with participants not on hormonal birth control having the highest average diversity. There was a positive relationship between average stress and vaginal microbial diversity, with preliminary results suggesting that this relationship depends on hormonal birth control status. Participants who menstruated during the 10-week study had a higher vaginal microbial diversity than those who did not. We are currently analyzing which microbes contribute to these differences in vaginal microbial diversity. Microbiota and fungal data from the daily vaginal and fecal swab samples will be analyzed to determine how stress, hormones and/or lifestyle factors relate to crosstalk between the vaginal and gut microbiomes. These findings may provide long-term, time-longitudinal insights into how these two important microbiomes are involved in important aspects of women’s health. Presentation: Sunday, July 13, 2025

1037 Background: TBCRC041, a randomized phase 2 trial of alisertib (A) ± fulvestrant (F) in women with HR+/HER2- MBC demonstrated promising clinical activity for alisertib (1). Interrogation of baseline (PreC1) and end of cycle 1 (EOC1) cfDNA and CTCs may identify biomarkers associated with response to A±F. Methods: Plasma cfDNA was sequenced using the Guardant INFINITY platform, which includes genomic and methylated tumor fraction (mTF) analysis. Pathogenic variants were determined using publicly available databases and Mayo Clinic annotation pipelines. CTCs were identified as nucleated, EpCAM+/ cytokeratin+/ CD45- cells and assessed for ER/HER2 staining (RareCyte, Seattle). PFS was defined as the time from randomization to progression or death. EOC1-PFS differs from PFS as time starts at C2D1. Stratified log-rank tests and conditional Cox modeling were used to assess whether PFS or EOC1-PFS differed by mutations in ESR1 or PIK3CA, pre-CTC ≥ 5, or mTF>1%. Results: Of the 91 eligible pts, 84 progressed, and 73 were deceased. In the 86 pts with PreC1-cfDNA results, variants were identified in ESR1 (42; 48.8%), PIK3CA (36; 41.9%), AKT1 (7; 8.1%), PTEN(7; 8.1%), BRCA1 (4; 4.7%), and BRCA2 (7; 8.1%). Pts with a PIK3CAmut had significantly decreased PFS (HR 1.8; 95%CI: 1.1 -2.9, p=0.014) but not by ESR1mut status (p=0.583). PreC1 and EOC1-mTF were determined for 78 and 76 pts, respectively. PreC1-mTF was 0-1% in 21; 1.1-10.0% in 27; and 10.1-100% in 30. mTF levels remained between 0-1% in 17 pts fell to 0-1% in 11 pts, and was 0-1% in 5 pts without a preC1-mTF determination. PFS did not differ with respect to PreC1-mTF (p=0.210), but EOC1-PFS was worse in pts with mTF >1% (HR 3.0; 95%CI: 1.6 -5.2, p<0.001). PreC1 and EOC1-CTC were determined for 78 and 76 pts. 36 (46.2%) pts had a PreC1 CTC count ≥ 5. EOC1-CTC levels remained at (n=17) or increased to (n=1) ≥ 5 and was ≥ 5 in 2 pts without a preC1-CTC determination. EOC1-PFS was not significantly different for EOC1-CTC ≥ 5 (p=0.065), but was significantly decreased in pts with PreC1-CTC≥5 (HR=1.8; 95%CI: 1.1-3.0; p=0.018). Broader cfDNA NGS panel and CTC-derived ER/HER2 staining results will be presented at the meeting. Conclusions: Among patients receiving A±F, PFS varied based on the PIK3CAmutation status. cfDNA and CTC assessment PreC1 and EOC1 provided complementary information. Further validation in larger datasets is needed. 1. JAMA Oncol 2023;9:815. Clinical trial information: NCT02860000 .

ImportanceThe BCG vaccine—used worldwide to prevent tuberculosis—confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non–muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses.ObjectiveTo evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event.Design, Setting, and ParticipantsThis cohort study was performed in patients aged 50 years or older initially diagnosed with NMIBC between May 28, 1987, and May 6, 2021, treated within the Mass General Brigham health care system. The study included a 15-year follow-up of individuals (BCG vaccine treated or controls) whose condition did not clinically progress to muscle-invasive cancer within 8 weeks and did not have an ADRD diagnosis within the first year after the NMIBC diagnosis. Data analysis was conducted from April 18, 2021, to March 28, 2023.Main Outcomes and MeasuresThe main outcome was time to ADRD onset identified using diagnosis codes and medications. Cause-specific hazard ratios (HRs) were estimated using Cox proportional hazards regression after adjusting for confounders (age, sex, and Charlson Comorbidity Index) using inverse probability scores weighting.ResultsIn this cohort study including 6467 individuals initially diagnosed with NMIBC between 1987 and 2021, 3388 patients underwent BCG vaccine treatment (mean [SD] age, 69.89 [9.28] years; 2605 [76.9%] men) and 3079 served as controls (mean [SD] age, 70.73 [10.00] years; 2176 [70.7%] men). Treatment with BCG vaccine was associated with a lower rate of ADRD (HR, 0.80; 95% CI, 0.69-0.99), with an even lower rate of ADRD in patients aged 70 years or older at the time of BCG vaccine treatment (HR, 0.74; 95% CI, 0.60-0.91). In competing risks analysis, BCG vaccine was associated with a lower risk of ADRD (5-year risk difference, −0.011; 95% CI, −0.019 to −0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, −0.056; 95% CI, −0.075 to −0.037).Conclusions and RelevanceIn this study, BCG vaccine was associated with a significantly lower rate and risk of ADRD in a cohort of patients with bladder cancer when accounting for death as a competing event. However, the risk differences varied with time.

ImportanceAurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i–resistant MBC is unknown.ObjectiveTo assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)–negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (&amp;lt;10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022.InterventionsAlisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2).Main Outcomes and MeasuresImprovement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.ResultsAll 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]).Conclusions and RelevanceThis randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i–resistant MBC. The overall safety profile was tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT02860000

Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. Approach and Results: This work is a Phase 1b/2 study (S4‐13‐001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21‐day cycle. Primary efficacy endpoint was progression‐free survival (PFS) in the modified intent‐to‐treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p = 0.0496); 10‐month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first‐line treatment of patients with locally advanced/metastatic cholangiocarcinoma.