Landscape of clinical trials and impact of precision medicine in biliary tract cancers in the last 45 years: a systematic review and meta-analysis of biomarker-driven trials

Introduction

Since the late 1970s, hundreds of clinical trials have been conducted to improve outcomes for patients with biliary tract cancers (BTCs). These studies, primarily conducted in Europe, Asia and North America, have explored a wide range of interventions including stenting, adjuvant and neoadjuvant therapies, liver-directed treatments, surgical procedures as well as treatment of advanced disease. Despite this extensive body of research, comprehensive analysis compiling and evaluating the findings from these trials is still lacking. In recent years, the incorporation of immunotherapy for upfront treatment of advanced disease (1,2), alongside the growing application of precision medicine in later treatment lines associated with increasing efforts to incorporate it earlier in the treatment course, have significantly transformed the therapeutic landscape for BTC patients (3-6).

To assess the current state of clinical trial development and therapeutic progress in BTCs, we conducted a comprehensive systematic review of published and presented trials. Our objective was to capture the broad spectrum of interventions, patient demographics, and geographical patterns of recruitment. Additionally, in recognition of the transformative role of precision medicine in BTC, we performed a meta-analysis of randomized trials evaluating biomarker-driven therapeutic arms. We present this article in accordance with the PRISMA reporting checklist (7) (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0015/rc).

Methods

Systematic review and meta-analysis

Search strategy, eligibility and study selection

In this systematic review we searched PubMed/Medline, Embase, Web of Science, and Scopus for phase I–III interventional trials on BTCs up to January 2024. Restricted to adult patients, duplicates were excluded. The search strategy, developed with an expert librarian (E.T.R), is detailed in Figure 1 and supplementary files (Appendix 1).

Figure 1 PRISMA flow diagram. BTC, biliary tract cancer; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analyses.

Data from the included trials were extracted (P.L.S.U.J.) and were resolved by referring to a second and third reviewer (F.M., M.J.B.). Trials included in the meta-analysis were reviewed and assessed for quality using the Cochrane risk of bias tool version 2 by P.L.S.U.J., M.J.B and F.M. (8).

This review included English prospective interventional trials across various treatments such as surgery, systemic therapy, radiology, and radiation, with no line restrictions. Studies were grouped into categories like stenting, surgery, systemic therapy lines, interventional oncology, and combination therapies. Trials included in the metanalysis were assessed for quality using the Cochrane risk of bias tool version 2 by (P.L.S.U.J. and F.M).

Statistical analysis

Meta-analysis utilized the inverse variance method with fixed-effect and random-effects models, using R software (4.3.3 or higher; R Foundation for Statistical Computing). Odds ratios (ORs) with 95% confidence interval (CI) were calculated. Heterogeneity was assessed via Q test, I², and H statistics. Biomarker-guided interventions for advanced BTC were compared to non-guided approaches, using R software (4.3.3 or higher; R Foundation for Statistical Computing).

Endpoints

The primary objective of this study was to assess the evolution and key characteristics of the trials, including demographics of enrolled patients and the geographical distribution of recruitment. Furthermore, disease-specific endpoints such as response rate and median overall survival (OS), as well as the influence of precision medicine in the management of advanced BTC over the past 45 years were also evaluated.

Results

From a total of 3,761 records, 1,410 were accessed for eligibility after filtering out duplicates. A total of 427 trials were selected after excluding pan-tumor trials where BTC-specific data could not be identified (610 articles), non-therapeutic interventional studies (128 articles), review articles (208 articles), and pre-clinical studies (38 articles) (Figure 1). All the trials were published between 1979 and 2024.

The descriptive analysis was based on three trial groups: all trials (427 trials, 534 arms), advanced BTC treatments (345 trials, 417 arms), and randomized biomarker-driven vs. standard therapies (5 trials).

Overall characteristics of the trials

This study analyzed 23,024 patients across 427 trials, including 46 phase I, 282 single-arm phase II, and 99 randomized or multicohort studies. A total of 84 interventions were assessed, such as chemotherapy, radiotherapy, brachytherapy, ablation, biliary drainage, and stenting. Of 345 trials on advanced BTC, 60% focused on first-line treatments, while 38.2% addressed second-line or later therapies. Notably, 38 trials targeted unresectable or locally advanced cases, with 42% including patients with oligometastatic disease.

Among 46 phase I trials, various treatments were tested: cytotoxic chemotherapy (56.5%), monoclonal antibodies/bispecifics (6.5%), tyrosine kinase inhibitors (28.2%), immunotherapies (17.4%), and interventional radiology (19%). Many strategies combined systemic treatments, with detailed data available in Table S1.

In the 282 single-arms phase II trials, the strategies included chemotherapy combinations in 209 (74.2%) trials, monoclonal antibodies in 22 (7.8%) trials, tyrosine kinase inhibitors and other small oral molecules (i.e. everolimus, MK-2206) as well the majority in combinations in 52 (18.4%) of the phase II trials, immunotherapies strategies in 29 (10.2%) trials and interventional radiology strategies combinations in 26 (9.2%) trials. Among 98 randomized trials, 60.6% used cytotoxic chemotherapy, 3% monoclonal antibodies, 10.1% tyrosine kinase inhibitors, 9.1% immunotherapies, and 27.2% interventional radiology, often combined with systemic treatments. The remaining trials included multi-cohort and randomized phase II/III studies exploring diverse therapeutic strategies.

Regarding primary endpoints, 29 were identified and the most common was objective response rate (ORR) at 51.5%, followed by progression-free survival (PFS) at 13.8%, and OS in 11%. Safety was the primary endpoint in 5.3%, with stenting dysfunction and maximum tolerated dose also noted. Phase I trials mainly focused on safety, while phase II trials prioritized response rate. In phase III, OS was the predominant endpoint, highlighting differing priorities across trial phases. Other primary endpoints can be found in Table S1.

Out of 427 trials, 40 (9.3%) focused solely on localized BTC, mainly evaluating neoadjuvant or adjuvant therapies, stenting, surgery, antibiotics, and nutrition. Stenting studies targeted dysfunction, with rates of 13.3–57.6%. Neoadjuvant regimens included photodynamic therapy and gemcitabine-based chemotherapy with or without radiotherapy. Among 19 adjuvant trials, endpoints included OS, recurrence-free survival, toxicity, and tolerability. Notably, 73.6% of adjuvant trials did not report resection margin status.

Among these 427 trials, 19.9% focused solely on cholangiocarcinoma (CCA), with 5.15% not reporting specific BTC subtypes. CCAs and gallbladder cancer (GBC) appeared in 42.3%, while 24.1% included CCA, GBC, and ampullary cancers (ACs). No prospective trials exclusively studied AC.

Analysis of 427 trials revealed that 74.7% did not report the number of patients screened, and 3 lacked screening period details. Of the remaining 105 trials (24.8%) that reported screening data, median screening duration ranged from 1 to 8 years, with enrollment time not correlated to the number of patients screened. For instance, Keynote 966, one of the largest trials with 1,564 patients, enrolled participants in just 2 years. The number of participating centers varied from 1 to 692. Statistical analysis showed associations between enrollment duration, number of sites, and patients enrolled or treated; longer enrollment times correlated with more sites and higher patient numbers, especially in studies without biomarkers. Conversely, in biomarker-driven trials, no significant relationship was observed between the number of sites or patients enrolled and enrollment duration. These findings highlight variability in trial design and enrollment dynamics across different study types (Figure S1).

A total of 56 trials (13.1%) were investigator-initiated, meaning they did not have a direct industry sponsor. A total of 115 trials (26.9%) did not report the sponsor or if they were investigator initiated. The 256 trials (60%) that reported a sponsor included pharma companies in 162 (37.9%), national grants in 67 (15.6%) or related foundations/societies/universities in 27 trials (6.3%).

Prior radiotherapy was reported in 82 trials (19.2%). Only 34 trials (7.9%) reported hepatitis B or C status. The number of patients with hepatitis B varied between 1–80%. The percentage of patients with hepatitis C varied between 1–27%. Programmed death ligand-1 (PD-L1) positivity was reported in 15 trials (3.5%) and varied between 0–71.8%. Prior surgery was reported in 259 trials (60.6%), in those trials, R1 resection was reported between 1–38% of the cases.

Group evaluations

Analysis of 427 trials shows varied focus: 44 on localized disease (3,246 patients), 38 on locally advanced disease (1,045 patients), and 345 on advanced stages (13,503 patients) (Table 1 and Table S2). Over time, there has been a shift from chemotherapy, radiotherapy, and intervention-based trials toward increased immunotherapy and biomarker-driven studies. This trend reflects evolving treatment strategies, emphasizing personalized and targeted therapies (Figure 2).

Figure 2 Sankey plot evaluating the evolution of trials conducted in biliary tract cancers over the past decades. A relative decrease can be noted in studies evaluating chemotherapy, radiotherapy, and interventional therapies, compared to biomarkers and immunotherapies trials.

The median age of patients included in all the trials was 63 years [60–65 years], the median age of patients recruited in the 427 trials remained stable between 1979–2024, with sings of increasing (Figure S2). Before 2001, the median age of patients recruited in the trials was 60.5 years [57.75–61 years], between 2001–2010 was 62 years [59–65 years], between 2010–2020 was 63 years [61–66.75 years], and after 2020 was 63.25 years [60–66 years].

Most clinical trials were conducted in North America, Europe, and Asia, with Asia becoming the dominant region by 2021–2024. Recent years also show increased representation from North America, Oceania, and Latin America, indicating growing geographic diversity. Most trials are conducted in Asia, likely due to higher incidence rates (Figure 3). Slightly more men (52.9%) participate overall, but women (56%) are more frequently recruited in biomarker-driven trials, though this difference is not statistically significant.

Figure 3 Temporal evolution of clinical trials. Over the years, a higher number of trials have been observed in Asia. Since 2020, more trials have been opened in Latin America and Oceania.

Race was reported in only 19.2% of 427 trials. Approximately 80% of participants were White, with less than 5% Black individuals. Among 117 North American trials, race was reported in 57.4%, with Black patients in 60% of these, ranging from 0.8–21%. Asian patients appeared in 67.1% of North American trials. In Europe, race was reported in 19.7% of 137 trials, with Black patients in 44.4%, ranging from 0.8–8% (Figure S3).

Eastern Cooperative Oncology Group (ECOG) performance status was unreported in 118 trials (27.6%), with 45 of these focusing on interventional procedures like stenting, ablation, radiotherapy, and other non-systemic treatments. Among the 309 trials (72.4%) reporting ECOG status, a median of 47% of patients had ECOG 0, and 50% had ECOG 1. ECOG 2 was documented in 141 trials (33%), with patient ranges from 1% to 100%, the last one notably in a brachytherapy trial as a palliative management for distal CCA. ECOG 3 was reported in 6 trials, with 3–36% of patients affected, all involving chemotherapy for advanced disease with primary response rate as an endpoint. Overall, the data highlight variability in ECOG reporting, especially in trials evaluating palliative interventions and systemic therapies.

When evaluating only randomized phase III trials, involving patients with good performance status (ECOG 0–1) and first-line treatment for advanced—metastatic BTC, a total of 11 trials were analyzed. It is evident that the sample size of trials has increased over time; in Figure 4, the orange line represents the sample size of the trials with increasing trends. However, despite these advancements, OS increments remained dismal, even with more chemotherapy or with immunotherapy. In Figure 4, the blue columns represent median OS. The columns show that median OS of all phase 3 trials for first-line systemic regimens for advanced disease remained around 8–12 months over the period (Figure 4).

Figure 4 Median overall survival of randomized phase 3 trials evaluating first-line treatment for advanced biliary tract cancers, 2005–2023. Although multiple regimens were evaluated on randomized controlled trials, modest benefit was observed over the years.

Based on Group 2 analysis, which focused on trials involving advanced BTC, the median response rate was higher in biomarker driven trials when compared to other trials (33% vs. 20%). A temporal evolution of all the trials among periods confirms the findings. It is also observed that there is a trend of more trials being conducted with biomarker strategies in countries outside Asia, Europe and North America from 2011 to current date (Figures S4-S7). Furthermore, the median OS and response rate has been increasing over time with the incorporation of immunotherapy and precision medicine for advanced BTCs (Figures 5,6). In Figures 5 and 6, the colored balls represent immunotherapy and biomarker-driven trials, respectively; grey represents chemotherapy trials. The size of the balls is related to the response rate (%). OS is represented by the y-axis. Under the direct view of both figures, we can see a tendency of increased survival and increased response rate with the incorporation of these technologies (Figures 5,6).

Figure 5 Average median overall survival and response rate of all the trials in the last 45 years, highlighting immunotherapy trials, including single arms studies and randomized trials. Colored balls represent immunotherapy trials; grey represents chemotherapy trials. The size of the balls is related to the response rate (%). CART, chimeric antigen receptor T; HAIC, hepatic arterial infusion chemotherapy; IO, immunotherapy; mAb, monoclonal antibody; RDT, radiation therapy; TKI, tyrosine kinase inhibitor.

Figure 6 Average median overall survival and response rate of all the trials in the last 45 years, highlighting biomarker-driven trials, including single arms studies and randomized trials. Colored balls represent biomarker-driven trials; grey represents chemotherapy trials. The size of the balls is related to the response rate (%). “mAb + mAb” represents association of two different mAbs; “TKI + TKI” represents association of two different TKIs. ADC, antibody-drug conjugate; CART, chimeric antigen receptor T; IO, immunotherapy; iMTOR, inhibitor of mammalian target of rapamycin; mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor.

Group 3 analyzed five randomized trials for meta-analysis: one on ivosidenib in IDH1 mutant patients and four on anti-epidermal growth factor receptor (EGFR) therapy in KRAS wildtype advanced BTC. Biomarker-selected treatments showed higher response rates (27% vs. 18%). The meta-analysis of 662 patients confirmed increased response odds with biomarker-based approaches [OR =2.16 (1.43, 3.28)], with low heterogeneity and low risk of bias across studies. These findings support the efficacy of biomarker-guided therapy in advanced BTC (Figure S8) and Figure 7. Additionally, a very low heterogeneity between the trials was observed. Overall, the included trials had a low risk of bias (Figure S9).

Figure 7 Meta-analysis of biomarker-driven trials. Higher response rate is observed in biomarker driven trials. CI, confidence interval; OR, odds ratio.

Discussion

In this systematic review, we evaluated the last 45 years of trials in BTC. Most trials conducted to date are phase II trials [282 (66%)]. While 71.6% [306] of the trials reported achieving primary endpoint (including multiple endpoints), improvements in median OS were rarely observed in definitive randomized trials. Precision medicine-based studies contributed to a marked improvement in overall response rates. Several gaps and limitations were identified in the design and reporting of the clinical trials over the years, highlighting the need for reflection on best practices in trial design and reporting.

BTCs are collectively one of the most challenging malignances to date. More than a decade after the publication of the ABC-02 trial, which established gemcitabine plus cisplatin (GC) as the standard of care (9), the incorporation of immunotherapy h as modestly improved outcomes for advanced BTC. In recent years, the median OS with durvalumab-GC was 12.8 months (95% CI: 11.1–14.0 months), and with GC, it was 11.5 months (95% CI: 10.1–12.5 months). Similarly, pembrolizumab-GC showed a median OS of 12.7 months (95% CI: 11.5–13.6 months) compared to 10.9 months (9.9–11.6 months) with GC (2). The impact of adding immunotherapy is a median reduction in the risk of death of about 20%, although modest is an important improvement in long-term survivors. However, based on the data, significant advances in median OS on first-line systemic treatment are still necessary. In the setting of refractory disease, although mostly single arm studies and OS are not a primary endpoint, precision medicine-based approaches have yielded promising results, with higher response rate and sometimes even higher median OS, when compared to standard chemotherapy approaches, as we can see in Figures 5,6 (10-12).

As an example, in chemotherapy refractory patients with FGFR2 fusions or rearrangements, the median OS with pemigatinib was 21.1 (14.8-NE) months; and with futibatinib 21.7 months (14.5-NE) (3,10). In BRAF V600E mutated chemotherapy-refractory patients, the median OS of dabrafenib and trametinib was 14 months [10–33 months] (11). Finally, human epidermal growth factor receptor 2 (HER-2) directed therapy is also very effective, in the same setting of advanced and refractory disease with HER-2 amplification, the median OS of trastuzumab and pertuzumab was 10.9 months [5.2–15.6 months] (12). Furthermore, the response rate of those strategies is much higher than the 5–10% seen with chemotherapy. Comparisons should not be made in both scenarios, however based on the literature to date and the findings, a clear unmet need is observed, and precision medicine should be evaluated urgently in earlier settings. However, barriers related to recruitment particularly for non-common or rare genomic alterations should be noted. Trials evaluating anti-FGFR2 as first-line options were discontinued suggesting that maybe basket trials should be considered enough for approval of targeted treatments in earlier settings in BTCs. Examples in other diseases such as vismodegib and imatinib, that received approvals as first-line options based on non-randomized data, for advanced basal-cell carcinoma and gastrointestinal stromal tumor (GIST), could be used (13,14). In most Western countries, BTC is defined as a rare disease and special situations could be or would be applied (15).

Our study revealed significant gaps in trial design and reporting over decades. Notably, 26.9% of trials omitted sponsor or investigator-initiated status; prior radiotherapy was mentioned in only 19.2%, and personal hepatitis B or C history in just 7.9%. Most trials lacked background liver disease data. Prior surgery was reported in 60.6%, with R1 resection rates ranging from 1–38%. Given the disease’s rarity, such data are valuable. Additionally, race was unreported in 80.8%, despite evidence of racial molecular disparities in BTC, such as TP53 and FGFR2 alterations being more common in African Americans and IDH1 mutations in Caucasians (16). ECOG status was missing at 27.6% of trials yet remains critical for prognosis and therapy decisions. Improvements in comprehensive reporting are essential to better understand disease characteristics and address unmet needs.

Overall, the trials that included black patients enrolled them in relatively small proportions, typically ranging from 1.6% to 20% of the total study population. Future trials design should prioritize greater accessibility and inclusion of socioeconomically disadvantaged and underrepresented groups to ensure more equitable research outcomes. Previous meta-analysis of anti-EGFR agents in advanced BTC did not identify better PFS or OS (17). Randomized data with potent agents like anti-HER-2 or FGFR inhibitors are not available to date, and caution should be made about this finding and precision medicine overall.

From all trials, 19.9% included only CCA, with the consideration that most currently druggable drivers are identified in this subtype. Multiple trials have evaluated the prevalence of actionable targets in BTCs. In intrahepatic CCA, the prevalence is up to 50% in some series, much higher than distal CCA and GBCs, that actionability ranges between 5–20% (18). Primary ACs had no specific prospective trials, and this could be a subject of future initiatives, although an extensive collaborative effort would be required to achieve this.

Analysis of the 427 trials revealed that 74.7% did not report the number of patients screened, and only 3 omitted screening period data. Statistically, enrollment time, number of sites, and patients enrolled correlated differently in biomarker-driven vs. non-biomarker trials. In non-biomarker studies, longer enrollment years linked to more sites and patients, with more sites associated with larger sample sizes. Conversely, in biomarker-driven trials, the number of sites did not affect patient numbers, indicating fewer sites targeting actionable biomarkers can be equally effective, potentially reducing costs. Biomarker testing has increased over time with recent approvals, shifting from single alterations to panel testing, which likely facilitates recruitment. These findings highlight evolving trial strategies, emphasizing efficient site use in biomarker-driven research and the importance of comprehensive testing approaches.

Survival analysis focuses on the time until a specific event, with censorship complicating data interpretation when observations are interrupted. Variability across studies—including differences in duration, patient profiles, and data collection practices—makes accurate replication challenge without detailed information. Lack of knowledge about survival time distributions and the presence of random effects further hinder accurate modeling. Simulating survival data, especially for Kaplan-Meier estimates, risks unreliable results due to assumptions about distribution and censorship, potentially compromising validity. Therefore, relying on real data, despite its limitations, remains more robust and scientifically sound than simulations in survival analyses.

This systematic review highlights key areas for improving future clinical trials in BTC. Standardizing inclusion criteria, such as sponsorship details, ECOG performance status, hepatitis status, minority representation, BTC subtypes, and staging, is essential. Thorough reporting of demographics, trial design, screening methods, and enrollment processes will enhance transparency and reproducibility. Incorporating precision medicine strategies for advanced disease and designing trials focused on specific BTC subtypes are recommended.

By evaluating the Sankey-plot figure, we can see that especially in the last 2 decades, most clinical trials are based on immunotherapy or precision medicine, and chemotherapy is ceasing to be the main investigative focus in biliary tract tumors. In this study we included several studies with high heterogeneity with the aim of providing a global view of the challenges in developing clinical trials in biliary tract tumors. Although the heterogeneity would be a limitation, the detailed analysis from phase I, II and III trials managed to narrow the gap between personalized therapy and innovation with conventional surgical and chemotherapy treatments. Further we were able to observe that the greatest advances currently have been achieved with precision medicine, incorporation of immunotherapy, and biomarker-based therapies. Therefore, prioritizing high-volume centers for biomarker-driven studies, rather than multiple low-volume sites, can improve outcomes. A limitation of this study involves the development of analyses based on published data. A study conducted with individual patient-level data would be more appropriate to assess the particularities of these patients, but it would be practically impossible considering that many of these studies no longer have retrievable individual data. Finally, developing consensus guidelines for BTC clinical trials will provide clearer pathways for investigators, sponsors, and regulatory agencies, ultimately advancing patient care and the field’s progress.

Conclusions

Precision medicine improvements support biomarker-driven trials in advanced disease. Combining immunotherapy and chemotherapy offers modest benefits over cisplatin plus gemcitabine. Future trials should enhance representativity, standardization, and strategic design to better advance BTC treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0015/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0015/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0015/coif). F.T. serves as an unpaid editorial board member of Translational Gastroenterology and Hepatology from August 2024 to December 2026. P.L.S.U.J. declares fees for Speaking and consulting/advisory from Roche, AstraZeneca, Bayer, BMS, J&J, Servier, Amgen, Merck, MSD, Sirtex, Pfizer, Takeda, Knight, Dr. Reddy’s, and Ipsen. F. Moura declares honoraria from J&J, Roche, Natera. D.A. declares fees from Bayer, Ipsen, Incyte, Exact Sciences, Exelixis; and stocks from Natera, Eli Lilly. M.B.S. declares research funding from Taiho and Eli Lilly; and consulting fees from Bayer and Novartis. J.W.V. declares fees from Astrazeneca; consulting fees and honoraria from Oncosil, Cogent Biosciences and Jazz Pharmaceuticals. J.M.B. declares consulting fees from Albireo-Ipsen, CIMABay, OWL-Rubió Metabolomics, Jazz, Astra Zeneca, Servier and Mirum; and honoraria from Incyte, Astra Zeneca, Eisai, Advanz, Ipsen, Servier and Mega. T.B.S. declares research funding (to institution) from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS, Revolution Medicine; consulting fees (to institution) from Servier, Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA, Revolution Medicines and Merck; consulting fees (to self) from Stemline, AbbVie, Blueprint Medicines , Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, Takeda, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine and Sanofi, Glaxo SmithKline, Arsenal Bio, Xilio and RYGHT AI; IDMC/DSMB from The Valley Hospital, Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan and 1Globe; participation on Scientific Advisory Board: Imugene, Immuneering, Xilis, Replimune, Artiva and Sun Biopharma; Royalties from Uptodate; and Inventions/Patents: WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF—Licensed to Imugene and WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA—Licensed to Recursion. M.J.B. declares grants from Alentis Therapeteutics, Arvinas, H3 Biomedicines, Tango Therapeutics, RayzeBio, Medinlink, Revolution Medicines, Incyte, Seagen, Pfizer, Nuvectis, Cogent, Astra Zeneca, Compass Therapeutics, Biond, Sanofi, Elevar, Elevation, Agios, Relay Therapeutics and Basilea; consulting fees from Amplia, Servier, Revolution Medicines, George Clinical, Guardant and Imugene; participation on advisory boards: Accession Therapeutics, Khora, Breakthru Bio, Reignite Therapeutics, Karkinos, Vionix, RayzeBio, Moderna, Revolution Medicines, Servier, Cogent, Sirtex, Processa, Jazz Pharmaceuticals, Elevar, Merck, Eisai, Compass Therapeutics, Kalivir Immunotherapeutics, Zielbio, Tempus, Cardinal Health, Exelixis, Kriya Therapeutics, Zymeworks, Orum Therapeutics, IMVAX, Cedilla, Senti Biosciences and Diffusion Pharmaceuticals; and stocks from ADC Therapeutics, Abeona, Assertio and Homology. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Okano N, Pirozzi A, O'Donnell C, et al. Time Toxicity in Patients With Advanced Biliary Tract Cancer Receiving Gemcitabine Plus Cisplatin With or Without Durvalumab. JCO Oncol Adv 2026;3:e2500126.
2. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;401:1853-65. [Crossref] [PubMed]
3. Pirozzi A, Hoyek C, Okano N, et al. Pharmacologic features, clinical applications, and drug safety evaluation of futibatinib in the treatment of biliary tract cancer (BTC). Expert Opin Drug Saf 2025;24:1383-90. [Crossref] [PubMed]
4. Uson PLS Junior, Borad MJ. Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date. Cancer Manag Res 2023;15:1025-31. [Crossref] [PubMed]
5. Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial. J Clin Oncol 2024;42:3207-17. [Crossref] [PubMed]
6. Harding JJ, Fan J, Oh DY, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol 2023;24:772-82. [Crossref] [PubMed]
7. Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 2021;372: [Crossref] [PubMed]
8. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [Crossref] [PubMed]
9. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
10. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med 2023;388:228-39. [Crossref] [PubMed]
11. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 2020;21:1234-43. [Crossref] [PubMed]
12. Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2021;22:1290-300. [Crossref] [PubMed]
13. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171-9. [Crossref] [PubMed]
14. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80. [Crossref] [PubMed]
15. U.S. FOOD & DRUG. Rare Diseases at FDA. Available online: https://www.fda.gov/patients/rare-diseases-fda#whatisraredis
16. Hu ZI, Pavlick DC, Ross JS, et al. Molecular Profiling of Biliary Tract Cancers in African American and Caucasian Patients. JCO Precis Oncol 2025;9:e2400712. [Crossref] [PubMed]
17. Rizzo A, Frega G, Ricci AD, et al. Anti-EGFR Monoclonal Antibodies in Advanced Biliary Tract Cancer: A Systematic Review and Meta-analysis. In Vivo 2020;34:479-88. [Crossref] [PubMed]
18. Uson PLS Junior, Borad MJ. Precision approaches for cholangiocarcinoma: progress in clinical trials and beyond. Expert Opin Investig Drugs 2022;31:125-31. [Crossref] [PubMed]