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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 >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 > 6 vs. CGD > 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., (© The Author(s) 2024. Published by Oxford University Press.)

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

Background: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes., Methods: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS)., Results: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine., Conclusion: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC., Competing Interests: Declaration of Competing Interest LR reports consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks. ACG reports consulting fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, IQVIA, MSD, Roche, Servier; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from AstraZeneca, Eisai. SLC serves an advisory member for AstraZeneca, MSD, Eisai, BMS, Ipsen, and Hengrui, received research funds from MSD, Eisai, Ipsen, SIRTEX, and Zailab, and honoraria from AstraZeneca, Eisai, Roche, Ipsen, and MSD. TP received consulting fees from Bayer, Ipsen, and AstraZeneca; institutional research funding from Roche, Bayer, and AstraZeneca; travel expenses from Roche. CB received honoraria as speaker (Astrazeneca, Incyte, Servier) and consultant (Incyte, Servier, Boehringer Ingelheim, Astrazeneca), received research funds (Avacta, Medannex, Servier) and her spouse is an employee of Astrazeneca. M. Ikeda reports honoraria from AstraZeneca, Chugai Pharma, Eisai, Incyte, Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Takeda, Teijin Pharma, Nihon Servier, Taiho and research funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Chiome Bioscience, Chugai, Eisai, Eli Lilly Japan, Delta-Fly Pharma, Invitae, J-Pharma, Merck biopharma, Merus N.V., MSD, Novartis, Nihon Servier, Ono, Syneos Health, and Rakuten Medical. GWP: Advisories and/or Speaker fees: Servier, Bayer, Roche Amgen, Merck, MSD, BMS, Sanofi, Lilly, Astra Zeneca, Astellas, Pierre-Fabre, Incyte, Arcus, CECOG. F. F. has received travel support from Ipsen, Abbvie, Astrazeneca and speaker’s fees from AbbVie, MSD, Ipsen, Astrazeneca. LP: Advisory role: AstraZeneca, Servier, Travel expenses: AstraZeneca, Ipsen. GG: Consulting Fees: Astra Zeneca, MSD, Servier, Seagen, Bayer, Amgen, Novartis, Ipsen, BMS. Travel Expenses: Astra Zeneca, Servier, Bayer, Novartis. S.L. reports research funding (to Institution) from Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; participation in advisory board for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm. JD received consulting fees and/or speaker honoraria from Amgen, AstraZeneca, Bayer, BMS, Eisai, Need Inc., Ipsen, Lilly, MediMix, Merck, MSD, Novartis, Roche and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive disease with increasing incidence and its genetic alterations could be the target of systemic therapies., Aims: To elucidate if radiomics extracted from computed tomography (CT) may non-invasively predict ICC genetic alterations., Methods: All consecutive patients with a diagnosis of a mass-forming ICC (01/2016-06/2022) were considered. Inclusion criteria were availability of a high-quality contrast-enhanced CT and molecular profiling by NGS or FISH for FGFR2 fusion/rearrangement. The CT scan at diagnosis was considered. Genetic analyses were performed on surgical specimens (resectable patients) or biopsies (unresectable ones). The radiomic features were extracted using the LifeX software. Multivariate predictive models of the commonest genetic alterations were built., Results: In the 90 enrolled patients (58 NGS/32 FISH, median age 65 years), the most common genetic alterations were FGFR2 (20/90), IDH1 (10/58), and KRAS (9/58). At internal validation, the combined clinical-radiomic models achieved the best performance for the prediction of FGFR2 (AUC = 0.892) and IDH1 status (AUC = 0.819), outperforming the pure clinical and radiomic models. The radiomic model for predicting KRAS mutations achieved an AUC = 0.767 (vs. 0.660 of the clinical model) without further improvements with the addition of clinical features., Conclusions: CT-based radiomics provides a reliable non-invasive prediction of ICC genetic status with a major impact on therapeutic strategies., Competing Interests: Declaration of competing interest LV reports speaker's honoraria from Johnson & Johnson. LR received consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Merck Serono, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Lorenza Rimassa consults for, is on the speakers’ bureau for, and received grants from AstraZeneca, Eisai, Incyte, Ipsen, Roche, and Servier. She consults for and is on the speakers’ bureau for Bayer and BMS. She consults for and received grants from Exelixis, MSD, Nerviano Medical Sciences, and Zymeworks. She consults for Basilea, Elevar Therapeutics, Genenta, Hengrui, IQVIA, Jazz Pharmaceuticals, and Taiho Oncology. She is on the speakers’ bureau for Merck Serono. She received grants from Agios, BeiGene, Fibrogen, and Lilly. The remaining authors have no conflicts to report.

Background: With the increasing of novel therapeutics for the treatment of Biliary Tract Cancers (BTC), and the need to assess their socio-economic impacts for national licence approvals, it is as important as ever to have real-life data in national populations., Methods and Results: We performed an audit of the first 2 year-activity (Sep 2019-Sep 2021) of the centralized West-of-Scotland-BTC clinic. 122 patients accessed the service, including 68% with cholangiocarcinoma (CCA), 27% with gallbladder cancer (GBC), and 5% with ampulla of Vater carcinoma with biliary phenotype (AVC). Median age at diagnosis was 66 (28-84), with 30% of newly diagnosed patients being younger than 60 years-old. Thirty-five cases (29%) underwent surgery, followed by adjuvant-chemotherapy in 66%. 60% had recurrent disease (80% with distant relapse). Sixty-four patients (58%) started first-line Systemic-AntiCancer-Treatment (SACT). Of these, 37% received second line SACT, the majority of which had iCCA and GBC. Thirty-% of those who progressed received third line SACT., Conclusions: About 30% of BTC were eligible for curative surgery. Fifty-eight and twenty% of the overall cohort of advanced BTC patients received first and second line SACT. Our data suggest that reflex genomic profiling may not be cost-effective until molecularly driven strategies are limited to second line setting., (© 2024. The Author(s).)

Background: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC)., Objective: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting., Patients and Methods: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis., Results: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab., Conclusion: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)