Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics—next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFS_targeted/PFS_{pre-chemotherapy}) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7–29.3) vs. 17.5 months (95% CI 1.7–19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.

Biliary tract cancers (BTCs) exhibit high mortality rates and significant heterogeneity in both clinical and molecular characteristics. This study aims to molecularly characterize a cohort of patients with BTC, with a specific focus on genomic alterations within homologous recombination repair (HRR) genes in a real-world setting. We carried out a retrospective analysis on 256 patients with BTC treated at five Austrian centers and one German comprehensive cancer center between 2016 and 2023 utilizing comprehensive genomic profiling platforms to assess HRR status and its correlation with clinical outcomes after platinum-based chemotherapy. A total of 67 patients (27.5%) exhibited HRR gene mutations (HRRm), with the most common pathogenic alterations in BAP1 (9%), ARID1A (7.8%), and ATM (6.1%). Time to failure of the first-line strategy (TFS) between patients with HRRm and non-HRRm treated with platinum agents was 7.9 and 6.7 months, respectively [hazard ratio (HR) 0.89; P = 0.49]. The overall survival (OS) estimates at 6, 18, and 24 months were 82%, 45%, and 39% in the HRRm group (median 16.01 months) and 81%, 42%, and 22% in the HRR group (median 15.68 months), respectively (Fleming-Harrington test P = 0.0004; log-rank P = 0.022). Significance did not persist in the multivariate analysis (HR 0.72; 95% confidence interval 0.489-1.059; P = 0.095). An interaction between HRRm status and molecular-informed therapeutic strategies in later lines was noted. In the second-line treatment, OS following an irinotecan-based regimen was comparable to re-exposure to platinum-based agents (12.36 versus 10.13 months; HR 0.92; P = 0.85). No better outcome was noted for patients with HRRm versus patients with non-HRRm with second-line platinum agents (HR 1.45; P = 0.35). Patients with HRRm with BTC showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable coalterations. Further investigation is needed to outline HRR within the scope of BTCs and detail a clinically meaningful sensitivity to platinum agents or targeted approaches with poly (ADP-ribose) polymerase (PARP) inhibitors.

Introduction This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes. Methods A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies. Results Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052). Conclusion This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.

MGEC is associated with poor overall survival (OS) of approximately 4–10 months. CtDNA is emerging as a promising prognostic biomarker with high potential for early relapse detection. However, until now, there was little knowledge on serial ctDNA detection and its impact on early treatment evaluation and prognosis in mGEC. Methods: ctDNA detection (ddPCR) was carried out serially in 37 matched tissue (NGS) patients with mGEC prior to systemic treatment initiation and every two weeks thereafter until restaging (n = 173 samples). The results have been correlated with response to treatment (restaging CT), overall survival (OS), and progression-free survival (PFS). Results: The pretherapeutic detection rate was 77.8%. Response to treatment assessment was correct in 54.2% (pretherapeutically pos./neg.) and 85.7% (dynamics at week 4). Moreover, a decline in ctDNA (MAF in %) below 57.1% of the pretherapeutic value after 2 weeks of systemic treatment was accompanied by a sensitivity of 57.1% and a specificity of 90% (AUC = 0.73) for correct restaging assessment (response evaluation by CT after 3 months) evaluating 76.5% of patients correctly after only 2 weeks. In contrast to mere pretherapeutic ctDNA positivity (p = 0.445), a decline in ctDNA dynamics to under 57.1% of its initial value was significantly associated with OS (4.1 (95% Cl 2.1–6.1) vs. 13.6 (95% CI 10.4–16.6) months, p < 0.001) and PFS (3.2 (1.9–4.5) vs. 9.5 (95% CI 5.5–13.5) months, p = 0.001) after two weeks of treatment. Additionally, the change in detectability from positive pretherapeutic levels to negative during treatment was associated with similar survival as for patients who were always regarded as ctDNA-negative (9.5 (95%Cl 0.4–18.5) vs. 9.6 (95%Cl 1.3–17.9)). The absence of becoming undetectable was associated with worse survival (4.7 months). Conclusions: ctDNA is a promising additional biomarker allowing for early evaluation of response to treatment and saving unevaluated treatment time for patients with mGEC, and could allow for an early change in treatment with anticipated prognostic benefit in the future.

NALIRIFOX, a triplet chemotherapy regimen combining nanoliposomal irinotecan, 5-fluorouracil/leucovorin, and oxaliplatin, demonstrated superior survival outcomes versus gemcitabine plus nab-paclitaxel in the NAPOLI 3 trial for metastatic pancreatic ductal adenocarcinoma (mPDAC). However, its performance in routine clinical practice remains underexplored. This multicenter retrospective study evaluated the real-world efficacy and safety of NALIRIFOX as first-line treatment in 80 patients with mPDAC. Primary endpoints were time to failure of strategy (TFS) and overall survival (OS). Secondary endpoints included treatment-related toxicity, disease control rate (DCR), and molecular subgroup analyses based on homologous recombination repair mutations (HRRm) and KRAS status. Median TFS and OS were 5.66 and 11.15 months, respectively, with improved outcomes (TFS 6.05 months; OS 12.92 months) in patients meeting strict NAPOLI 3 inclusion criteria. DCR was 57.5%, and grade 3-4 toxicities occurred in 22.5% of patients-lower than reported in randomized trials. HRRm patients (20%) achieved significantly prolonged TFS (7.96 versus 5.23 months, P = 0.049) and OS (16.24 versus 11.11 months, P = 0.043). KRAS G12D/V mutations were associated with worse OS (11.15 months versus not reached, P < 0.05), but not TFS. This first real-world analysis of NALIRIFOX confirms its clinical effectiveness and manageable toxicity in an unselected patient population. The favorable outcomes in HRRm subgroups and the prognostic impact of KRAS variants underscore the need for molecular stratification in guiding first-line therapy for mPDAC.

Biliary tract cancers (BTCs) are a diverse group of malignancies with varied genetic backgrounds. The prevalence of intrahepatic cholangiocarcinoma (iCC) is increasing, particularly in Western countries. Despite advancements in treatments, the prognosis for BTC remains poor. Recent molecular profiling has revealed that up to 40% of iCC cases have targetable genetic alterations. MET amplification, although rare, presents a significant target for therapy. A 25-year-old female with a history of ulcerative colitis presented with shoulder pain and a positron emission tomography–computed tomography (PET–CT) scan revealed an enlarged liver and multiple metastases. Histopathological analysis diagnosed poorly differentiated adenocarcinoma. First-line therapy with Cisplatin, Gemcitabine, and Durvalumab resulted in disease progression. Molecular profiling identified a TP53 mutation and MET amplification. Based on these findings, Tepotinib was initiated. Tepotinib treatment led to a significant reduction in tumor size and normalization of CA 19-9 levels within 2 months, achieving a complete metabolic remission lasting up to 17 months. The treatment was well tolerated with minimal side effects. MET-amplified BTCs are exceedingly rare, and evidence for targeted treatment is limited. This case demonstrates the efficacy of Tepotinib in a young patient with MET-amplified iCC, showing a long-term response and suggesting a potential new standard treatment option for this molecularly defined entity. This case also highlights the aggressive nature of MET-amplified tumors and the need for targeted second-line therapies. Tepotinib showed remarkable efficacy in treating MET-amplified intrahepatic cholangiocarcinoma, underscoring the importance of molecular profiling in BTCs and suggesting a potential new therapeutic approach for this rare cancer subtype.