Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials.

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Background: CDK7 inhibition is a promising therapeutic strategy in cancer; acting as a regulator of the cell cycle, transcription and endocrine receptor signalling [1]. Patients with HR+BC post CDK4/6 inhibitor treatment have a poor prognosis; median progression free survival (mPFS) of ~ 8 weeks for fulvestrant post CDK4/6i in HR+BC [2,3]. Pre-clinical HR+BC models indicate the potential for synergy when the CDK7 inhibitor samuraciclib is combined with the Selective Estrogen Receptor Degrader fulvestrant [4]Materials and Methods: This single arm cohort assessed the tolerability and efficacy of samuraciclib in combination with standard dose fulvestrant in patients with advanced HR+BC; all patients had previously received an aromatase inhibitor and a CDK4/6i for advanced disease.Results: 31 patients with HR+BC received the combination of standard dose with fulvestrant and samuraciclib. 6 patients received samuraciclib dose of 240mg once daily (QD) and 25 patients a dose of 360mg QD. The combination treatment was generally well tolerated, with adverse drug reactions (AE) of note being G1-2 nausea, vomiting and diarrhoea; the majority of patients staying on treatment until disease progression.RECIST evaluation indicates evidence of reduction in tumor disease burden, including a partial response in one patient who has been on treatment for ~ 1 year.Graphic illustrations of data, including ‘waterfall’ and ‘swimmer’ plots, will be presented along with stratification data based on demographic factors such as hepatic involvement and cfDNA analysis (ESR1m, PI3Km).Conclusions: Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity in combination with fulvestrant for patients with advanced HR+BC who have progressed on their prior CDK4/6i.References:1.Patel et al., Mol Cancer Therap. 20182.Juric et al., SABCS 20183.Lindeman et al., JCO 20214.Jeselsohn et al., SABCS 2019 Citation Format: Charles Coombes, Sasha J Howell, Matthew G Krebs, Simon Lord, Laura M Kenny, Ash Bahl, Glen Clack, Edward Ainscow, Paul A Dickinson, Raluca Fostea, Janine Mansi, Carlo Palmieri, Gianflippo Bertelli, Rinath Jeselsohn, Zahi Mitri, William J Gradishar, Sagar Sardesai, Joyce O'Shaughnessy, Patrick Ward, Pavani Chalasani, Manfred Lehnert, Simak Ali, Stuart McIntosh. Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-10.

Trifluridine/tipiracil is a compound drug, approved in 2015 by the Food and Drug Administration, and in 2016 by the European Medicines Agency, for the treatment of chemorefractory metastatic colorectal cancers, after the phase 3 RECOURSE trial demonstrated significant benefit. Another phase 3 trial (TAGS) showed significant improvement of overall survival and progression-free survival in refractory gastric cancer and gastroesophageal junction cancer, leading to further approval from the FDA on February 2019, followed by Japan in August 2019 and the European Union in September 2019. As promising results have already been observed in the chemorefractory gastric and gastroesophageal-junction cancers, ongoing trials are assessing the use of trifluridine/tipiracil with other standard of care agents, aiming to further improve the survival rate of these patients.