Advances in medical treatment of advanced hepatobiliary and pancreatic cancer in 2022

Zhang, Le; Liu, Rui; Deng, Ting; Ba, Yi

doi:10.1002/cai2.60

Cited by 2 publications

(1 citation statement)

References 78 publications

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“…Indeed, precision medicine approaches in cholangiocarcinoma have rapidly expanded in recent years, and pharmacological targeting of FGFR2 fusions ( Goyal et al, 2023 ), IDH1 neomorphic mutants ( Zhu et al, 2021 ), and mutations in kinases including BRAF, HER2 (ERBB2) and NTRK ( Doebele et al, 2020 ; Javle et al, 2021 ; Subbiah et al, 2020 ) have shown clinical promise. Moreover, although initial results with immunotherapy in cholangiocarcinoma were disappointing ( Piha-Paul et al, 2020 ), the combination of immunotherapy with chemotherapy or targeted therapy is showing increased clinical potential ( Oh et al, 2022 ; Zhang et al, 2023 ).…”

Section: Activation Of Notch Signalling As a Driver Of Cholangiocarci...mentioning

confidence: 99%

NOTCH signalling – a core regulator of bile duct disease?

Martinez Lyons,

Boulter

2023

Disease Models &Amp; Mechanisms

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The Notch signalling pathway is an evolutionarily conserved mechanism of cell–cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.

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Section: Activation Of Notch Signalling As a Driver Of Cholangiocarci...mentioning

confidence: 99%

NOTCH signalling – a core regulator of bile duct disease?

Martinez Lyons,

Boulter

2023

Disease Models &Amp; Mechanisms

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Population Pharmacokinetics and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer

Abegesah,

Oh,

Lim

et al. 2024

Preprint

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Purpose: Durvalumab in combination with gemcitabine/cisplatin has shown a favorable benefit-risk profile in the TOPAZ-1 study for advanced biliary tract cancers (BTC). This analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response for efficacy and safety (ERES) of TOPAZ-1. Methods: The PopPK model for durvalumab was updated using data from 5 previously analysed studies and TOPAZ-1. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for exposure-response (ER) analysis related to efficacy and safety. Results: Consistent with previous analyses, the durvalumab pharmacokinetics in BTC followed a 2-compartment model with time-dependent clearance. The final population parameters were: CL, 0.298 L/day; V1, 3.42 L; V2, 1.99 L; Q, 0.452 L/day; and the time dependent clearance suggests that the clearance could decrease up to 39% over the time course of treatment. There were 111 patients (3.53%) with treatment-emergent ADA positive in the pooled group of 6 studies, and the exposure was comparable for ADA positive and negative patients. Covariates had minimal clinical impact on PopPK parameters. No significant associations were found between exposure and overall survival (OS), progression-free survival (PFS), using Cox proportional analysis (CPH). Logistic regression analysis indicated no significant relationship between the exposure and relevant adverse events measures of Grade 3 and higher treatment-related AE, Grade 3 and higher treatment-related AESI (AEs of special interest), or AE leading to treatment discontinuation. Conclusions: No dose adjustment for durvalumab is needed based on PopPK and ERES analyses. The analysis supports the TOPAZ-1 regimen for patients with advanced BTC.

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Advances in medical treatment of advanced hepatobiliary and pancreatic cancer in 2022

Cited by 2 publications

References 78 publications

NOTCH signalling – a core regulator of bile duct disease?

NOTCH signalling – a core regulator of bile duct disease?

Population Pharmacokinetics and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer

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