The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

Shroff, Rachna T.; Yarchoan, Mark; O’Connor, Ashley; Gallagher, Denise; Zahurak, Marianna; Rosner, Gary L.; Ohaji, Chimela; Sartorius-Mergenthaler, Susan; Subbiah, Vivek; Zinner, Ralph; Azad, Nilofer S.

doi:10.1038/bjc.2017.119

Cited by 57 publications

(38 citation statements)

References 36 publications

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“…In an open‐label, single‐arm study, combination therapy with oral vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib and trametinib, reported modest clinical activity with signs of possible cumulative toxicity in patients with advanced cholangiocarcinoma. The study did not achieve statistically significant improvement in 4‐month PFS over the prespecified null hypothesized 4‐month PFS ( P = .063) . Although the aforementioned phase II trials present some scientific evidence, adequately powered trials are needed to identify the most suitable regimen and patient population who may benefit from such treatment.…”

Section: Discussionsupporting

confidence: 82%

“…The study did not achieve statistically significant improvement in 4-month PFS over the prespecified null hypothesized 4-month PFS (P = .063). 27 Although the aforementioned phase II trials present some scientific evidence, adequately powered trials are needed to identify the most suitable regimen and patient population who may benefit from such treatment.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

et al. 2017

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Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK1/MEK2. In this phase IIa open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐PD rate. Secondary assessments included safety, progression‐free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss‐of‐function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

et al. 2017

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“…In the recent decades, pathway-targeted therapies made a rapid progress in solid tumors [49,50]. Previous studies found that approximately 30%~40% of ICC patients exhibited actionable mutations, such as epidermal growth factor receptor (EGFR), and fibroblast growth factor receptor (FGFR) which shed light on the molecular targeted therapies on ICC [51,52].…”

Section: Assessment Of Outcomementioning

confidence: 99%

The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: A systematic review and meta-analysis

Lin

Deng

et al. 2020

PLoS ONE

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Backgroud Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. However, the benefit of adjuvant therapy (AT) remains controversial, although it has been conducted prevalently. Hence, a meta-analysis was warranted to evaluate the effect of AT for patients with ICC after resection. Patients and methods PubMed, MedLine, Embase, the Cochrane Library, Web of Science were used to identify potentially eligible studies from Jan.1 st 1990 to Aug. 31 st 2019, investigating the effect of AT for patients with ICC after resection. Primary endpoint was overall survival (OS), and secondary endpoints was recurrence-free survival (RFS). Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size. Results 22 studies with 10181 patients were enrolled in this meta-analysis, including 832 patients in the chemotherapy group, 309 patients in the transarterial chemoembolization (TACE) group, 1192 patients in the radiotherapy group, 235 patients in the chemoradiotherapy group, and 6424 patients in the non-AT group. The pooled HR for the OS rate and RFS rate in the AT group were 0.63 (95%CI 0.52~0.74), 0.74 (95%CI 0.58~0.90), compared with the non-AT group. Subgroup analysis showed that the pooled HR for the OS rate in the AT group compared with non-AT group were as follows: chemotherapy group was 0.57 (95%CI = 0.44~0.70), TACE group was 0.56 (95%CI = 0.31~0.82), radiotherapy group was 0.71 (95%CI = 0.39~1.03), chemoradiotherapy group was 0.73 (95%CI = 0.57~0.89),

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“…Additionally, a trial has been designed that combines a PD-1 antibody, a tyrosine kinase inhibitor (TKI, lenvatinib) and GEMOX for the treatment of ICCs (NCT0395197). All studies accessing the therapeutic e cacies of TKIs (including the multitarget TKIs cabozantinib 30 , vandetanib 31 , sorafenib 32 ; the panErbB family receptor TKI afatinib 33 ; the VEGF family receptor TKI cediranib 34 ; and the combination of pazopanib and trametinib 35 ) failed to show survival improvements. The use of checkpoint inhibitor and TKIs in combination may bring hope to patients with ICC.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

Wang

Zhu²,

Zhao³

et al. 2020

Preprint

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PURPOSE: The genomic alterations of intrahepatic cholangiocarcinoma (ICC) in the Chinese population have not been fully revealed. Molecular profiling may provide a reference for clinical management, especially targeted therapy. METHODS: A retrospective study was conducted in 122 ICC patients. All patients have been performed next-generation sequencing (NGS) assays that analyzed 417 cancer-associated genes. The genetic characteristics, clinical management and therapeutic responses were analyzed. RESULTS: The most commonly mutated genes were TP53 (34%), KRAS (25%) and ARID1A (17%). Targeted agents were used referring to molecular profiling, in combination with chemotherapy. Twenty-two patients with wild-type KRAS/NRAS/BRAF were treated with cetuximab. The disease control and response rates were 78% and 47%, respectively, which were higher than those achieved with chemotherapy alone (72% and 11%, P=0.16). Fifty-four patients underwent anti-VEGF treatment with bevacizumab. The disease control and response rates were 85% and 60%, respectively. Better therapeutic efficiency (P=0.001) and longer progression-free survival (PFS) were observed in the bevacizumab-treated group compared to chemotherapy alone group (15.4 and 6.7 months, respectively; P=0.04) . The PFS of ten patients who underwent hepatectomy after combined treatment with chemotherapy and bevacizumab was longer than that of 139 patients who underwent surgical treatment (28.9 vs 18.0 months, P=0.03). Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. CONCLUSIONS: This study provides an overview of genetic alterations in Chinese ICC patients and indicates the potential clinical implications for NGS-based personalized therapies.

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The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

Cited by 57 publications

References 36 publications

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: A systematic review and meta-analysis

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

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