AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review

Hsu, Chih‐Hung; Huang, Yi Hsiang; Lin, Shi‐Ming; Hsu, Chiun

doi:10.1159/000520501

Cited by 16 publications

(12 citation statements)

References 94 publications

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“…Overexpression of MET is seen with sorafenib treatment, suggesting that increased activation of the MET pathway contributes to sorafenib treatment resistance in patients with HCC 11,12 . Cabozantinib is a multiple RTK inhibitor targeting RTKs implicated in tumor growth, metastasis, and angiogenesis, including MET, vascular endothelial growth factor receptor 2, RET, AXL, KIT, and TIE‐2 10,13 . The pivotal phase III CELESTIAL study enrolled more than 700 patients with advanced HCC previously treated with sorafenib across 19 countries 14 .…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Cabozantinib is a multiple RTK inhibitor targeting RTKs implicated in tumor growth, metastasis, and angiogenesis, including MET, vascular endothelial growth factor receptor 2, RET, AXL, KIT, and TIE-2. 10,13 The pivotal phase III CE-LESTIAL study enrolled more than 700 patients with advanced HCC previously treated with sorafenib across 19 countries. 14 CELESTIAL results indicated a significant survival benefit with cabozantinib versus placebo in patients with advanced HCC, with a 24% reduction in the relative risk of death.…”

Section: Introductionmentioning

confidence: 99%

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Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study

Kato

Kudo

Tsuchiya

et al. 2023

Hepatology Research

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Aim Cabozantinib showed a favorable benefit–risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open‐label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. Methods Patients with previously treated, advanced HCC received cabozantinib 60 mg/day. Progression‐free survival (PFS) and tumor response rates in prior‐sorafenib and sorafenib‐naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin–bilirubin (ALBI) score. Results Median cabozantinib exposure was 5.6 months. In the prior‐sorafenib cohort (n = 20), median PFS was 7.4 months per IRC assessment and 5.6 months per investigator assessment. In the sorafenib‐naïve cohort (n = 14), median PFS was 3.6 and 4.4 months per IRC and investigator assessment, respectively. Six‐month PFS rate per IRC and investigator assessment in the prior‐sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib‐naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior‐sorafenib cohort and 64.3% in the sorafenib‐naïve cohort. Median overall survival (Kaplan–Meier estimate) was 19.3 and 9.9 months in the prior‐sorafenib and sorafenib‐naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar–plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. Conclusions Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study

Kato

Kudo

Tsuchiya

et al. 2023

Hepatology Research

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“…Third, the presence or absence of an interaction between cabozantinib and RT could not be ensured before the study; therefore, the current study did not explore the possible mechanism. However, the lines of evidence provide the rationale for radiosensitization with cabozantinib for RT [ 11 , 15 , 30 , 32 , 52 , 53 ]. Further studies to detect the possible mechanism in vivo and in vitro are warranted in the future.…”

Section: Discussionmentioning

confidence: 99%

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats

Huang

Hsieh

Wang

et al. 2023

IJMS

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The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT–drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH2PO4)–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f’x and RT9Gy×3 f’x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f’x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×3 f’x group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT2Gy×3 f’x in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT9Gy×3 f’x sequential regimen. Compared to the RT9Gy×3 f’x concurrent regimen, the RT9Gy×3 f’x sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT9Gy×3 f’x is more significant with the sequential regimen than with the concurrent regimen.

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“…Furthermore, inhibition of MET and AXL helps overcome resistance to agents that target the VEGF receptor pathway. 7 The CELESTIAL phase 3 trial demonstrated a significant survival benefit with cabozantinib versus placebo in patients previously treated with sorafenib. 6 However, sorafenib is no longer recommended as the first-line chemotherapy and the effectiveness of cabozantinib in different situations that occur frequently in real-world practice has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of cabozantinib treatment in advanced hepatocellular carcinoma

Nouso,

Shiota,

Fujita

et al. 2023

Liver Cancer International

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Background and AimCabozantinib is a molecular targeted agent (MTA) used for treatment of advanced hepatocellular carcinoma (HCC). Although its superiority over placebo has been proven, its effectiveness and risk factors in real‐world practice are needed to be elucidated.MethodsThis study retrospectively enrolled 54 advanced HCC patients, who were treated with cabozantinib. The effectiveness of cabozantinib, adverse events (AE) and risk factors for survival was analysed.ResultsMajority of the patients (88.9%) were treated with two or more MTAs before starting cabozantinib and atezolizumab plus bevacizumab was the most prevalent MTA used (59.3%). The median overall survival and progression‐free survival (PFS) were 6.9 and 4.4 months, respectively. The objective response rate and disease control rate were 3.7% and 40.7%, respectively. Grade 3/4 AE occurred in 37.0% of the patients; however, unpredictable AE was not observed. Multivariate analysis revealed that high neutrophil–lymphocyte ratio (NLR, >4) was a risk factor for survival (hazard ratio for death, 2.35; 95% confidence interval [CI], 1.41–4.82; p = 0.020). Moreover, the occurrence of Grade 3/4 AE was a negative risk factor for both survival (hazard ratio for death, 0.36; 95% CI, 0.16–0.83; p = 0.016) and PFS (hazard ratio for disease progression or death, 0.33; 95% CI, 0.15–0.73; p = 0.006). Neither preceding therapy with atezolizumab/bevacizumab nor a reduced starting dose correlated with patient survival.ConclusionsCabozantinib can be used safely in real‐world practice. The study identified high NLR as a positive risk factor and the occurrence of Grade 3/4 AE as a negative risk factor for survival.

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AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review

Cited by 16 publications

References 94 publications

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats

Characteristics of cabozantinib treatment in advanced hepatocellular carcinoma

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