Exposure–response relationship of regorafenib efficacy in patients with hepatocellular carcinoma

Solms, Alexander; Reinecke, Isabel; Fiala-Buskies, Sabine; Keunecke, Anne; Drenth, Henk‐Jan; Bruix, Jordi; Meinhardt, Gerold; Cleton, Adriaan; Ploeger, Bart

doi:10.1016/j.ejps.2017.05.050

Cited by 19 publications

(8 citation statements)

References 18 publications

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“…7 In a exposure-response analysis in patients with hepatocellular carcinoma a trend, although not significant, towards a shorter overall FIGURE 1 Kaplan-Meier progression free survival analysis after gastric surgery survival in the low exposure group was seen when compared to the patients with a medium or high exposure. 26,27 In our subanalysis, the sum exposure to regorafenib and its pharmacological active metabolites in the total gastrectomy group was slightly lower compared to the no or nonsignificant gastrectomy group. On the contrary, the exposure in the partial gastrectomy group was higher than the exposure in the no or nonsignificant gastrectomy group.…”

Section: Discussionmentioning

confidence: 64%

The effect of gastrectomy on regorafenib exposure and progression‐free survival in patients with advanced gastrointestinal stromal tumours

Lubberman

Graaf²,

et al. 2019

Brit J Clinical Pharma

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We investigated whether major gastrectomy influences the plasma exposure of regorafenib and treatment outcome. Methods: Efficacy and pharmacokinetic data from 133 gastrointestinal stromal tumour patients included in a phase III trial were analysed. Patients were subdivided into 2 groups according to the extent of the gastrectomy (no/nonsignificant gastrectomy and major gastrectomy). Progression-free survival (PFS) on regorafenib was measured and regorafenib and its pharmacological active metabolites plasma exposure were measured. Results: A total of 133 patient were included, of whom 27 underwent major gastrectomy. In patients with no/nonsignificant gastrectomy the median PFS was 145 (interquartile range 43-281) days. The PFS in patients with a major gastrectomy was 172 (interquartile range 57-280) days. Regorafenib pharmacokinetic samples were collected in 80 patients of which 19 patients with a major gastrectomy and 61 patients with no/nonsignificant gastric surgery. The average ± standard deviation total concentration of regorafenib including the metabolites M-2 and M-5 was 6.9 ± 1.53 μmol/L and 6.7 ± 1.56 μmol/L in patient with major gastrectomy and no/nonsignificant gastrectomy respectively. Conclusion: Our study shows that major gastrectomy did not influence plasma exposure of regorafenib and metabolites. In addition, no difference in PFS between the subgroups was seen.

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Section: Discussionmentioning

confidence: 64%

The effect of gastrectomy on regorafenib exposure and progression‐free survival in patients with advanced gastrointestinal stromal tumours

Lubberman

Graaf²,

et al. 2019

Brit J Clinical Pharma

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“…The fact that in our study the combination of sorafenib + pravastatin increased the TTP in three months compared to a previous Phase III clinical trial including Child-Pugh A patients with advanced HCC [23] could be related to characteristics of the patients of our cohort, since our study population was five years younger (median age). In fact, higher age was previously associated with shorter TTP for regorafenib treatment in aHCC [27], although it should be noted that neither Child B patients nor those with extrahepatic metastases were included in this trial, as were included in our study. These data on TTP and OS, together with the evidence of multiple retrospective studies indicating the preventive effect of statins on cancer development and several clinical trials reporting positive results in OS with pravastatin treatment [20][21][22], prompt us to hypothesize that the therapeutic effects of statins could be more evident in preventing HCC development (i.e., in cirrhosis and/or after early HCC tumor resection) and/or treatment of earlier stages of carcinogenesis, rather than in the treatment of aHCC.…”

Section: Discussionmentioning

confidence: 95%

Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial)

Riaño

Martin

Varela

et al. 2020

Cancers

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Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced hepatocellular carcinoma (aHCC). A total of 31 patients were randomized. Median OS did not differ between both groups (12.4 months for the sorafenib + pravastatin group vs. 11.6 months for the control group). Of note, however, the radiological TTP was higher in patients treated with sorafenib + pravastatin than in the control group (9.9 months vs. 3.2 months; p = 0.008). Considering all the study population, the presence of portal vein thrombosis (PVT) was associated with worse OS, being lower in patients with PVT compared to patients without PVT (6.3 months vs. 14.8 months; p = 0.026). Data also showed a decrease in OS in patients with vascular invasion (VI) compared to patients who did not present it (6.3 months vs. 14.8 months; p = 0.041). The group of patients without dermatological events (DE) showed lower OS (6.9 months vs. 14.5 months; p = 0.049). In conclusion, combination of sorafenib + pravastatin was safe and well-tolerated, prolonging the TTP of patients with aHCC but not improving the OS compared to sorafenib + placebo. The absence of PVT and VI and the development of DE are positive prognostic factors of sorafenib response.

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“…As regorafenib resembles the structure and mechanism of action of sorafenib, an exposure–response relationship could be suspected for regorafenib as well. In a secondary analysis of the phase III RESORCE trial in patients with HCC, median overall survival and time‐to‐progression tended to be longer in patients with higher regorafenib exposure during the first treatment cycle; however, after correction for several covariates, it did not reach statistical significance . To our knowledge, this trial is the only available evidence on a possible exposure – response relationship for regorafenib; therefore, more research is necessary on this point.…”

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confidence: 87%

Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study

Man

Hussaarts

Hoop

et al. 2019

Clin Pharma and Therapeutics

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Regorafenib exposure could potentially be influenced by an interaction with acid‐reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference ( RD ) in geometric means for regorafenib 0–24‐hour area under the concentration‐time curve ( AUC 0–24h ) and was analyzed by a linear mixed model in 14 patients. AUC 0–24h for regorafenib alone was 55.9 μg·hour/mL (coefficient of variance ( CV ): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC 0–24h was 53.7 μg·hour/mL ( CV : 34%) and 53.6 μg·hour/mL ( CV : 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole ( RD : −3.9%; 95% confidence interval ( CI ): −20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior ( RD : −4.1%; 95% CI : −22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice.

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Exposure–response relationship of regorafenib efficacy in patients with hepatocellular carcinoma

Cited by 19 publications

References 18 publications

The effect of gastrectomy on regorafenib exposure and progression‐free survival in patients with advanced gastrointestinal stromal tumours

The effect of gastrectomy on regorafenib exposure and progression‐free survival in patients with advanced gastrointestinal stromal tumours

Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial)

Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study

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