Experience with regorafenib in the treatment of hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Granito A
PROVIDER: S-EPMC8165525 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background/aimsSeveral treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients.MethodsConsecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias.ResultsAmong 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0-10.8) months for regorafenib and 5.9 (95% CI, 3.7-8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30-0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51-1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04).ConclusionAfter sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.
| S-EPMC7364358 | biostudies-literature
Project description:PurposeMultikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined.MethodsCell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot.ResultsAfter regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor.ConclusionsRemoval of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
| S-EPMC3836575 | biostudies-literature
Project description:Background and aimsHepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths. Patients with advanced HCC are treated with sorafenib. A recent randomized controlled trial demonstrated a survival benefit for regorafenib treatment in patients with advanced HCC who had progressed on sorafenib. We aimed to evaluate the cost-effectiveness of this approach.MethodsTo evaluate the cost effectiveness of regorafenib, we used a Markov model that incorporates health outcomes, measured by life-years and quality-adjusted life-years (QALYs). Drug costs were based on 2017 discounted prices. Model robustness was validated by probabilistic sensitivity analyses using Monte Carlo simulations.ResultsThe use of regorafenib results in a gain of 19.76 weeks of life (0.38 Life Years) as compared to placebo. When adjusted for quality of life, using regorafenib produced a gain of 0.25 quality adjusted life years (QALYs). The incremental cost-effectiveness ratio for regorafenib compared with best supportive care was between $201,797 and $268,506 per QALY.ConclusionThe modest incremental benefit at a relatively high incremental cost of regorafenib treatment suggests that it is not cost-effective at commonly accepted willingness to pay thresholds.
| S-EPMC6224101 | biostudies-literature
Project description:Over the past ten years, sorafenib, a multikinase inhibitor, has been the only systemic agent approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Whereas only recently lenvatinib was shown to be noninferior to sorafenib, in terms of survival, all other agents previously tested failed to prove noninferiority (or superiority) when compared with sorafenib. Similarly, in a second-line setting, most investigational drugs have failed to provide better survival outcomes than placebo. However, in 2016, data from the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Overall, side-effects were in line with the known safety profile of regorafenib. More recently, the survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with cabozantinib in the frame of the phase 3 CELESTIAL trial. As HCC seems to be an attractive target for immunotherapy, a phase 1/2 trial reported promising efficacy signals from nivolumab, and results of a larger phase 3 trial with another checkpoint inhibitor, namely, pembrolizumab, are still pending. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and immunotherapy that will likely change the treatment scenario of HCC.
| S-EPMC6038776 | biostudies-literature
Project description:Background: Regorafenib is a second-line therapy drug used for advanced hepatocellular carcinoma (HCC). Unfortunately, the survival benefit of the patients receiving this treatment is modest, which may be attributed to drug resistance. In the present study, sphingosine kinase 2 (SphK2) was targeted to reverse regorafenib resistance in HCC. Methods: The functions of SphK2 and sphingosine-1-phosphate (S1P), the catalytic product of SphK2 in regorafenib resistance of HCC cells, were evaluated by cell counting kit-8 assay, colony formation, cell cycle evaluation, and annexin V-fluorescein isothiocyanate/propidium iodide double-staining assay. The antitumor activity of combined treatment of regorafenib and the SphK2-specific inhibitor ABC294640 was examined in HCC cells in vitro and xenograft model in vivo. The molecular mechanisms of SphK2/S1P-mediating regorafenib resistance were investigated using cell line establishment and Western blot analysis. Results: Well-developed regorafenib-resistant HCC cells indicated high expression levels of SphK2. The sensitivity to regorafenib of regorafenib-resistant HCC cells was restored following SphK2 knockdown or pharmacological inhibition by ABC294640. In addition, ectopic expression of SphK2 and exogenous addition of S1P decreased the sensitivity of HCC cells to regorafenib. Furthermore, the combination treatment with ABC294640 sensitized resistant tumor to regorafenib in xenograft model of HCC. The phosphorylation levels of nuclear factor κB (NF-κB), as well as those of signal transducer and activator of transcription 3 (STAT3), were positively associated with SphK2 and S1P. Conclusions: SphK2/S1P mediates regorafenib resistance of HCC through NF-κB and STAT3 activation. Targeting SphK2 by ABC294640 potently reduces regorafenib resistance of HCC cells both in vitro and in vivo. The combination of ABC294640 and regorafenib could be developed as a novel potential treatment strategy for advanced HCC.
| S-EPMC7327090 | biostudies-literature
Project description:BackgroundNo trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC).ObjectivesConduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib.MethodsThe CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared.ResultsIn the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9-17.0] versus 10.6 [9.1-12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9-7.3] versus 3.1 [2.8-4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib (p ≤ 0.001).ConclusionsCabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.
| S-EPMC7467441 | biostudies-literature
Project description:Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC.
| S-EPMC5036543 | biostudies-literature
Project description:Low-dose regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR antibody) but produced higher T cell activation and M1 macrophage polarization, Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148947 | GEO
Project description:Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.
| S-EPMC8595883 | biostudies-literature
Project description:Purpose: This regulatory post-marketing surveillance (PMS) study was performed to evaluate the safety and effectiveness of regorafenib on Korean patients with colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC) in a real-world clinical setting. Methods: This PMS was conducted as a multi-center, prospective, observational study at 34 centers in Korea from August 2013 to August 2019. The primary objective was to evaluate the safety of regorafenib in real-world practice, with the secondary objective to investigate its effectiveness, including its overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In total, 301 patients were included in the analysis (254 patients with CRC, 14 patients with GIST, and 33 patients with HCC). The incidence rates of adverse events (AEs) were 85.0%, 78.6%, and 81.8% in patients with CRC, GIST, and HCC, respectively. The most frequent AE related to regorafenib in the three cancer types was palmar-plantar erythrodysesthesia syndrome (PPES). The ORRs of patients with CRC, GIST, and HCC were 4.7%, 0%, and 41.4%, respectively. The median PFS and OS were 2.1 and 6.1 months for CRC, respectively; 9.2 and 16.4 months for GIST, respectively; and 5.5 months and not estimated (NE) for HCC, respectively. Patients who experienced a dose modification or discontinuation of regorafenib showed significantly shorter median PFS and OS (2.2 vs. 2.6 months, respectively, P = 0.0335 for PFS; 5.3 vs. 8.5 months, respectively, P = 0.0010 for OS). Conclusion: This PMS study, which is the largest surveillance study of CRC in Korea, found no newly identified safety concerns for patients who received regorafenib in the real-world setting. Additionally, the results of this study were consisted with those previously reported in phase III trials.
| S-EPMC9608207 | biostudies-literature