Cost-effectiveness analysis of 11 pharmacotherapies for recurrent glioblastoma in the USA and China.

Background: Several studies have systematically assessed the efficacy and safety of progressive or recurrent glioblastoma multiforme (GBM). However, the discernible limitations of efficacy and the elevated costs of interventions instigate an investigation into the cost-effectiveness of these treatments. Objectives: This study aimed to evaluate cost-effectivenesses of 11 pharmacotherapeutic interventions for recurrent GBM from the perspective of healthcare payers in the United States (US) and China. Design: A model-based pharmacoeconomic evaluation. Methods: A partitioned survival model was employed to evaluate the cost-effectiveness of 11 distinct drug-based treatments. The clinical efficacy and safety data were obtained from a network meta-analysis, while the medical expenditure and health utility were primarily derived from published literature. One-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses (PSA) were performed to scrutinize the impact of potential uncertainties to ensure the robustness of the model. The primary endpoint was the incremental cost-effectiveness ratio. Results: Among the therapeutic interventions evaluated, lomustine emerged as the cheapest option, with costs amounting to $78,998 in the United States and $30,231 in China, respectively. Regorafenib displayed the highest quality-adjusted life years at 0.475 in the United States and 0.465 in China. The one-way sensitivity analyses underscored that drug price was a key factor influencing cost-effectiveness. Both scenario and PSA consistently demonstrated that, considering the willingness-to-pay thresholds, lomustine was a cost-effective treatment with probability of more than 94%. Conclusion: In comparison to the alternative antitumor agents, lomustine was likely to be a cost-effective option for relapsed GBM patients from the perspective of healthcare payers in both the United States and China.

Real-world dosing of regorafenib and outcomes among patients with metastatic colorectal cancer: a retrospective analysis using US claims data.

BACKGROUND: The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines. METHODS: Patients with CRC in the Optum's de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group. RESULTS: 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% (n = 66/310) to 45% (n = 178/393), the proportion who received standard dosing decreased from 79% (n = 244/310) to 55% (n = 215/393), the proportion who initiated their third treatment cycle increased from 36% (n = 113/310) to 46% (n = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1). CONCLUSIONS: Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib.

CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma.

BACKGROUND AND PURPOSE: Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there is an inevitably high rate of drug resistance associated with regorafenib, which reduces its effectiveness in clinical treatment. Thus, there is an urgent need to find a potential way to solve the problem of regorafenib resistance. The metabolite of disulfiram complexed with copper, the Diethyldithiocarbamate-copper complex (CuET), has been found to be an effective anticancer drug candidate. In the present study, we aimed to evaluate the effect of CuET on regorafenib resistance in HCC and uncover the associated mechanism. EXPERIMENTAL APPROACH: Regorafenib-resistant HCC strains were constructed by applying an increasing concentration gradient. This study employed a comprehensive range of methodologies, including the cell counting kit-8 (CCK-8) assay, colony formation assay, cell cycle analysis, wound healing assay, Transwell assay, tumor xenograft model, and immunohistochemical analysis. These methods were utilized to investigate the antitumor activity of CuET, assess the combined effect of regorafenib and CuET, and elucidate the molecular mechanism underlying CuET-mediated regorafenib resistance. KEY RESULTS: The inhibitory effect of regorafenib on cell survival, proliferation and migration was decreased in regorafenib-resistant MHCC-97H (MHCC-97H/REGO) cells compared with parental cells. CuET demonstrated significant inhibitory effects on cell survival, proliferation, and migration of various HCC cell lines. CuET restored the sensitivity of MHCC-97H/REGO HCC cells to regorafenib in vitro and in vivo. Mechanistically, CuET reverses regorafenib resistance in HCC by suppressing epithelial-mesenchymal transition (EMT) through inhibition of the ERK signaling pathway. CONCLUSION AND IMPLICATIONS: Taken together, the results of this study demonstrated that CuET inhibited the activation of the ERK signaling pathway, leading to the suppression of the epithelial-mesenchymal transition (EMT) and subsequently reversing regorafenib resistance in HCC both in vivo and in vitro. This study provides a new idea and potential strategy to improve the treatment of regorafenib-resistant HCC.

Regorafenib plus FOLFIRINOX as first-line treatment for patients with RAS-mutant metastatic colorectal cancer (FOLFIRINOX-R trial): a dose-escalation study.

PURPOSE: The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. METHODS: The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180 mg/m²). Regorafenib (120 or 160 mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. RESULTS: Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. CONCLUSION: The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov : NCT03828799.

Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer.

BACKGROUND: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models. METHODS: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized. RESULTS: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib. CONCLUSIONS: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.

Efficacy comparison of fruquintinib, regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer.

BACKGROUND: Regorafenib (R) and fruquintinib (F) are the standard third-line regimens for colorectal cancer (CRC) according to the National Comprehensive Cancer Network guidelines, but both have limited efficacy. Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair (MSS/pMMR) CRC. Due to the lack of studies comparing the efficacy between F, R, F plus programmed death-1 (PD-1) inhibitor, and R plus PD-1 inhibitors (RP), it is still unclear whether the combination therapy is more effective than monotherapy. AIM: To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC (mCRC) patients in clinical practice. METHODS: A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital, and 313 MSS/pMMR mCRC patients were finally included. RESULTS: A total of 313 eligible patients were divided into F (n = 70), R (n = 67), F plus PD-1 inhibitor (FP) (n = 95) and RP (n = 81) groups. The key clinical characteristics were well balanced among the groups. The median progression-free survival (PFS) of the F, R, FP, and RP groups was 3.5 months, 3.6 months, 4.9 months, and 3.0 months, respectively. The median overall survival (OS) was 14.6 months, 15.7 months, 16.7 months, and 14.1 months. The FP regimen had an improved disease control rate (DCR) (P = 0.044) and 6-month PFS (P = 0.014) and exhibited a better trend in PFS (P = 0.057) compared with F, and it was also significantly better in PFS than RP (P = 0.030). RP did not confer a significant survival benefit; instead, the R group had a trend toward greater benefit with OS (P = 0.080) compared with RP. No significant differences were observed between the R and F groups in PFS or OS (P > 0.05). CONCLUSION: FP is superior to F in achieving 6-month PFS and DCR, while RP is not better than R. FP has an improved PFS and 6-month PFS compared with RP, but F and R had similar clinical efficacy. Therefore, FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

Efficacy and safety analysis of PD-1 combined with regorafenib in the treatment of advanced hepatocellular carcinoma.

OBJECTIVE: To investigate the therapeutic efficacy and safety of programmed death-1 (PD-1) inhibitors combined with regorafenib in the treatment of advanced hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was performed on 82 patients diagnosed with advanced HCC at Lanzhou Petrochemical General Hospital and the Second People's Hospital of Lanzhou City from October 2021 to October 2022. Patients were divided into two groups: the observation group (42 patients) received combined therapy with regorafenib and a PD-1 inhibitor, while the control group (40 patients) received only regorafenib monotherapy. Treatment efficacy, changes in serum tumor markers pre- and post-treatment, incidence of adverse reactions, progression-free survival (PFS), 1-year survival rate, and independent prognostic factors were evaluated for both groups. RESULTS: The treatment efficacy in the observation group was significantly better than that in the control group (P<0.05). Post-treatment levels of VEGF, sIL-2R, and CEA were significantly lower in the observation group compared to the control group (all P<0.05). The incidence of adverse reactions was similar between the two groups (P>0.05). However, the observation group demonstrated a significantly higher median PFS and 1-year survival rate than the control group (both P<0.05). Vascular invasion, degree of differentiation, and treatment regimen were identified as independent prognostic factors affecting outcomes (all P<0.05). CONCLUSION: For patients with advanced HCC, integrating PD-1 inhibitors with regorafenib treatment not only enhances clinical efficacy but also maintains safety. This combination therapy significantly improves progression-free survival and 1-year survival rates, supporting its further clinical application.

STELLAR-303: randomized phase III study of zanzalintinib + atezolizumab in previously treated metastatic colorectal cancer.

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases.Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

Metastatic colorectal cancer (mCRC) is cancer of the colon or rectum that has spread to other parts of the body, most often to the liver, lungs and abdomen. People with mCRC that has worsened after initial treatment have limited options. Zanzalintinib is a novel oral investigational drug that can slow or stop cancer growth. It works by blocking certain proteins that play important roles in the development, growth and spread of cancer. Zanzalintinib may also help improve the effectiveness of another class of cancer drugs called immune checkpoint inhibitors (ICIs), which work by activating the patient's immune system to fight cancer. Here, we describe the design of STELLAR-303, an ongoing study that is comparing the effects of combining zanzalintinib and an ICI drug called atezolizumab with an approved treatment for mCRC called regorafenib. About 900 participants with mCRC will be enrolled in the study worldwide. To be included in the study, participants must have mCRC that worsened after previous therapies and must not have a high level of microsatellite instability, which is a specific feature of some mCRCs. Participants will be randomly given one of the two treatments. The main goal of the study is to evaluate zanzalintinib plus atezolizumab compared with regorafenib by measuring the length of time participants are alive after starting treatment, specifically in patients with mCRC that has not spread to the liver. Additionally, the study will look at the side effects with each treatment. The study is currently seeking participants.

An Efficacy and Safety Comparison of Regorafenib and Nivolumab in Unresectable Hepatocellular Cancer Patients: A Systematic Review.

OBJECTIVE: This systematic review aimed to compare the efficacy and safety of regorafenib and nivolumab, two FDA-approved second-line treatments for unresectable Hepatocellular Carcinoma (HCC). METHODS: Literature comparing the efficacy and safety of regorafenib and nivolumab in unresectable HCC patients was systematically searched across seven databases, including: PubMed, SCOPUS, Cochrane Database of Systematic Reviews, ScienceDirect, EBSCOhost, EMBASE, and ProQuest, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search was done on April 2nd, 2023. Study quality and risk of bias were assessed using the Agency for Healthcare Research and Quality (AHRQ) and ROBINS-1 tools. The selected studies were included in the qualitative data synthesis. RESULTS: Three trials found that HCC patients taking nivolumab had statistically insignificantly longer OS, TTP, and progression-free survival than those on regorafenib. Nivolumab increased ORR, with largely partial responses, and mixed DCR, with little statistical significance. All three studies showed that nivolumab had fewer side effects and improved tolerance. DISCUSSION: Three retrospective cohort studies with a total of 383 regorafenib-receiving cohorts and 230 nivolumab-receiving cohorts were included in the qualitative analysis. Nivolumab was found to be superior in regards of longer overall survival, longer time to progression, higher objective response rate, and lower adverse event occurrence. However, statistical significance was not achieved in most of the parameters. CONCLUSIONS: The use of nivolumab is preferable as the second-line systemic therapy for unresectable HCC. More high-quality studies are urgently needed to generate quantitative analysis, and to encourage the formation of guidelines for second-line systemic therapy.

Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives.

Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Background: Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Methods: Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Results: Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Conclusion: The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. Clinical trial registration: https://clinicaltrials.gov, identifier NCT01933958.

Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.

Third-line treatment and beyond in metastatic colorectal cancer: What do we have and what can we expect?

Colorectal cancer remains the third most common cancer worldwide and the second cause of cancer-related death. Treatment advances and precision oncological medicine for these tumours have been stalled in comparison to those for other common tumours such as lung and breast cancer. However, the recent publication of the SUNLIGHT trial results with the trifluridine/tipiracil (TAS-102)-bevacizumab combination and the irruption of new molecular targets with guided treatments have opened new possibilities in third-line metastatic colorectal cancer management. Anti-EGFR rechallenge, anti-HER2 targeted therapies or the promising results of Pressurised Intraperitoneal Aerosol Chemotherapy (PIPAC), are some of the available options that may modify what is presumably third-line colorectal treatment. Hereby, we present the evidence of the different treatment options in third-line colorectal cancer and beyond, as well as the possibilities of sequencing them.

Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: a retrospective cohort study.

Background: The majority of studies of regorafenib now were small-sample and single-arm, which potentially limits the strength of evidence. We conduct the study to identify the efficacy and safety of regorafenib for patients with metastatic colorectal cancer (mCRC) in real-world applications. Methods: mCRC patients who underwent regorafenib second line or post-second line treatment with at least one assessable lesion were analyzed. Patients received different doses of regorafenib and different combination regimens. The patients were followed up with laboratory tests and imaging examinations every 3 months to evaluate the efficacy and adverse events (AEs). The primary endpoint of this study was median overall survival (mOS), and the secondary endpoints were median progression-free survival (mPFS), the objective response rate (ORR), the disease control rate (DCR), and AEs. Results: A total of 77 patients (45 males and 32 females, aged 58.80±11.65 years) were enrolled in the study. Most primary tumors were located in the rectum (59.74%), and the vast majority of tumors (89.62%) had an adenocarcinoma histological type. The 77 patients had an mOS of 17.8 months, a progression-free survival (PFS) of 4.63 months, an ORR of 6.76%, and a DCR of 55.41%. Patients underwent regorafenib third-line therapy had significantly higher overall survival (OS) than those underwent regorafenib post- third-line treatment (P=0.03). The neutrophil to lymphocyte ratio (NLR) was an independent factor affecting the OS of the mCRC patients [hazard ratio (HR) =1.12, P=0.03]. In both univariate and multivariate analyses, discontinued use of regorafenib after progression reduced patients' PFS (HR =3.07, P<0.001; HR =2.78, P=0.007). In terms of the tolerated dose, patients receiving 120 mg regorafenib had the longest OS numbers, but there was no statistical difference. We analyzed the effect of the baseline NLR on the OS of patients receiving regorafenib combined with immunotherapy, and found that the NLR ratio cut-off value was 4.4, and patients with a NLR ratio ≤4.4 benefited significantly in terms of OS (P=0.03). The AEs included 21 (27.27%) cases of hand and foot skin reaction, 15 (19.48%) cases of fatigue, 9 (11.69%) cases of pain, 9 (11.69%) cases of nausea, 9 (11.69%) cases of fever, 9 (11.69%) cases of cough, and so on. Conclusions: Regorafenib is relatively effective and safe as a third-line and posterior treatment of mCRC. Patients underwent regorafenib third-line therapy had longer OS than those underwent regorafenib post- third-line treatment. Moreover, PFS benefits can still be obtained by continuing regorafenib treatment after progression. Grade 1-2 AEs were common, but these were usually tolerated by most patients.

Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study.

Background: The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. Methods: We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records. Results: Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively. Conclusions: Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.

Cost-Effectiveness Analysis of Regorafenib versus Other Third-Line Treatments for Metastatic Colorectal Cancer.

Background: Regorafenib, a novel multikinase inhibitor, has been approved by the US Food and Drug Administration as a standard treatment choice for metastatic colorectal cancer (mCRC). Nonetheless, its substantial cost places a significant burden on social health resources and patients. However, the cost-effectiveness (CE) of regorafenib compared to other third-line therapies is still undetermined. Objective: This study aims to assess the CE of regorafenib compared to other third-line therapies for the treatment of mCRC. Methods: We conducted a comprehensive literature search in PubMed, Medline, Scopus, Embase, Cochrane Library, as well as nine other databases to identify relevant studies published up to October 2023, focusing on patients with mCRC and examining the cost-effectiveness of regorafenib. Following the screening and extraction of pertinent data, the study quality was assessed using the Quality of Health Economic Studies (QHES) checklist. Results: The literature search yielded 751 records, and after applying the inclusion criteria, 13 studies from 7 different countries were included. Of these, 7 studies evaluated the cost-effectiveness of regorafenib compared to trifluridine/tipiracil (TAS-102), 3 studies compared regorafenib with best supportive care (BSC), and 3 studies compared regorafenib with fruquintinib, serplulimab, and regorafenib dose optimization (ReDo).The quality of the included studies was high with an average QHES scores of 85.62. Regorafenib standard dose proves to be less cost-effective than alternative third-line therapies. Implementing a dose optimization strategy could potentially rectify this disparity and enhance the cost-effectiveness of regorafenib. Conclusion: The use of the standard dose of regorafenib is generally regarded as not cost-effective when compared to other third-line therapies for patients with mCRC. However, implementing a dose-escalation strategy may enhance regorafenib's cost-effectiveness. Consequently, significant price reductions or optimizing the dose of regorafenib are required to achieve cost-effectiveness.

Regorafenib in patients with metastatic colorectal cancer in Spain: from clinical trials to real-world evidence.

Aim: To describe the evolution of regorafenib use, since its approval, in patients with previously treated metastatic colorectal cancer (mCRC) in routine clinical practice in Spain. Methods: We extracted patient characteristics, dosing, safety and efficacy data for the Spanish cohorts of the CORRECT and CONSIGN trials, and the real-world CORRELATE study. Results: The Spanish cohorts represented 10.7-13.8% of the global cohorts. Efficacy and safety in the Spanish cohorts reflected findings from the global cohorts, with evidence of a flexible dosing approach being adopted in routine clinical practice. Conclusion: Regorafenib use in patients with mCRC has evolved in the real-world setting, emphasizing the need for further research evaluating dosing patterns that can optimize clinical outcomes in these patients.Clinical trial registration: The CORRECT trial is registered at ClinicalTrials.gov, number NCT01103323; the CONSIGN trial is registered at ClinicalTrials.gov, number NCT01538680; the CORRELATE study is registered at ClinicalTrials.gov, number NCT02042144.

Bowel cancer (also called colorectal cancer) affects the large bowel, including the colon and rectum. Approximately one in ten patients with advanced bowel cancer that has spread to other areas of the body (metastatic bowel cancer) survive 5 years after diagnosis or the start of treatment.Regorafenib is a treatment for patients with advanced bowel cancer that has continued to spread after receiving other treatments. It can slow down cancer growth, as shown in three international studies (CORRECT, CONSIGN and CORRELATE). In Spain, bowel cancer is the most common type of cancer and the cancer that causes the second most deaths. This study describes how the use of regorafenib in Spain has changed since it was approved in 2012, by looking at the patients from Spain who made up 11­14% of the participants in the three international studies.The CORRECT trial that compared regorafenib with a non-therapeutic placebo and the CONSIGN trial of regorafenib alone showed that treatment with regorafenib prolonged life and was well tolerated in patients with metastatic bowel cancer who had previously received or were not suitable to receive other treatments. The CORRELATE study showed that in the real world (i.e., outside of a controlled clinical trial), patients are sometimes prescribed regorafenib at lower starting doses than the recommended dose, without an apparent overall effect on how well regorafenib works or side effects. In the future, it will be important to continue researching how doctors prescribe regorafenib in daily clinical practice in Spain.

The cumulative antitumor effects of regorafenib and radiotherapy in hepatocellular carcinoma.

Regorafenib is a second-line standard treatment for hepatocellular carcinoma (HCC). However, the efficacy of regorafenib is often limited due to drug resistance, individual differences among patients, and irrational drug use. Radiotherapy (RT) is an important method of localized HCC treatment, and combining RT with other therapies may exert a synergetic antitumor effect. Platelet-derived growth factor receptor-like (PDGFRL) is a tumor suppressor in various solid tumors. However, the function of PDGFRL in HCC is still unknown. In this study, we explored whether regorafenib and RT exert a synergetic effect on the treatment of HCC. The antitumor effect and mechanisms of the combination of regorafenib and RT were verified in a xenograft mouse model in vivo and in HCC cells in vitro. The combination treatment significantly inhibited cell proliferation and promoted apoptosis both in vitro and in vivo. PDGFRL, a potential target of regorafenib, was increased after cumulative treatment in HCC cells, and PDGFRL suppressed HCC cell proliferation and promoted apoptosis by inhibiting STAT3 pathway activation. Furthermore, the cumulative antitumor effect was dependent on the upregulated expression of PDGFRL and inhibition of STAT3 signaling pathway activation in HCC cells. This study increased the understanding of the molecular mechanism underlying the effect of regorafenib plus RT on HCC and provided a theoretical basis for the clinical practice of HCC.

Comparison between Nivolumab and Regorafenib as Second-line Systemic Therapies after Sorafenib Failure in Patients with Hepatocellular Carcinoma.

PURPOSE: Nivolumab and regorafenib are second-line therapies for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the effectiveness of nivolumab and regorafenib. MATERIALS AND METHODS: We retrospectively reviewed patients with HCC treated with nivolumab or regorafenib after sorafenib failure. Progression-free survival (PFS) and overall survival (OS) were analyzed. An inverse probability of treatment weighting using the propensity score (PS) was performed to reduce treatment selection bias. RESULTS: Among the 189 patients recruited, 137 and 52 patients received regorafenib and nivolumab after sorafenib failure, respectively. Nivolumab users showed higher Child-Pugh B patients (42.3% vs. 24.1%) and shorter median sorafenib maintenance (2.2 months vs. 3.5 months) compared to regorafenib users. Nivolumab users showed shorter median OS (4.2 months vs. 7.4 months, p=0.045) than regorafenib users and similar median PFS (1.8 months vs. 2.7 months, p=0.070). However, the median overall and PFS did not differ between the two treatment groups after the 1:1 PS matching (log-rank p=0.810 and 0.810, respectively) and after the stabilized inverse probability of treatment weighting (log-rank p=0.445 and 0.878, respectively). In addition, covariate-adjusted Cox regression analyses showed that overall and PFS did not significantly differ between nivolumab and regorafenib users after 1:1 PS matching and stabilized inverse probability of treatment weighting (all p>0.05). CONCLUSION: Clinical outcomes of patients treated with nivolumab and regorafenib after sorafenib treatment failure did not differ significantly.

Regorafenib plus programmed death­1 inhibitors vs. regorafenib monotherapy in second­line treatment for advanced hepatocellular carcinoma: A systematic review and meta­analysis.

The present study compared the efficacy and safety of regorafenib plus programmed death-1 inhibitors (R-P) with regorafenib monotherapy as second-line therapies for advanced hepatocellular carcinoma (HCC). A systematic search of relevant literature published in PubMed, Embase, Web of Science and Cochrane Library databases until October 2023 was conducted. Two authors independently performed data extraction and screening using standardized protocols. Stata/MP 17.0 was used for the meta-analysis to evaluate the impact of R-P treatment on major outcome indicators, including overall survival, progression-free survival (PFS), tumor response and adverse reactions, in patients with advanced HCC. The results indicated that five cohort studies involving 444 patients with advanced HCC were included. The results revealed that R-P treatment improved overall survival [hazard ratio (HR), 0.61; 95% confidence interval (CI) 0.48-0.77; I2=0.0%; P=0.663] and PFS (HR, 0.51; 95% CI 0.41-0.63; I2=17.5%; P=0.303). Additionally, it increased the objective response rate (risk ratio, 2.33; 95% CI, 1.49-3.64; I2=0.0%; P=0.994) and disease control rate (HR, 1.40; 95% CI, 1.20-1.63; I2=0.0%; P=0.892) compared with those of regorafenib. However, R-P treatment was associated with an increased incidence of adverse events, such as hypothyroidism, thrombocytopenia and rash, compared with that in regorafenib. In conclusion, R-P is superior to regorafenib monotherapy in terms of survival benefits and tumor response.