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130 Background: Tyrosine kinase inhibitors (TKI) are the most common oral drugs in cancer patients. Similarly, proton pump inhibitors (PPI) are commonly used to relieve dyspeptic symptoms in patients with cancer. However, gastric pH levels may affect the absorption of TKI through the gastrointestinal system. However, all TKIs do not have the same chemical structure, and the absorption rate of each TKI depends on their solubility in different gastric pH levels. Limited data is available about the clinical outcomes of concomitant use of PPI and regorafenib in patients with metastatic colorectal cancer (mCRC). We present here the results of the multicenter study following the initial results of our single-center experience. Methods: Patients with mCRC treated with regorafenib were included in this multicenter and retrospective study. Patients prescribed PPI after initiation of regorafenib were assigned to the PPI user group, and the remaining patients were assigned to the PPI non-user group. To exclude immortal time bias, the log-rank test was performed between PPI non-user and all patients. The primary outcome was overall survival (OS), and secondary outcomes were time to treatment failure (TTF) and adverse events (AEs) profile. Results: Two hundred and seventy-two patients from eight cancer centers were included in this study. Most patients were male (59.9%), had liver metastasis (62.1%), and received regorafenib in the third line (52.2%). The median age at the initiation of regorafenib was 60 years (interquartile range (IQR): 51-66)). Eastern Cooperative Oncology Group performance score was 0 or 1 in approximately three out of four patients. The rate of patients with K-RAS mutation was 46.7%. There were 131 (48.2%) and 141 (51.8%) in the PPI user and non-user groups, respectively. The most prescribed PPI was pantoprazole (40.4%). At a median 34.2 months follow-up, the median OS was 6.9 months (95% Confidence Interval (CI): 5.3-8.5) and 7.7 months (95% CI:6.6-8.8) in the PPI non-user and all patients, respectively. No statistical significance was observed between the groups (p = 0.913). The median TTF was 3.3 months (95% CI: 2.6-3.9) and 3.4 months (95% CI:2.9-4.0) in the PPI non-user and all patients, respectively. No statistical significance was observed between the groups (p = 0.651). In the time-dependent covariate Cox regression model, there was no difference between PPI user and non-user groups in OS and TTF (adjusted Hazard Ratio (aHR):0.96, 95% CI:0.74-1.24, p = 0.735 for OS; aHR:0.88, 0.68-1.14, p = 0.354 for TTF). The rates of all AEs were also similar in the PPI user and non-user groups (p = 0.628). Conclusions: To our knowledge, this was the first study evaluating the effect of concomitant use of PPI and regorafenib in patients with mCRC, and no adverse survival and safety outcome was observed with the concomitant use of PPI and regorafenib in those patients.

Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.

In Switzerland, physicians do not have national guidelines for metastatic colorectal cancer (mCRC) patient care and utilize international versions for management recommendations. Moreover, information about adherence to these guidelines and real-world practice patterns in Switzerland or other countries is lacking. The Screening and COnsensus based on Practices and Evidence (SCOPE) program were designed by an international expert panel of gastrointestinal oncologists to gather real-world insights in the current clinical setting to manage patients with mCRC who have received prior treatment. We sought to understand general practice patterns, the influence of molecular diagnostics (e.g., testing for KRAS, NRAS, BRAF, and MSI), tumor sidedness, and patient-centric factors on treatment selection utilizing in-person surveys and three hypothetical patient case scenarios. Here, we describe and evaluate the Swiss data from the SCOPE program within the context of an international viewpoint and discuss the findings of our analysis. In general, we find that the real-world clinical decisions of Swiss physicians (SWI) closely follow international (INT) recommendations and guidelines, largely paralleling their regional and international counterparts in using the two approved treatments in the third- and fourth-line settings, namely trifluridine-tipiracil and regorafenib. Finally, our data suggest a tendency toward the use of trifluridine-tipiracil (SWI: 79%; INT: 66%) over regorafenib (SWI: 18%; INT: 18%) as the preferred third-line treatment choice in mCRC patients regardless of KRAS status.

Triple-negative breast cancer (TNBC) is a highly resistant, lethal, and metastatic sub-division of breast carcinoma, characterized by the deficiency of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In women, TNBC shows a higher aggressive behavior with poor patient prognosis and a higher recurrence rate during reproductive age. TNBC is defined by the presence of epithelial- to-mesenchymal-transition (EMT), which shows a significant role in cancer progression. At the epigenetic level, TNBC is characterized by epigenetic signatures, such as DNA methylation, histone remodeling, and a host of miRNA, MiR-193, LncRNA, HIF- 2α, eEF2K, LIN9/NEK2, IMP3, LISCH7/TGF-β1, GD3s, KLK12, mediated regulation. These modifications either are silenced or activate the necessary genes that are prevalent in TNBC. The review is based on epigenetic mediated mechanistic changes in TNBC. Furthermore, Thymoquinone (TQ), Regorafenib, Fangjihuangqi decoction, Saikosaponin A, and Huaier, etc., are potent antitumor natural compounds extensively reported in the literature. Further, the review emphasizes the role of these natural compounds in TNBC and their possible epigenetic targets, which can be utilized as a potential therapeutic strategy in the treatment of TNBC.

Based on the structural modification of regorafenib, 28 pyrazinyl–aryl urea derivatives were synthesized and their in vitro antiproliferative activities were evaluated. Six compounds (5-16, 5-17, 5-18, 5-19, 5-22, and 5-23) exhibited favorable inhibitory activity against the human bladder cancer T24 cell line, and 5-23 demonstrated the strongest inhibitory activity (IC(50) = 4.58 ± 0.24 μM) with high selectivity. Compound 5-23 induced apoptosis in the low concentration range (≤7.5 μM) combined with shorter incubation time (≤10 h) via the activation of caspases, while high concentrations and prolonged incubation times led to necroptotic cell death by activating the RIPK1/RIPK3/MLKL signaling pathway. Induced apoptosis and necroptosis were closely associated with intracellular reactive oxygen species generation and decreased mitochondrial membrane potential. Compared with regorafenib, 5-23 displayed improved pharmacokinetic profiles in an in vivo rat model. Molecular docking and structure–activity relationship analyses were in agreement with the biological data. Compound 5-23 may be a potent anti-bladder cancer agent and this small molecule can be considered as a promising structure for further optimization.

Sorafenib and its derivative regorafenib are the first- and second-line targeted drugs for advanced HCC, respectively. Although both drugs improve overall survival, drug resistance remains the major barrier to their full efficacy. Thus, strategies to enhance sorafenib and regorafenib efficacy against HCC are solely needed. Interleukin-6 receptor alpha (IL-6Rα) is the receptor of IL-6, a multi-functional cytokine, which plays key roles in liver-regeneration, inflammation and development of hepatocellular carcinoma (HCC). Here we show the expression of IL-6Rα was induced in response to sorafenib. Depletion of IL-6Rα abolished IL-6 induced STAT3 phosphorylation at 705th tyrosine and tumor growth of HCC cells under sorafenib treatment. Mechanistically, activating transcription factor 3 (ATF3) was induced in response to sorafenib and subsequently bound to the promoter of IL-6Rα, leading to its transcriptional activation. Depletion of ATF3 or its upstream transcription factor, ATF4, attenuated IL-6Rα induction and IL-6 mediated sorafenib resistance. The ATF4-ATF3-IL-6Rα cascade is also activated by regorafenib. Furthermore, blockade of IL-6Rα with the FDA approved IL-6Rα antibody drug, Sarilumab, drastically attenuated both sorafenib and regorafenib resistance in patient-derived xenograft (PDX) tumors, where human IL-6 could be detected by a novel in situ hybridization technique, named RNAscope. Together, our data reveal that ATF3-mediated IL-6Rα up-regulation promotes both sorafenib and regorafenib resistance in HCC, and targeting IL-6Rα represents a novel therapeutic strategy to enhance sorafenib/regorafenib efficacy for advanced HCC treatment.

BackgroundRight- (R) and left-sided (L) metastatic colorectal cancer (mCRC) exhibit different clinical and molecular features. Several retrospective analyses showed that survival benefit of anti-EGFR-based therapy is limited to RAS/BRAF wt L-sided mCRC patients. Few data are available about third-line anti-EGFR efficacy according to primary tumor site.MethodsRAS/BRAF wt patients mCRC treated with third-line anti-EGFR-based therapy versus regorafenib or trifluridine/tipiracil (R/T) were retrospectively collected. The objective of the analysis was to compare treatment efficacy according to tumor site. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), response rate (RR) and toxicity.ResultsA total of 76 RAS/BRAF wt mCRC patients, treated with third-line anti-EGFR-based therapy or R/T, were enrolled. Of those, 19 (25%) patients had a R-sided tumor (9 patients received anti-EGFR treatment and 10 patients R/T) and 57 (75%) patients had a L-sided tumor (30 patients received anti-EGFR treatment and 27 patients R/T). A significant PFS [7.2 vs 3.6 months, HR 0.43 (95% CI 0.2-0.76), p= 0.004] and OS benefit [14.9 vs 10.9 months, HR 0.52 (95% CI 0.28-0.98), p= 0.045] in favor of anti-EGFR therapy vs R/T was observed in the L-sided tumor group. No difference in PFS and OS was observed in the R-sided tumor group. A significant interaction according to primary tumor site and third-line regimen was observed for PFS (p= 0.05). RR was significantly higher in L-sided patients treated with anti-EGFR vs R/T (43% vs. 0%; p ConclusionsOur results demonstrated a different benefit from third-line anti-EGFR-based therapy according to primary tumor site, confirming the role of L-sided tumor in predicting benefit from third-line anti-EGFR vs R/T. At the same time, no difference was observed in R-sided tumor.

Background: Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, FTD/TPI plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received trifluridine/tipiracil (TFTD) plus bevacizumab is unclear.Results: We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43−81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56−91), and the overall survival was 233 days (95% CI: 188−324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%).Conclusion: Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.

Colon cancer therapy currently includes at least 3 cytostatic agents and 6 targeted drugs, combinations of which constitute many different treatment regimens. Nevertheless, as shown by various clinical studies, the use of oxaliplatin, irinotecan and fluoropyrimidine regimens in conjunction with monoclonal targeted drugs remains the main one. After progression on the main lines of therapy and registration of refractory disease, there are not many standard options for treatment in the 3rd line that have statistical confidence in terms of improving survival rates. There have been attempts to search for genetic aberrations for targeted therapy, predictors of the effectiveness of immunotherapy, the use of re-introduction regimens (re-application of a regimen that the patient stopped taking due to intolerance phenomena) and re-challenge (use of previous regimens, with response at first time, and then developed progression), and the abundance of solutions could only be limited by the imagination of the researcher. However, with the advent of the new multi-kinase inhibitor regorafenib, recommendations for the treatment of colorectal cancer have changed. The drug has received indications for use in the third line of therapy for refractory colorectal cancer. A review of the existing options for targeted therapy and an analysis of studies of different regimens in the 3rd line of therapy in comparison with regorafenib was carried out. It has been established that regorafenib is currently the optimal option for the treatment of metastatic colorectal cancer in the third line of therapy, regardless of previous lines of therapy and mutational status, and has a satisfactory spectrum of side effects, many of which may be predictors of therapy efficacy.

Background: Breast cancer is the most common malignancy in women worldwide. P2X7 is a transmembrane receptor expressed in breast cancer and activated by the ATP tumor microenvironment, driving cell proliferation, angiogenesis, and metastasis via different signaling pathways. The role of the P2X7 receptor, hypoxia, and autophagy in regulating tumor progression is controversial. The multikinase inhibitor regorafenib prevents the activation of numerous kinases involved in angiogenesis, proliferation, and metastasis. The present study aimed to evaluate the modulatory effect of regorafenib on the hypoxia/angiogenesis/P2X7R/autophagy axis on the MCF7 breast cancer cell line and its impact on different signaling pathways involved in breast cancer pathogenesis. Methods: The levels of VEGF, VEGFR, PI3K, NF-κB, HIF-1α, and LC3-II were analyzed using ELISA, and caspase-3 activity was also assessed colorimetrically. Phosphorylated (p)-p38 MAPK and purinergic ligand-gated ion channel 7 (P2X7) receptor protein expression levels were analyzed via Western blotting. Reverse transcription-quantitative PCR was used to determine the mRNA expression levels of Beclin 1 (BECN1), LC3-II, and sequestosome 1 (p62). Results: Regorafenib reduced MCF7 cell viability in a dose-dependent manner. Furthermore, regorafenib significantly reduced levels of PI3K, NF-κB, VEGF, VEGFR, P2X7 receptor, and p-p38 MAPK protein expression, and markedly reduced p62 mRNA expression levels. However, regorafenib significantly increased caspase-3 activity, as well as BECN1 and LC3-II mRNA expression levels. Conclusions: Regorafenib was demonstrated to possibly exhibit antitumor activity on the breast cancer cell line via modulation of the P2X7/HIF-1α/VEGF, P2X7/P38, P2X7/ERK/NF-κB, and P2X7/beclin 1 pathways.

Background/aim Recurrent osteosarcoma is recalcitrant with poor response rates to first-line chemotherapy due to heterogeneity and metastatic potential. This disease requires novel drug discovery and precision treatment. Materials and methods The osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model mimics the clinical disease and has identified effective clinically-approved drugs and experimental agents, especially drug combinations, that hold much clinical promise. Results Effective treatment for drug-resistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenib-everolimus, sorafenib-palbociclib, and olaratumab-doxorubicin-cisplatinum, as combinations. Conclusion The PDOX model can be used to improve the outcome of osteosarcoma patients, including individualized, precision therapy.

Aim: Reviewing outcomes of regorafenib use in metastatic colorectal cancer using real-world data from the South Australian Metastatic Colorectal Cancer Registry. Methods: A retrospective review of the characteristics and outcomes of patients who received regorafenib in the Registry up to December 2018. The registry started in February 2006. Results: Fifty-three patients received regorafenib therapy since approved by the therapeutic goods administration in November 2013. The median age was 66 (range 34–82). 66% were male, 66% had stage IV disease at diagnosis, 53% had liver only involvement, whereas 13% had liver and lung disease and 6% had lung only involvement. 75% had left-sided primary. KRAS was available in 35/53 patients with 49% of them being WT. BRAF status was known in 8/53 with 25% of them having a mutated variant. MSI testing was known in 14 patients in whom 21% of them had MSI-High tumors. Prior lines of treatment received: one line 4%, two 9%, three 23%, four 26%, >four 37%. Prior biological use: bevacizumab 72%, anti-EGFR 100% (for RAS WT). Median survival from diagnosis was 3.3 years (95% CI, 2.8–3.8 years). Median survival from the start of regorafenib was 7.1 months (95% CI, 4.8–9.4 months) and the 12-month survival rate was 28%. Conclusion: The survival outcome for those patients from our population-based registry who access regorafenib is in keeping with reports from large, randomized trials. Thus, clinicians can quote local real world data when discussing efficacy and access to regorafenib therapy for mCRC patients. Refereed/Peer-reviewed

Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.

There exists a dilemma in the treatment of microsatellite stability (MSS) metastatic colorectal cancer (mCRC) owing to limited therapeutic options. Based on the promising results of the REGONIVO trial, combination of anti-PD-1 and regorafenib could be applicable for this kind of patients. Here we first report a case of an MSS mCRC patient who received sinitilimab plus regorafenib as third-line treatment and suffered severe multisystem treatment-related adverse events including Grade 3 myocarditis, myositis, myasthenia gravis, dermatitis, hepatitis, etc. Fortunately, all these adverse events were reversed with administration of corticosteroids. Though evidence of tumor shrinkage was not found, CEA levels markedly decreased. Therefore, anti-PD-1 plus regorafenib might be optional for the MSS mCRC patients which requires special caution in the clinical practice.Lay abstract There exists a dilemma in the treatment of metastatic colorectal cancer (mCRC) owing to limited therapeutic options. Based on the results of clinical trials, combination of anti-PD-1 and regorafenib is promising for these patients. Here we first report a case of an mCRC patient who received sinitilimab plus regorafenib as third-line treatment and suffered severe multisystem treatment-related adverse events including grade 3 myocarditis, myositis, myasthenia gravis, dermatitis, hepatitis, etc. Fortunately, all these adverse events were reversed with administration of corticosteroids. Though evidence of tumor shrinkage was not found, serum tumor marker level markedly decreased. Therefore, anti-PD-1 plus regorafenib might be optional for the mCRC patients which requires special caution in the clinical practice.

Regorafenib and trifluridine/tipiracil are standard third-line chemotherapies for colorectal cancer patients, but their efficacy is limited. Anti-epidermal growth factor receptor antibody rechallenge has been reported to be promising for patients who have obtained clinical benefit from first-line cetuximab-based chemotherapy. Moreover, panitumumab showed non-inferior efficacy to cetuximab. This study assessed the efficacy and safety of third-line panitumumab rechallenge in patients with metastatic KRAS exon 2 wild-type metastatic colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy. This was a prospective, multicenter, phase II trial conducted from October 2013 to August 2017. Major eligibility criteria included KRAS exon 2 wild-type and achievement of complete response, partial response, or continued stable disease for at least 6 months in first-line panitumumab-based therapy. Irinotecan plus panitumumab treatment was continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the 3-month progression-free survival (PFS) rate. Twenty-five patients were enrolled in this study. Their median age was 66.5 years, and the 3-month PFS rate was 50.0% (95% confidence interval 30.0–70.0). The median PFS and overall survival were 3.1 months and 8.9 months, respectively. The response rate and disease control rate were 8.3% and 50.0%, respectively. Common grade 3/4 adverse events were acneiform rash (17%), hypomagnesemia (13%), and dry skin (13%). No treatment-related deaths occurred. Irinotecan plus panitumumab rechallenge is a promising third-line treatment regimen in patients with metastatic wild-type KRAS colorectal cancer. UMIN000015916.

Background Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor β (PDGFR-β), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2-B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum-containing chemotherapy. Methods A Fleming single-arm, single-stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8-week progression-free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8-week PFS rate of ≥50% (≥8 of 19 evaluable patients progression-free at 2 months). Results From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi-criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8-week PFS rate was 78.9% (15 of 19 patients). Grade 3-4 treatment-related adverse events were observed in 10 patients (52.6%). Conclusions The primary end point of this study was reached. The high rate of PR (Choi-criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies.

The aim of this paper is to summarize the current treatment landscape in metastatic colorectal cancer, as well as those on the horizon in the third-line and beyond settings. Herein, recent data regarding TAS-102, regorafenib, and novel anti-angiogenic agents are described. Data on chemotherapy re-challenge and EGFR re-challenge is reviewed. A summary of data on the use of BRAF-targeted therapies, HER-2-targeted therapies, rare fusions (NTRK, RET), MET amplification, and KRAS G12C is included, as well as a brief review on the current role of immune checkpoint inhibitors in metastatic colorectal cancer. Multiple new agents are on the horizon. There is increasing relevance of next generation sequencing to look for rare targets, and potentially to assess tumor mutational burden. ctDNA appears to be a valuable asset which may guide the use of therapies in the re-challenge setting.

Introduction : Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers. Areas covered : Our review covers the recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, and dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ have the potential of proteomic/genomic biomarkers for sorafenib treatment. Alanine aminotransferase, aspartate aminotransferase, and albumin-bilirubin grade can predict the efficacy of other MKIs. Rb, p16, and Ki-67, and genes involved in cell cycle regulation, CDK1-4, CCND1, CDKN1A, and CDKN2A have been proposed for CD4/6 inhibitors, while dysregulated TERT, CTNNB1, TP53 FGF19, and TP53 are found to be predictors for ICI efficacy. Expert opinion : There are still limited clinically applicable and validated predictive biomarkers to identify HCC patients who benefit from systemic therapy. Further prospective biomarker validation studies for HCC personalized systemic therapy are required.

Three-dimensional (3D) spheroid culture provides opportunities to model tumor growth closer to its natural context. The collagen network in the extracellular matrix supports autonomic tumor cell proliferation, but its presence and role in tumor spheroids remain unclear. In this research, we developed an in vitro 3D co-culture model in a microwell 3D (μ-well 3D) cell-culture array platform to mimic the tumor microenvironment (TME). The modular setup is used to characterize the paracrine signaling molecules and the role of the intraspheroidal collagen network in cancer drug resistance. The μ-well 3D platform is made up of poly(dimethylsiloxane) that contains 630 round wells for individual spheroid growth. Inside each well, the growth surface measured 500 μm in diameter and was functionalized with the amphiphilic copolymer. HCT-8 colon cancer cells and/or NIH3T3 fibroblasts were seeded in each well and incubated for up to 9 days for TME studies. It was observed that NIH3T3 cells promoted the kinetics of tumor organoid formation. The two types of cells self-organized into core-shell chimeric tumor spheroids (CTSs) with fibroblasts confined to the shell and cancer cells localized to the core. Confocal microscopy analysis indicated that a type-I collagen network developed inside the CTS along with increased TGF-β1 and α-SMA proteins. The results were correlated with a significantly increased stiffness in 3D co-cultured CTS up to 52 kPa as compared to two-dimensional (2D) co-culture. CTS was more resistant to 5-FU (IC50 = 14.0 ± 3.9 μM) and Regorafenib (IC50 = 49.8 ± 9.9 μM) compared to cells grown under the 2D condition 5-FU (IC50 = 12.2 ± 3.7 μM) and Regorafenib (IC50 = 5.9 ± 1.9 μM). Targeted collagen homeostasis with Sclerotiorin led to damaged collagen structure and disrupted the type-I collagen network within CTS. Such a treatment significantly sensitized collagen-supported CTS to 5-FU (IC50 = 4.4 ± 1.3 μM) and to Regorafenib (IC50 = 0.5 ± 0.2 μM). In summary, the efficient formation of colon cancer CTSs in a μ-well 3D culture platform allows exploration of the desmoplastic TME. The novel role of intratumor collagen quality as a drug sensitization target warrants further investigation.

Objective: to perform a pharmacoeconomic evaluation of the effectiveness of therapies for metastatic colorectal cancer (mCRC) based on real practical data on medical help for patients with this disease.Material and methods. The authors performed a comparative cost-effectiveness analysis and the calculation of resource consumption in the application of several options of chemotherapy for mCRC: FOLFOX, FOLFIRI, and FOLFOXIRI; targeted therapy: FOLFOX + bevacizumab, FOLFOX + panitumumab, FOLFIRI + cetuximab, FOLFIRI + aflibercept, regorafenib monotherapy.Results. The cost-effectiveness parameter, calculated as a ratio of the cost of therapy to the median survival without progression, for chemotherapeutic schemes varied from 108 to 167 thousand rubles and for the targeted therapy schemes – from 223 to 930 thousand rubles. The calculation of resource consumption showed that in the case of a limited budget, 100% of patients can be treated by FOLFOX scheme, or 26% of patients by FOLFOX + panitumumab, or 47% of patients by FOLFOX + bevacizumab; and 100% of patients by FOLFIRI scheme or 11.5% of patients by FOLFIRI + cetuximab (aflibercept). Besides, it was established that in the case of a similar budget, 100% of patients with mCRC can be treated by chemotherapy schemes or a limited number of patients with regorafenib.Conclusion. The cost of targeted therapy significantly exceeds the cost of chemotherapeutic schemes. Still, considering the gross domestic product per capita in the Russian Federation, they can be an economically feasible investment and the optimum option of therapy

Background Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist. Materials and Methods A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, real-world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second- or third-line were performed. Results One hundred twenty-six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value Conclusion Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second- or third-line suggests that early use of FTD/TPI may have clinical benefits. Implications for Practice In this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. This study offers insight into patients' treatment experience in real-world clinical settings.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer characterized by dysregulation of several crucial cellular signaling pathways such as PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. Novel therapies targeting these pathways have been discovered such as regorafenib which is small molecular multi-kinase inhibitor mainly targets VEGF/VEGFR2. Catalpol is an iridoid glycoside richly found in rehmannia glutinosa which is a fundamental herb used extensively in traditional Chinese medicine. It is evidenced that catalpol has many pharmacological effects on nervous and cardiovascular systems, in addition to exhibiting hypoglycemic, anti-inflammatory, anti-proliferative and anti-tumour activities. However, its effect on HCC isn’t clear enough. So, this study aimed to investigate the anti-tumour effects of catalpol either alone or in combination with regorafenib on HCC. In vitro experiments were performed using HepG2 and HUH-7 hepatocellular carcinoma cell lines. MTT assays evaluated anti-proliferative effects of catalpol and/or regorafenib. Combination index was calculated via compusyn software to detect synergism. Tumour biomarkers were measured using ELISA technique. Results showed that catalpol has anti-tumour effects against HCC via targeting PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. In addition, results revealed that our novel combination of catalpol and regorafenib showed potent synergistic anti-tumour effect via suppressing both of PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and their downstreams. Catalpol and/or regorafenib markedly suppressed PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and consequently showed potent anti-tumour effects against HCC. Results encourage further pre-clinical and clinical studies of this novel combination as a promising targeted therapy for HCC management.

Several molecular-targeted agents have been tested as first- or second-line therapies for hepatocellular carcinoma (HCC) but failed to improve clinical outcomes; sorafenib has been the only approved systemic agent for treating HCC for almost 10 years. Regorafenib resulted in a significant improvement in overall survival and thus was approved for HCC patients previously treated with sorafenib. Subsequently, cabozantinib and ramucirumab demonstrated superior overall survival compared with placebos in phase III clinical trials. Immune checkpoint inhibitors such as nivolumab with or without ipilimumab and pembrolizumab are also available in some countries for patients who are unresponsive to sorafenib. Some second-line agents are available for patients who are unresponsive to sorafenib; however, little is known about the considerations for selecting appropriate secondline systemic agents. Hence, this study aimed to review the current and future perspectives of second-line systemic agents. (J Liver Cancer 2021;21:124-138)

Purpose Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFRis) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFRi afatinib (Giotrif®) is being evaluated in a multicentric Phase II trial. As tyrosine kinase inhibitor (TKI) monotherapies are invariably followed by resistance, we aimed to evaluate potential therapeutic combinations with EGFRis. Methods We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFRis (afatinib and erlotinib) in the clival chordoma cell line UM-Chor1. Synergistic combinations were analysed in a 7 × 7 matrix format. The most promising combination was further explored in clival (UM-Chor1, MUG-CC1) and sacral (MUG-Chor1, U-CH1) chordoma cell lines. Secretomes were analysed for receptor tyrosine kinase ligands (EGF, TGF-α, FGF-2 and VEGF-A) upon drug treatment. Results Drugs that were active as single agents (n = 45) included TKIs, HDAC and proteasome inhibitors, and cytostatic drugs. Six combinations were analysed in a matrix format: n = 4 resulted in a significantly increased cell killing (crizotinib, dabrafenib, panobinostat and doxorubicin), and n = 2 exhibited no or negligible effects (regorafenib, venetoclax). Clival chordoma cell lines were more responsive to combined EGFR-MET inhibition. EGFR-MET cross-talk (e.g. via TGF-α secretion) likely accounts for the synergistic effects of EGFR-MET inhibition. Conclusion Our screen revealed promising combinations with EGFRis, such as the ALK/MET-inhibitor crizotinib, the HDAC-inhibitor panobinostat or the topoisomerase-II-inhibitor doxorubicin, which are part of standard chemotherapy regimens for various bone and soft-tissue sarcomas.

Although nanoparticles based on Group 8 elements such as Fe and Ru have been developed, not much is known about Os nanoparticles. However, Os-based nanostructures might have potential in various applications including biomedical fields. Therefore, in this study, we synthesized Os-Te nanorods (OsTeNRs) by solvothermal galvanic replacement with Te nanotemplates. We explored the nanozymatic activity of the synthesized OsTeNRs and found that they exhibited superior photothermal conversion and photocatalytic activity. Along with chemotherapy (regorafenib) and immunotherapy, the nanozymatic, photothermal, and photodynamic activities of OsTeNRs were harnessed to develop a pentamodal treatment for hepatocellular carcinoma (HCC); in vitro and in vivo studies demonstrated that the pentamodal therapy could alleviate hypoxia in HCC cells by generating oxygen and reduced unintended drug accumulation in organs. Moreover, bone-marrow toxicity due to regorafenib could be reduced as the drug was released in a sustained manner. Thus, OsTeNRs can be considered as suitable nanotemplates for combinatorial cancer therapy.

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1–5 and 8–12 of a 28-day cycle, REG on days 2–22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51–5.29), median OS 11.1 months (95% CI: 2.3–18.2). Conclusion: The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.

Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. After surgery, up to 70% of patients experience relapses. The current first-line therapy for advanced cases of hepatocellular carcinoma (HCC) comprises sorafenib and lenvatinib administered as single-drug therapies. Regorafenib, cabozantinib, and ramucirumab are administered as second-line therapies. Recently, it has been reported that using the immune checkpoint inhibitors atezolizumab (anti-PDL1 antibody) and bevacizumab (anti-VEGF antibody) leads to longer overall survival of unresectable cases, when compared with the use of sorafenib. The role of cancer immunity against HCC has attracted the attention of clinicians. In this review, we describe our phase I/II clinical trials of peptide vaccines targeting GPC3 in HCC and discuss the potential of peptide vaccines targeting common cancer antigens that are highly expressed in HCC, such as WT-I, AFP, ROBO1, and FOXM1. Further, we introduce recent cancer vaccines targeting neoantigens, which have attracted attention in recent times, as well as present our preclinical studies, the results of which might aid to initiate a neoantigen vaccine clinical trial, which would be the first of its kind in Japan.

Portal vein involvement is considered one of the most fearful complications of hepatocellular carcinoma (HCC). Portal vein tumor thrombosis (PVTT) is associated with aggressive tumor biology (high grade), high tumor burden (number and size of lesions), high levels of serum markers (AFP), poor liver function (deranged LFT), and poor performance status of patients. The Barcelona Clinic Liver Cancer staging system places HCC patients with PVTT in advanced stage (BCLC Stage-C). This group contains a fairly heterogeneous patient population, previously considered candidates for palliative systemic therapy with sorafenib. However, this provided modest overall survival (OS) benefit. The results of a recent Phase III (IMbrave150) trial favor the combination of atezolizumab and bevacizumab over sorafenib as a standard of care in advanced unresectable HCC. While only lenvatinib proved to be non-inferior against sorafenib in a phase III (REFLECT trial), regorafenib (RESORCE trial), ramucirumab (REACH-2), and cabozantinib (CELESTIAL) have been approved second-line therapy in phase III clinical trials. Recently, the data on the prospect of other modalities in the management of HCC with PVTT is mounting with favorable results. Targeting multiple pathways in the HCC cascade using a combination of drugs and other modalities such as RT, TACE, TARE, and HAIC appear effective for systemic and loco-regional control. The quest for the ideal combination therapy and the sequence set is still widely unanswered and prospective trials are lacking. With the armament of available therapeutic options and the advances and refinements in the delivery system, down-staging patients to make them eligible for curative resection has been reported. In a rapidly evolving treatment landscape, performing surgery when appropriate, in the form of LR and even LT to achieve cure does not seem farfetched. Likewise, adjuvant therapy and prompt management of the recurrences holds the key to prolong OS and DFS. This review discusses the management options of HCC patients with PVTT.

Pancreatic cancer is an almost incurable malignancy whose incidence has increased over the past 30 years. Instead of pursuing the development of modalities utilizing 'traditional' cytotoxic chemotherapeutic agents, we have explored the possibilities of developing novel multi-kinase inhibitor drug combinations to kill this tumor type. Several approaches using the multi-kinase inhibitors sorafenib, regorafenib, and neratinib have been safely translated from the bench to the bedside, with objective anti-tumor responses. This review will discuss our prior preclinical and clinical studies and discuss future clinical opportunities in this disease.

Colorectal cancer (CRC) is one of the leading cancers in terms of prevalence and mortality. Almost 1/4 of patients with CRC have metastases at the initial presentation. The survival rate of this group of patients remains low. With the onset of the COVID-19 pandemic, cancer patients have faced difficulties in getting diagnosis or treatment, which could potentially lead to an increase in late-stage tumors and mortality. This situation required changes in approaches to the treatment of cancer patients, such as replacing drugs with tablet forms, schemes with long intervals, and much more. It is known that about 50% of patients with metastatic colorectal cancer survive in satisfactory condition until the 3rd line drug therapy or longer. One of the main drugs for this category of patients is regorafenib, which, thanks to the tablet formulation, has become especially important in the COVID-19 pandemic. In numerous clinical studies, the drug showed an increase in patient overall survival and good safety profile. In addition, there is growing evidence of the effect of regorafenib on tumor sensitivity to treatment with platinum drugs, irinotecan, and EGFR inhibitors. © 2021 Consilium Medikum. All rights reserved.

Background and aim Regorafenib is a potent multikinase inhibitor for the second-line targeted therapy against hepatocellular carcinoma (HCC); however, drug resistance is emerging in clinical settings. Although cancer stem cells (CSCs) are considered as key determinate of drug sensitivity, it remains unclear how CSCs may communicate with the differentiated counterparts (non-CSC) to dictate therapeutic efficacy. Therefore, we sought to investigate the regorafenib resistance mechanism of CSCs in HCC. Methods We used sphere formation and soft agar colony formation assays to evaluate the stemness capacity of cancer cells. Cell viability assay was performed to detect the sensitivity of cancer cells to regorafenib. Real-time quantitative polymerase chain reaction and western blot were used to analyze gene expression. Mouse xenograft tumor model was performed to assess Regorafenib sensitivity in vivo. Results Exosomes are highly enriched in CSC supernatant compared with that of non-CSC, and RAB27A mediates exosome secretion from CSCs to maintain stem-like phenotype and regorafenib insensitivity. Moreover, exosomes released by CSCs upregulate the expression of Nanog in non-CSC, while depleting Nanog sensitizes non-CSC to regorafenib in the presence of CSC exosomes. Consistently, analysis of TCGA datasets reveals that RAB27A expression tightly correlates with Nanog in HCC tissues. More importantly, depletion of RAB27A downregulates Nanog expression and sensitizes cancer cells to regorafenib in nude mice. Conclusions Our findings suggest that CSCs release exosomes in a RAB27A-dependent manner to induce Nanog expression and regorafenib resistance in differentiated cells, targeting this exosome signaling between distinct cellular subsets may be a potential therapeutic strategy for HCC patients.

Colorectal cancer (CRC) is the second cause of cancer death worldwide. The metastatic disease is mainly treated with aggressive therapies consisting on combinations of cytotoxic chemotherapy plus anti-EGFR or anti-VEGF drugs. In spite of the improvements in clinical outcomes achieved in the last decade, these are the result of multiple new combinations using the existing therapeutic options and the introduction of regorafenib and TAS-102 in second or later lines of treatment. As immunotherapies are limited to less than 5% of CRC patients harboring tumors with deficient mismatch repair, there is an urgent need of finding new drugs to increase our patients' survival opportunities. Among all the natural products that are candidates to be used for the treatment of CRC cancer, curcumin (the golden spice) is in the spotlight. Used for centuries in the Ayurveda medicine, its demonstrated anticancer properties and low toxicity profile made it the focus of hundreds of preclinical and clinical investigations. So far we know that it can be combined with most of the aforementioned drugs in a safe and synergistic way. Regretfully, its poor bioavailability has been one of the main issues for its successful introduction in the clinic. Nevertheless, a plethora of new formulations with a huge increase in bioavailability are under study with promising results. In this review we discuss the possibility of incorporating curcumin in the treatment of CRC; specifically, we review preclinical and clinical data supporting its possible combination with current therapies as well as new formulations under clinical study. It is time for the golden spice revolution.

Background This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients and methods Patients (aged 6 months to Results Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60–93 mg/m2). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m2. The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand–foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. Conclusions The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m2. Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. Clinical trial number NCT02085148.

Lentinan is a natural β–glucan with various bioactivities and is combined with chemotherapy drugs for cancer treatment. Regorafenib is an oral multi-kinase inhibitor approved by FDA for treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors. Regorafenib has poor water solubility and multiple toxicities. We report drug–drug nanosuspensions of regorafenib and lentinan. Results of dynamic light scattering and scanning electron microscopy showed that the mean particle size of the regorafenib–lentinan nanosuspensions was approximately 200 nm and was uniformly distributed. Transmission electron microscopy findings indicated that lentinan stabilized the nanosuspensions by steric manner. Hydrogen bonds and hydrophobic interactions were found between regorafenib and lentinan by molecular dynamics simulation. The results of cytotoxicity assay and pharmacokinetics study in rats showed that the regorafenib–lentinan nanosuspensions reduced the toxicity and enhanced the in vitro anticancer activity and oral bioavailability of regorafenib. Lentinan as a natural stabilizer has the potential using for drug nanosuspensions. Drug–drug nanosuspensions are a new form of combination therapies that can reduce the number of drugs taken by patients and improve their compliance.

Ralf-Dieter Hofheinz,1 Jordi Bruix,2 George D Demetri,3 Axel Grothey,4 Marisca Marian,5 Jennifer Bartsch,6 Dawn Odom6 1Interdisciplinary Tumor Center, University of Heidelberg, Mannheim, Germany; 2Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic. IDIBAPS, University of Barcelona, CIBERehd, Barcelona, Spain; 3Ludwig Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; 4Gastrointestinal Cancer Research, West Cancer Center, OneOncology, Germantown, TN, USA; 5Oncology, Pharmaceuticals Division of Bayer AG, Basel, Switzerland; 6Department of Biostatistics, RTI Health Solutions, Research Triangle Park, NC, USACorrespondence: Ralf-Dieter HofheinzInterdisciplinary Tumor Center, University of Heidelberg, Theodor-Kutzer Ufer 1-3, Mannheim, 68167, GermanyTel +49 621 383 2855Fax +49 621 383 2488Email ralf.hofheinz@umm.dePurpose: The efficacy and safety of regorafenib have been demonstrated in phase 3 trials for multiple tumor types, including metastatic colorectal cancer (mCRC) (CORRECT [NCT01103323]; CONCUR [NCT01584830]), advanced gastrointestinal stromal tumor (GIST) (GRID [NCT01271712]), and hepatocellular carcinoma (HCC) (RESORCE [NCT01774344]). The objective of this post hoc exploratory analysis was to explore the impact of regorafenib on delaying health-related quality of life (HRQOL) deterioration across these tumor types.Patients and Methods: HRQOL data (assessed with EORTC QLQ-C30 and EQ-5D questionnaires) were pooled for all trials to determine time until definitive deterioration (TUDD), defined as the patient’s first minimal clinically important deterioration in HRQOL score from baseline that does not resolve, using stratified Kaplan–Meier estimators and Cox proportional hazards models adjusted for relevant trial, cancer type, and baseline covariates. Additional analyses based on cancer type were conducted by pooling mCRC trials (CORRECT and CONCUR) and pooling the two mCRC trials with the HCC trial (RESORCE).Results: A total of 1699 patients with HRQOL data were pooled across the four trials. The results showed that regorafenib significantly delayed TUDD compared with placebo across all three tumor types. Median time to deterioration across the five scales ranged from 16.3 to 24.1 weeks for regorafenib and 8.6 to 12.1 weeks for placebo. The results from the individual studies, the pooled mCRC trials, and the pooled mCRC and HCC trials were similar to the overall pooled results.Conclusion: A pooled analysis of four phase 3 trials demonstrated that regorafenib delayed a clinically relevant exploratory endpoint, defined as TUDD, compared with placebo across three different tumor types (mCRC, GIST, and HCC), which supports a novel benefit of the impact of regorafenib with respect to patients with these three types of cancers by allowing initial declines in HRQOL to resolve and patients the opportunity to continue treatment.Keywords: gastrointestinal cancer, metastatic colorectal cancer, hepatocellular cancer, quality of life, regorafenib

A 68-year-old man with hepatocellular carcinoma (HCC) visited his previous hospital due to abdominal pain and was diagnosed with ruptured HCC. Before visiting our hospital, he underwent HCC treatment at his previous hospital, but his tumors did not improve. Although he started treatment with sorafenib, the tumors rapidly grew. Subsequently, regorafenib was given, and the tumors shrank. After 22 months being treated with regorafenib, HCC reoccurred, with a new lung metastasis and a contrast-enhanced nodule on the peritoneal dissemination appearing. He underwent conversion surgery and survived for 4.5 years after his HCC was diagnosed.

Qian Zhang,1,2 Zhiqiang Wang,1– 3 Jingying Wu,1,2 Zhen Zhou,3 Renpeng Zhou,1,2 Wei Hu1,2 1Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Anhui Provincial Institute of Translational Medicine, Hefei, People’s Republic of China; 3Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, AustraliaCorrespondence: Renpeng Zhou; Wei Hu Email zhourenpeng@ahmu.edu.cn; huwei@ahmu.edu.cnBackground: Regorafenib is an oral multi-kinase inhibitor approved for the treatment of solid tumours, but the pharmacokinetic profile of regorafenib in the Chinese population is unclear.Objective: The aim of this study was to examine the pharmacokinetics, bioequivalence, and safety of two formulations of regorafenib 40 mg in healthy Chinese volunteers under fed and fasting conditions.Methods: A single-centre, randomised, open-label, two-period, two-way crossover phase 1 trial was conducted by randomising a single oral dose of test (T) or reference (R, Stivarga®) regorafenib (40 mg) to healthy Chinese volunteers under both fasting and fed conditions (high-fat and high-calorie diet). Pharmacokinetic parameters were calculated using non-compartmental methods. Adverse events were recorded to assess drug safety.Results: Sixty-six participants were enrolled for both fasting and fed treatments. The 90% CIs geometric least-square means of ratioT/R for regorafenib were completely contained within the equivalence margin of 80– 125% under both fasting and fed conditions. Both formulations displayed similar and generally good safety profiles.Conclusion: Single oral dose of the T (40 mg) and R (40 mg) regorafenib was bioequivalent under fasting and fed conditions and had similar favourable safety profiles among healthy Chinese volunteers.Keywords: regorafenib, phase 1, pharmacokinetic, bioequivalence, Chinese healthy volunteers

Pseudoprogression (PP) is a diagnostic dilemma in the follow-up of brain high grade gliomas (HGG), and the introduction of new therapies has further complicated its identification in Magnetic Resonance Imaging (MRI). We report a case of pseudoprogression after intraoperative radiotherapy (ioRT) and Regorafenib therapy in a patient with anaplastic astrocytoma recurrence. A 65-year-old man, treated in August 2017 for a right frontal anaplastic astrocytoma, with surgical resection and following radiotherapy and Temozolomide, in October 2019 was again treated for peri-surgical bed recurrence with resection and ioRT followed by Regorafenib therapy, interrupted in February 2020, after the onset of adverse reactions. MRI examination showed a large irregular alteration posterior to the surgical bed, T2 weighted hypointense featuring strong diffusion restriction (low ADC values), with an irregular contrast-enhancement (CE) pattern, and surrounded by a vast vasogenic oedema; Dynamic Susceptibility Contrast (DSC) perfusion imaging (PWI) showed no increase of relative cerebral blood volume (rCBV). Particularly, lesion appeared markedly hypointense and dusty-like on susceptibility weighted images (SWI) probably due to a constant hemorrhagic diapedesis promoted by Regorafenib. Therefore, pseudoprogression was suspected. Follow-up MRI exams showed gradual reduction of SWI and CE abnormalities, but a persistent DWI restriction. Unfortunately, the last MRI control showed a secondary cerebellar localisation of the disease. New therapies are changing MRI pattern in HGG imaging and this case underlines how a multimodality approach is increasingly necessary. In particular, when using anti-VEGF drugs, SWI can have a crucial role in identifying therapy-related haemorrhagic changes.

Background & Aims A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option. Methods Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels. Results Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50–0.79), cabozantinib (HR = 0.76, 95% CI = 0.63–0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70–0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36–0.52), regorafenib (HR = 0.46, 95% CI = 0.37–0.56), ramucirumab (HR = 0.54, 95% CI = 0.43–0.68), brivanib (HR = 0.56, 95% CI = 0.42–0.76), S-1 (HR = 0.60, 95% CI = 0.46–0.77), axitinib (HR = 0.62, 95% CI = 0.44–0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57–0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients’ stratification. Conclusions The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

Background This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy. Patients and methods Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%). Results From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib. Conclusion Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy. Clinical trial registration The trial is registered at ClinicalTrials.gov ( NCT02389244 ).

Objectives: Advanced-stage biliary tract cancers (BTC) are rare malignancies with poor prognosis. There are few prospective trials, but several retrospective studies regarding treatment options. In this study, we aimed to investigate the role of systemic inflammatory parameters (SIP) and other possible independent factors that may affect survival and treatment approaches and to determine the benefit of later-line treatments in these patients. Methods: A total of 284 patients, initially diagnosed with advanced stage or progressed after curative treatment of BTC, from different oncology centers in Turkey were included in this retrospective study. The prognostic significance of clinicopathological factors, SIPs and treatment options was analyzed. Results: At a median follow-up of 13 months, the median progression-free survival (PFS) was 6.1 months (95% CI:5.51–6.82), and the median overall survival (OS) time was 16.8 months (95% CI: 13.9–19.6). Treatment choice (p

Regorafenib (REG) is a tyrosine kinase inhibitor approved for treatment refractory metastatic colorectal cancer (mCRC) and has been shown to improve median overall (OS) and progression-free survival (PFS) by 1.4 and 0.2 months respectively. As >50% of patients experienced adverse REG-induced toxicities, biomarkers to predict responders are urgently required. To address this, we established a pre-clinical platform of molecularly subtyped cell line xenografts (CDXs) and patient derived xenografts (PDXs), and employed a multi-‘omic strategy to interrogate biomarkers of response. CDXs representing CRC consensus molecular subtypes (CMS) were established and REG (10mg/kg) was administered orally for a maximum of 4 weeks. Contrast-enhanced ultrasound (CEUS) was used to monitor early effects of REG on tumour vasculature in CDX models. A CRC PDX study was performed models were assigned to CMS and novel copy number clusters. To better understand subtype specific responses to REG unsupervised differential gene expression analysis was used to identify mechanisms of resistance. Finally, a validated systems model of BCL2 proteins (‘DR_MOMP’) and a gene-based proliferation signature were employed in an attempt to predict REG response withing molecular subtypes. CDXs and PDXs replicated the subtype specific drug response observed in the clinic. CEUS analysis indicated no treatment effects of REG on vessel function at early time points. CMS4 subtyped CDXs and PDXs showed the best response to REG. We further observed a significant (P = 0.04) predictive correlation between proliferation index and tumour response in CMS4 derived PDXs. Differential gene expression analysis revealed a potential role for EPHA2, UTG1A1, MAPK11, KIT and CYP2B6 in mediating REG resistance and revealed that EPHA2 expression was predictive of REG response in PDXs. There was also a linear correlation between DR_MOMP stress dose (P = 0.03), and tumour growth in CMS4 models. Tumours with high copy number exhibited favourable response to REG vs copy number stable tumours. This was verified in patient samples from the REARRANGE trial (NCT02835924). PDXs maintained consistent copy number profiles across consecutive passages. Overall, we have provided evidence for a differential effect of REG across CRC subtypes. We further demonstrated the utility of employing multi-omic analysis in clinically relevant models to identify putative biomarkers for multi-targeted tyrosine kinase inhibitors.

Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β-catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.

The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT. Tumor heterogeneity for secondary resistant KIT mutations within the same patient adds further complexity to GIST treatment. Several other mechanisms converge and reactivate the MAPK pathway upon KIT/PDGFRA–targeted inhibition, generating treatment adaptation and impairing cytotoxicity. To address the multiple potential pathways of drug resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the FDA for the treatment of adult patients with advanced GIST who have received previous treatment with 3 or more kinase inhibitors, including imatinib. Here we show that ripretinib treatment in combination with MEK inhibitors is effective at inducing and enhancing the apoptotic response and preventing growth of resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, even after long-term removal of drugs. The effect was also observed in systemic mastocytosis (SM) cells, wherein the primary drug–resistant KIT D816V is the driver mutation. Our results show that the combination of KIT and MEK inhibition has the potential to induce cytocidal responses in GIST and SM cells.

Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.

Background/aim Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. Patients and methods Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. Results We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). Conclusion The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.

The families of miR-34 and miR-449 share the same seed region. However, the members showed differential effects on the expression of B7-H3 and PD-L1 in HCT-116 cells. Using miR-34a as a template, the non-seed region was modified by nucleotide alteration, yielding four synthetic microRNA (miRNA) analogs. Among those, NS-MX3, with a base alteration from G to C at the 18th locus of miR-34a, showed the most potent inhibition on both B7-H3 and PD-L1 expression. Subsequent investigations demonstrated that NS-MX3 had a broad anti-proliferation activity against several colorectal tumor cell lines and its antitumor effect was consistently reflected by tumor growth inhibition (TGI) in the HCT-116 xenograft model. In addition, NS-MX3 displayed a synergistic effect on TGI when combined with bevacizumab or regorafenib. Further analysis revealed that the superior antitumor activity of NS-MX3 was correlated to concomitant suppression of both B7-H3 and PD-L1 expression in tumor tissues. Taken together, the present study indicates that the non-seed region of miRNAs plays an important role in the regulation of checkpoint genes, thus showcasing single nucleotide alteration of the non-seed region as a promising approach to discover and develop novel immunotherapies.

To investigate the clinical importance of the inflammatory prognostic index (IPI) in patients with metastatic colorectal cancer treated with regorafenib. A retrospective analysis of 65 metastatic CRC patients treated with regorafenib between 2015 and 2020 was performed. The association between NLR, PNLR, IPI, and overall survival (OS) and progression-free survival (PFS) was evaluated. According to the cut-off points, patients were divided into two groups. The patients in the high IPI group showed poorer OS compared to patients in the low IPI groups. The PFS was better in patients with low neutrophil-lymphocyte ratio (NLR) and platelet-neutrophil to lymphocyte ratio (PNLR), and the OS was better in patients with low IPI. Among the immune inflammation scores analyzed in mCRC patients receiving regorafenib, NLR and PNLR were the best predictor of recurrence, whereas IPI was the best predictor of long-term survival. After being confirmed by better designed controlled trials, IPI can be used to identify the group of patients who will benefit more from regorafenib treatment.

Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy.