cabozantinib and regorafenib

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Hepatectomy; Humans; Liver Neoplasms; Liver Transplantation; Phenylurea Compounds; Pyridines; Quinolines; Ramucirumab; Retreatment; Sorafenib

The present network meta-analysis was conducted to perform an indirect comparison among ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma (HCC) progressed on sorafenib treatment.. A systematic review through Medline, Embase, and Cochrane library was developed, with eligible randomized clinical trials been included. Hazard ratios (HRs) including progression-free survival (PFS), overall survival (OS), odds ratios of disease control rate (DCR), objective response rate (ORR), and adverse events were compared indirectly with network meta-analysis using random model in software STATA version 13.0.. A total of 4 randomized clinical trials including 2137 patients met the eligibility criteria and enrolled. Indirect comparisons showed that there was no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among agents of regorafenib, cabozantinib, and ramucirumab in advanced HCC patients with elevated α-fetoprotein (AFP) (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib was the only agent associated with significant superiority in OS, compared with placebo (hazard ratio 0.67, 95% CI, 0.50-0.90).. The present network meta-analysis revealed that there might be no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among regorafenib, cabozantinib, or ramucirumab in advanced HCC patients with elevated AFP (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib might be associated with significant superiority in OS, compared to placebo, which need further investigation in clinical practice.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Administration Schedule; Humans; Liver Neoplasms; Neoplasm Metastasis; Phenylurea Compounds; Pyridines; Ramucirumab; Randomized Controlled Trials as Topic; Sorafenib

Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice.. Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA).. Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection.. Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib; Survival Analysis; Vascular Endothelial Growth Factor A

Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first-line and second-line treatment options should yield significant improvements in survival.. To summarize the evolving landscape of treatment options for patients with advanced HCC.. We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences.. Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine-kinase inhibitor, was recently shown to have non-inferior survival vs sorafenib and is another first-line treatment option. The tyrosine-kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second-line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population.. There are several first-line and second-line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Disease Progression; Humans; Immunotherapy; Liver Neoplasms; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib; Therapies, Investigational

Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.

Topics: Algorithms; Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib; Treatment Outcome

The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that can only benefit from systemic treatments. Although HCC is highly treatmentresistant, significant achievements have been made in the molecular targeted therapy and immunotherapy of HCC. In addition to regorafenib, cabozantinib and ramucirumab were approved for the second- line targeted treatment by the FDA after disease progression on sorafenib. Nivolumab failed to demonstrate remarkable benefit in overall survival (OS) as first-line therapy, while pembrolizumab did not achieve pre-specified statistical significance in both OS and progression-free survival (PFS) as second-line treatment. Combinations of targeted agents, immune checkpoint inhibitors and other interventions showed favorable results. In this review, we summarized the progress of systemic therapy in HCC and discussed the future directions of the treatment of HCC.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Nivolumab; Phenylurea Compounds; Progression-Free Survival; Pyridines; Ramucirumab

Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.

Topics: Anilides; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinolines; Sorafenib

Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

Topics: Anilides; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Pyridines; Quinolines; Ramucirumab; Sorafenib; Treatment Outcome

The principal advancements in the treatment of hepatocellular carcinoma (HCC) are the use of new systemic treatments, such as lenvatinib in first-line treatment and regorafenib, cabozantinib, and ramucirumab in second-line treatment, because of their benefits in terms of overall survival. In addition, nivolumab as a second-line agent was approved by the US Food and Drug Administration in 2017 based on improved radiological response data. Physicians and patients alike will greatly benefit from this expanded arsenal of treatments once all these new drugs for the treatment of HCC finally become available. Unfortunately, in our review of the available data, we found a conspicuous lack of approved systemic treatments for HCC in the distinct setting of after liver transplantation (LT). Careful evaluation of the clinical trials for approved systemic treatments of HCC is crucial when considering the best options for those with HCC recurrence after LT. Although several first-line or second-line treatments have been shown to be effective for HCC, each of these trials was composed of its own specific populations, and those with HCC recurrence after LT were excluded. We have also summarized from a critical and clinical point of view the issues involved in the management of patients who are candidates for systemic treatment in this era of multiple drugs for the same indication.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Humans; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Nivolumab; Patient Selection; Phenylurea Compounds; Progression-Free Survival; Pyridines; Quinolines; Ramucirumab; Randomized Controlled Trials as Topic

The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.

Topics: Aged; Aged, 80 and over; Anilides; Animals; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Disease Progression; Female; Humans; Liver Neoplasms; Male; Models, Animal; Molecular Targeted Therapy; Pharmacokinetics; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Sorafenib; Treatment Outcome

Portal vein tumour thrombosis is common among patients with advanced hepatocellular carcinoma. Tremendous differences exist in the management of hepatocellular carcinoma with portal vein tumour thrombosis between the east and the west, which derive from heterogeneities in its epidemiology, causes, pathology, comorbidities, prognosis, and other demographics. These divergences between the east and the west are not only caused by hepatocellular carcinoma itself, but are also affected by many variables including social factors, physician preferences, accessibility to costly or novel treatments, and reimbursement schemes. In this Review, we compare and contrast the management of hepatocellular carcinoma with portal vein tumour thrombosis in the east and in the west in terms of systemic and surgical treatments, radiotherapy, transcatheter arterial therapies, and portal vein revascularisation. We conclude that a personalised, data-driven approach to care with active management from a multidisciplinary team, as well as increased communication and collaboration between clinicians and researchers based in east and the west, could help to reduce the differences in management and optimise treatment strategies.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Endovascular Procedures; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Liver Transplantation; Nivolumab; Patient Care Team; Phenylurea Compounds; Portal Vein; Pyridines; Quinolines; Radiotherapy, Adjuvant; Ramucirumab; Sorafenib; Stents; Venous Thrombosis

The approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first- and second-line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.. To summarise the evolving field of systemic therapy of hepatocellular carcinoma.. We reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.. We discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.. The tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib-experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib-experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.

Topics: Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib

The global burden of hepatocellular carcinoma (HCC) is increasing and might soon surpass an annual incidence of 1 million cases. Genomic studies have established the landscape of molecular alterations in HCC; however, the most common mutations are not actionable, and only ~25% of tumours harbour potentially targetable drivers. Despite the fact that surveillance programmes lead to early diagnosis in 40-50% of patients, at a point when potentially curative treatments are applicable, almost half of all patients with HCC ultimately receive systemic therapies. Sorafenib was the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months. New drugs - lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line - have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year; thus, therapeutic breakthroughs are still needed. Immune-checkpoint inhibitors are now being incorporated into the HCC treatment armamentarium and combinations of molecularly targeted therapies with immunotherapies are emerging as tools to boost the immune response. Research on biomarkers of a response or primary resistance to immunotherapies is also advancing. Herein, we summarize the molecular targets and therapies for the management of HCC and discuss the advancements expected in the near future, including biomarker-driven treatments and immunotherapies.

Topics: Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Precision Medicine; Pyridines; Quinolines; Ramucirumab; Sorafenib

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.

Topics: Angiogenesis Inhibitors; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab

The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

Topics: Anilides; Axitinib; Fatigue; Humans; Imidazoles; Indazoles; Neoplasms; Odds Ratio; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor

The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.

Topics: Anilides; Crizotinib; Humans; Imatinib Mesylate; Imidazoles; Indoles; Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyridines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sorafenib; Sunitinib

Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC).. A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020.. A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29-0.62;. This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation.. Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC.

Topics: Colorectal Neoplasms; Humans; Prospective Studies; Pyridines; Vascular Endothelial Growth Factor A

Some studies indicate that the angiogenesis process is related to vascular endothelial growth factor, which can interact with endothelial cell surface receptors (VEGF-R1, VEGF-R2, and VEGF-R3); this biochemical process and other factors result in the promotion and growth of new blood vessels under normal conditions. However, some studies indicate that this phenomenon could also occur in cancer cells. It is important to mention that some amino derivatives have been prepared as VEGF-R1 inhibitors; however, their interaction with VEGF-R1 is not clear, perhaps due to different experimental approaches or differences in their chemical structure.. The aim of this study was to evaluate the theoretical interaction of several amino-nitrile derivatives (Compounds 1 to 38) with VEGF-R1.. The theoretical interaction of amino-nitrile derivatives with VEGF-R1 was carried out using the 3hng protein as the theoretical model. In addition, cabozantinib, pazopanib, regorafenib, and sorafenib were used as controls in the DockingServer program.. The results showed different amino acid residues involved in the interaction of amino-nitrile derivatives with the 3hng protein surface compared with the controls. In addition, the inhibition constant (Ki) was lower for Compounds 10 and 34 than for cabozantinib. Other results show that Ki for Compounds 9, 10, 14, 27-29 and 34-36 was lower in comparison with pazopanib, regorafenib, and sorafenib.. All theoretical data suggest that amino-nitrile derivatives could produce changes in the growth of some cancer cell lines through VEGFR-1 inhibition. Therefore, these amino-nitrile derivatives could be a therapeutic alternative to treat some types of cancer.

Topics: Humans; Models, Theoretical; Neoplasms; Sorafenib; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980. In recent years, new systemic therapies for HCC have been approved and a critical assessment of the existing data is necessary to balance benefits and harms and inform the development of evidence-based guidelines.. The American Gastroenterological Association formed a multidisciplinary group consisting of a Technical Review Panel and a Guideline Panel. The Technical Review Panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of systemic therapies in patients with advanced-stage HCC. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations.. The Panel reviewed the evidence, summarized in the Technical Review, for the following medications approved by the US Food and Drug Administration for HCC: first-line therapies: bevacizumab+atezolizumab, sorafenib, and lenvatinib; second-line therapies: cabozantinib, pembrolizumab, ramucirumab, and regorafenib; and other agents: bevacizumab, nivolumab, and nivolumab+ipilimumab.. The Panel agreed on 11 recommendations focused on systemic therapy for HCC in patients who are not eligible for locoregional therapy or resection, those with metastatic disease and preserved liver function, those with poor liver function, and those on systemic therapy as adjuvant therapy.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Hepatectomy; Humans; Liver Neoplasms; Liver Transplantation; Phenylurea Compounds; Pyridines; Quinolines; Ramucirumab; Retreatment; Sorafenib

Topics: Aminopyridines; Anilides; Animals; Benzamides; Cell Line, Tumor; Colonic Neoplasms; Histone Deacetylase Inhibitors; Immune Checkpoint Inhibitors; Mice; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridines; Receptors, Vascular Endothelial Growth Factor; RNA; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Recently, three published phase III trials highlighted the superiority of investigational drugs compared to placebo, thus leading to their approval in the second-line setting. We report here a MAIC of second-line MKI options for patients with HCC previously treated with sorafenib using individual real-world data of regorafenib and aggregate data of second-line cabozantinib from the CELESTIAL trial.. Data from 278 patients who received regorafenib as second-line therapy after sorafenib failure for unresectable HCC were used as IPD. Data inclusion were adapted to those reported in the CELESTIAL trial in the subset of patients who received sorafenib as the only prior therapy. Survival medians and rates were obtained from Kaplan-Meier curves, and differences between regorafenib and cabozantinib groups were explored through Cox regression adjusted for weights originating from MAIC.. The median OS of the weighted regorafenib group was 11.1 months (IQR: 5.6-16.4) and 11.3 (IQR: 6.7-22.4) for cabozantinib; HR 0.83 (95%CI 0.62-1.09). The median PFS of the weighted regorafenib group was 3.0 months (IQR: 1.9-4.8) and 5.5 (IQR: 2.3-9.3) for cabozantinib; HR 0.50 (95%CI 0.41-0.62). In the subgroup who received prior sorafenib for < 3 months, the median OS of the regorafenib group was 6.5 months (IQR: 4.7-10.9) and 9.5 months (IQR: 5.9-18.2) for cabozantinib; HR 0.68 (95%CI 0.39-1.16). In the subgroup receiving prior sorafenib for 3 to < 6 months, the median OS of the regorafenib group was 8.0 months (IQR: 4.2-15.2) and 11.5 (IQR: 6.5-23.9) for cabozantinib; HR 0.66 (95%CI 0.42-1.02). In the subgroup receiving prior sorafenib for ≥ 6 months, the median OS of the regorafenib group was 13.4 (IQR: 8.1-46.5) and 12.3 (IQR: 6.6-22.9) for cabozantinib; HR 0.89 (95%CI 0.52-1.51).. Our results confirmed no differences between regorafenib and cabozantinib in terms of OS. However, in earlier progressors on prior sorafenib a larger benefit might be expected from cabozantinib treatment.

Topics: Adult; Aged; Anilides; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Female; Humans; Liver Neoplasms; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Pyridines; Salvage Therapy; Sorafenib

The CELESTIAL, RESORCE, and REACH-2 trials showed survival benefit of cabozantinib, regorafenib, and ramucirumab, respectively, in hepatocellular carcinoma (HCC) patients treated with sorafenib who had good performance status (ECOG 0-1) and liver function (Child-Pugh-A). This study characterizes subsequent treatments received by HCC patients after sorafenib, and determines the proportion of patients eligible for novel therapies if strict eligibility criteria (SEC) were utilized compared to more liberal modified eligibility criteria (MEC, including ECOG 2, Child-Pugh-B7).. HCC patients who received sorafenib between 2008 and 2017 were included from the Canadian HCC CHORD Database. Patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, and REACH-2 trial SEC or MEC. Median overall survival (mOS) was assessed using the Kaplan-Meier method.. A total of 730 patients were identified; and 172 (23.6%) received subsequent treatment. Patients who received subsequent treatment had longer mOS than those who did not (12.1 vs 3.3 months; P < .001). Using SEC, only 13.1% of patients would be eligible for cabozantinib, regorafenib, or ramucirumab. Expanding eligibility to include patients who meet MEC increased the proportion of eligible patients to 31.7%. Higher ineligibility for regorafenib and ramucirumab was driven by trial-specific criteria, including sorafenib intolerance (28%) for RESORCE and AFP <400 (58.9%) for REACH-2.. A small proportion of real-world HCC patients would be eligible for cabozantinib, regorafenib, or ramucirumab if SEC in clinical trials were followed, while more than double would be eligible if MEC were applied. Patients who received subsequent treatment had improved mOS, regardless of whether they met SEC or MEC.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Canada; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Databases, Factual; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Patient Selection; Phenylurea Compounds; Pyridines; Ramucirumab; Randomized Controlled Trials as Topic; Sorafenib; Time Factors

Sorafenib and Regorafenib are the recommended first- and second-line therapies in patients with advanced hepatocellular carcinoma (HCC). Lenvatinib and Cabozantinib have shown non-inferior antitumoral activities compared with the corresponding recommended therapies. The clinical trials have established recommended doses for each treatment that lead different blood concentrations in patients for Sorafenib (10 µM), Regorafenib (1 µM), Lenvatinib (0.1 µM), and Cabozantinib (1 µM). However, very low response rates are observed in patients attributed to intrinsic resistances or upregulation of survival signaling. The aim of the study was the comparative dose-response analysis of the drugs (0-100 µM) in well-differentiated (HepG2, Hep3B, and Huh7), moderately (SNU423), and poorly (SNU449) differentiated liver cancer cells in 2D/3D cultures. Cells harbors wild-type p53 (HepG2), non-sense p53 mutation (Hep3B), inframe p53 gene deletion (SNU423), and p53 point mutation (Huh7 and SNU449). The administration of regular used in vitro dose (10 µM) in 3D and 2D cultures, as well as the dose-response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Lenvatinib and Cabozantinib were particularly effective in moderately to poorly differentiated cells with mutated or lacking p53 that have lower basal oxygen consumption rate (OCR), ATP, and maximal respiration capacity than observed in differentiated HCC cells. Sorafenib and Regorafenib downregulated, and Lenvatinib and Cabozantinib upregulated epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor receptor (c-Met) in HepG2 cells. Conclusions: Sorafenib and Regorafenib were especially active in well-differentiated cells, with wild-type p53 and increased mitochondrial respiration. By contrast, Lenvatinib and Cabozantinib appeared more effective in moderately to poorly differentiated cells with mutated p53 and low mitochondrial respiration. The development of strategies that allow us to deliver increased doses in tumors might potentially enhance the effectiveness of the treatments.

Topics: Adult; Anilides; Apoptosis; Cell Culture Techniques; Cell Differentiation; Cell Proliferation; Cell Respiration; Female; Hep G2 Cells; Hepatocytes; Humans; Liver Neoplasms; Male; Mitochondria; Oxygen Consumption; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Sorafenib; Spheroids, Cellular; Tumor Suppressor Protein p53

No trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC).. Conduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib.. The CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared.. In the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9-17.0] versus 10.6 [9.1-12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9-7.3] versus 3.1 [2.8-4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib (p  ≤ 0.001).. Cabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.. Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma. Video by Professor Katie Kelley.E. (MP4 420454 kb) Methods used in the matching-adjusted indirect comparison of cabozantinib versus regorafenib in patients with advanced hepatocellular carcinoma. A video. (MP4 160304 kb).. Cabozantinib and regorafenib are treatments approved for some patients with advanced hepatocellular carcinoma (HCC), a type of liver cancer, after disease progression despite prior sorafenib treatment. Cabozantinib, regorafenib and sorafenib are tyrosine kinase inhibitors (TKIs), meaning that they slow cancer progression by targeting specific ways that tumors grow. Cabozantinib and regorafenib offer benefits to patients compared with placebo (i.e., no treatment) for those who have progressed despite sorafenib treatment. No clinical studies have compared cabozantinib and regorafenib directly. This study compared the efficacy and safety of cabozantinib and regorafenib using data from trials of each drug versus placebo: CELESTIAL for cabozantinib and RESORCE for regorafenib. These two trials were similar—both involved patients with progressive advanced HCC who had received previous cancer treatment. There were some important differences, but these were minimized using statistical methods (matching and adjustments/“weighting”) allowing outcomes to be meaningfully compared. One difference that could not be removed by the statistical methods was that patients who were intolerant to prior sorafenib were excluded from RESORCE but were eligible for the CELESTIAL trial. In the otherwise matched populations, treatment with cabozantinib was associated with similar overall survival and significantly longer progression-free survival than regorafenib. Rates of diarrhea were significantly lower for regorafenib than cabozantinib, suggesting that regorafenib may be better tolerated, but this may reflect the exclusion of sorafenib-intolerant patients from RESORCE. These findings cannot replace a head-to-head study, but may help in guiding decision-making between cabozantinib and regorafenib in patients with progressive advanced HCC after soraftenib treatment.

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Comparative Effectiveness Research; Disease Progression; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Outcome and Process Assessment, Health Care; Phenylurea Compounds; Progression-Free Survival; Pyridines; Randomized Controlled Trials as Topic; Sorafenib

Hepatocellular carcinoma (HCC) is one of the most lethal cancers. After many years of stagnation, there are now several systemic treatments available for patients with HCC.. To analyse the feasibility and efficacy of sequential systemic treatments in patients with HCC in clinical practice.. In this multicentre study, patients who were treated with novel systemic therapies for HCC between 2014 and 2019 at two referral centres, Hannover Medical School, Germany, and Medical University of Vienna, Austria, were included.. Overall, 85 patients were included of which 76 patients (89.4%) received more than one and a maximum of five systemic treatment lines. The most common therapy sequence was sorafenib (n = 72; 84.7%) followed by regorafenib (n = 37; 48.7%), whereas 11 patients were initially treated with lenvatinib (12.9%). Other second-line treatments included pembrolizumab, nivolumab, cabozantinib and ramucirumab. Hepatic function deteriorated during sequential systemic treatment in 48.6% of the patients as defined by an increase in at least one Child-Pugh point. Median overall survival (mOS) from the start of first systemic treatment was 35 months for patients with sequential systemic treatment compared to 9 months for patients with one systemic treatment line (P < 0.001). Patients previously treated with surgical/locoregional therapies had a longer mOS compared to patients with initial systemic treatment (66 vs 25 months; P = 0.020).. Sequential systemic treatment is feasible and effective in selected patients with HCC in clinical practice. Our study underlines the critical importance of well-preserved liver function for successful administration of sequential systemic therapy.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Ramucirumab; Sorafenib

Hepatocellular carcinoma (HCC) is one of the most common types of cancer with increasing incidence. It accounts for approximately 90% of primary liver cancers and it is a significant global health problem. Globally, it represents the 5th most common disease and it is considered to be the third most common cause of cancer related deaths. The occurrence of HCC is related to environmental factors, eating habits and lifestyle. It is more common in men than in women. The highest incidence of HCC is in Southeast Asia, China, West and Central Africa, and among immigrants from high-risk areas in the United States. In North America, Europe and Japan, hepatitis C virus infection is its major risk factor along with alcohol consumption. Modern therapeutic methods improved the results of the treatment in patients with HCC. In early stages of HCC, curative treatment, surgical resection, liver transplantation, and radiofrequency ablation are possible. In advanced disease, local chemotherapy and systemic targeted therapy have prolonged survival.. The aim of the article is to present the possibilities of systemic treatment of HCC in first and second lines of the treatment. Sorafenib was the first drug to be approved by the U. S. Food and Drug Administration for the treatment of advanced HCC and is a standard first-line drug. The first choice in the second line treatment of patients with progressive disease (after the treatment with sorafenib) is regorafenib. Nowadays, immunotherapy is also an adequate treatment option. Cabozantinib and ramucirumab represent additional treatment.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Phenylurea Compounds; Pyridines; Ramucirumab; Sorafenib

Protein kinase inhibitors have been widely used as therapeutic agents to treat a variety of diseases, but many of them may cause off-target effects by unexpectedly targeting other noncognate kinases due to high conversion across the protein kinase family. The mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in tumorigenesis, which has been recognized as a high priority in the druggable target candidates of anticancer therapy. Here, we attempt to investigate the untargeted kinase-inhibitor interactions (UKIIs) of kinase-targeted therapies for the cancer MAPK signaling cascade via an integration of biomolecular modeling, cell viability assay and kinase inhibition analysis. A systematic kinase-inhibitor interaction profile is created for 28 FDA-approved kinase inhibitor drugs across 9 caner-related MAPK kinases. The created profile is analyzed at structural, energetic and dynamic levels and, consequently, totally 18 promising UKII pairs with high theoretical affinity are derived, from which the noncognate inhibitors Cabozantinib, Regorafenib and Crizotinib are selected to test their cytotoxic effects on human epithelial colorectal adenocarcinoma Caco-2 cell line and inhibition activity against the recombinant protein of human p38α kinase domain. The obtained results are compared with two cognate MAPK inhibitors JNK-IN-8 and BIRB796. As might be expected, the Regorafenib, Crizotinib and Cabozantinib exhibit high, moderate and low cytotoxicities, respectively. In addition, the Regorafenib is determined to have a potent p38α-inhibitory activity. This is basically in line with the test results of positive controls JNK-IN-8 and BIRB796 and can be well confirmed by computational modeling.

Topics: Amino Acid Sequence; Anilides; Caco-2 Cells; Cell Survival; Colorectal Neoplasms; Crizotinib; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Ligands; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Sequence Alignment; Structure-Activity Relationship