cabozantinib and Liver-Neoplasms

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

Recurrent hepatocellular carcinoma (HCC) develops in 15-20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatments and no prior treatment with cabozantinib. In this study, 60 mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8 weeks to evaluate response. The primary end point of this study will be the disease control rate at 4 months after treatment. The secondary end points will be overall survival, progression-free survival and safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3 years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.. Liver cancer is the sixth most diagnosed cancer worldwide with few available curative treatments. Liver transplantation (LT) is considered as one of the treatments for liver cancer especially in earlier stages of cancer. However, after LT, cancer develops again in 15–20% of the patients who undergo transplant for liver cancer. Compared with liver cancer in the nontransplant population, recurrent cancer grows faster and spreads in the body very quickly. Therefore, unfortunately, to date there are limited treatment options for these patients without significant effect on their survival. In this study, we aim to evaluate the effect of a new medication called cabozantinib on patients who develop recurrent liver cancer after their LT. Cabozantinib has been already tested in patients with liver cancer and was shown to be effective and safe in nontransplant patients. However, this is the first study to evaluate the effect of cabozantinib in liver transplant recipients with recurrent liver cancer. Clinical Trial Registration: NCT04204850 (ClinicalTrials.gov).

Topics: Adult; Anilides; Carcinoma, Hepatocellular; Clinical Trials, Phase II as Topic; Humans; Liver Neoplasms; Liver Transplantation; Pyridines

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

Hepatocellular carcinoma (HCC) is rising in incidence and remains a leading cause of cancer-related death. After a decade of disappointing trials following the approval of sorafenib for patients with advanced HCC, a number of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting angiogenesis and immune checkpoints have recently been approved. The phase 3 CELESTIAL trial demonstrated improved progression-free and overall survival with the TKI cabozantinib compared to placebo, supporting it as a treatment option for patients with advanced HCC previously treated with sorafenib. Cabozantinib blocks multiple key pathways of HCC pathogenesis, including VEGFR, MET, and the TAM (TYRO3, AXL, MER) family of receptor kinases, and promotes an immune-permissive tumor microenvironment. Here, we review the mechanisms of action of cabozantinib, including effects on tumor growth and its immunomodulatory properties, providing pre-clinical rationale for combination strategies with checkpoint inhibitors. We discuss the design and outcomes of CELESTIAL including improved survival across subgroups defined by age, disease etiology, baseline AFP level, prior therapies (including duration of prior sorafenib), and tumor burden. Cabozantinib had a manageable safety profile with dose modification. Studies combining cabozantinib with atezolizumab (COSMIC-312) and durvalumab (CAMILLA) in the first and second-line settings are ongoing, as well as a neoadjuvant study of cabozantinib with nivolumab. Future investigations are warranted to define the use of cabozantinib in patients with Child-Pugh B liver function and identify markers predictive of clinical benefit. The role of cabozantinib in HCC continues to evolve with an anticipated role in immunotherapy combinations.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyridines

Altered receptor tyrosine kinase (RTK) signaling contributes to tumorigenesis and suppression of immune-mediated destruction of cancer cells. Cabozantinib is an oral tyrosine kinase inhibitor that inhibits several RTKs involved in tumorigenesis, and is approved for the treatment of patients with progressive metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma that has been previously treated with sorafenib.. We present an up-to-date evaluation of preclinical evidence for RTK inhibition with cabozantinib, specifically VEGFR, MET, KIT, RET, AXL, FLT3, and associated antitumor effects. Preclinical investigations of cabozantinib in combination with other anticancer drugs are also reviewed.. Preclinical evidence shows that cabozantinib has antitumor activity against various cancer cells and exhibits synergy with other anticancer agents, including immune checkpoint inhibitors and hormone receptor or metabolic pathway inhibitors. Further optimization of cabozantinib treatment requires the identification of biomarkers of response and resistance, and exploration of complementary drug targets. Investigation of mechanisms of adaptive resistance, such as epithelial to mesenchymal transition (cancer intrinsic) and immunomodulation by the tumor microenvironment (cancer extrinsic), as well as identification of novel drug targets based on characterization of cancer stem cell metabolomic phenotypes, appear to be promising approaches.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Epithelial-Mesenchymal Transition; Humans; Kidney Neoplasms; Liver Neoplasms; Protein Kinase Inhibitors; Pyridines; Tumor Microenvironment

Topics: alpha-Fetoproteins; Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; beta Catenin; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Nivolumab; Patient Selection; Prognosis; Pyridines; Ramucirumab; RNA-Seq; Single-Cell Analysis; Tumor Microenvironment

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

Hepatocellular carcinoma (HCC) is one of the most frequent tumors affecting the gastrointestinal tract and a universal cause of morbidity and mortality. Cabozantinib is a strong multi-inhibitor of receptor tyrosine kinases approved for renal cell carcinoma that could be useful also for the treatment of HCC.. This review describes the chemical structure, the pharmacologic properties and current knowledge of the efficacy of cabozantinib in the treatment of HCC based on data available from first phase and later phase clinical trials. The ongoing studies testing cabozantinib, either alone or in combination with other drugs, are also described.. Despite the recent achievements in the use of cabozantinib for patients diagnosed with hepatocellular carcinoma, data are still needed to allow clinicians to make better decisions on how to treat specific patient subgroups.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Pyridines

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

Cabozantinib (Cabometyx

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Liver Neoplasms; Pyridines

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

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Traditional chemotherapy drugs are hard to reach a satisfactory therapeutic effect since advanced HCC is highly chemo-resistant. Sorafenib is an oral multikinase inhibitor that can suppress tumor cell proliferation, angiogenesis and induce cancer cell apoptosis. However, the poor solubility, rapid metabolism and low bioavailability of sorafenib greatly restricted its further clinical application. During the past decade, numerous sorafenib derivatives have been designed and synthesized to overcome its disadvantages and improve its clinical performance. This article focuses on the therapeutic effects and mechanisms of various sorafenib derivatives with modifications on the N-methylpicolinamide group, urea group, central aromatic ring or others. More importantly, this review summarizes the current status of the structure-activity relationship (SAR) of reported sorafenib derivatives, which can provide some detailed information of future directions for further structural modifications of sorafenib to discovery new anti-tumor drugs with improved clinical performance.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Chemistry, Pharmaceutical; ErbB Receptors; Humans; Liver Neoplasms; Molecular Structure; Protein Kinase Inhibitors; Sorafenib

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic

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

Topics: Anilides; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Liver Neoplasms; Prognosis; Protein Kinase Inhibitors; Pyridines; Survival Rate

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

Over the past 10 years, sorafenib has been the only systemic agent approved for the treatment of patients with unresectable hepatocellular carcinoma. Recently, lenvatinib was demonstrated noninferior to sorafenib, and regorafenib and ramucirumab were demonstrated superior to placebo in patients progressing on sorafenib and in patients with elevated α-fetoprotein-failing sorafenib, respectively. Phase I-II trials of immune checkpoint inhibitors reported promising efficacy signals. Recently, the randomized, placebo-controlled, Phase III CELESTIAL trial demonstrated statistically and clinically significant increase in overall survival from 8 months with placebo to 10.2 months with cabozantinib in patients failing sorafenib. Furthermore, the study showed a significant improvement in all the efficacy end points. Main adverse events were palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue and diarrhea.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Molecular Structure; Molecular Targeted Therapy; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Retreatment; Sorafenib; Treatment Outcome

Topics: Anilides; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Female; Humans; Liver Neoplasms; Male; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridines; Quinolines; Risk Assessment; Sorafenib; Survival Analysis; 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

Hepatocellular carcinoma (HCC) remains among the neoplastic diseases with the most unfavorable prognosis. Historically, systemic treatments for HCC have been scarce. In particular, sorafenib was the only registered drug for the treatment of unresectable HCC until 2017. Last year, regorafenib was approved by the global regulatory agencies as second-line therapy. Since then, further randomized, controlled trials have been successful in this patient population. This paper deals with the most recent data concerning cabozantinib and ramucirumab, the two drugs that have recently demonstrated efficacy in phase III, randomized, controlled trials in HCC patients who failed previous treatment with sorafenib.

Topics: Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Humans; Liver Neoplasms; Phenylurea Compounds; Pyridines; Ramucirumab; Randomized Controlled Trials as Topic; Sorafenib

Hepatocellular carcinoma (HCC) is a major pathological type of primary liver cancer. Sorafenib has demonstrated definite efficacy in targeted therapy for HCC. However, when treatment with sorafenib fails, suitable drugs must be found for further treatment. This article reports a case of an HCC patient who was treated with angiogenesis inhibitor axitinib and c-Met inhibitor cabozantinib following treatment with sorafenib. The report focuses on clinical treatment and toxicity. Rational application of targeted therapy is also explored.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Hepatocellular; Fatal Outcome; Humans; Imidazoles; Indazoles; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Retreatment; Sorafenib; Tomography, X-Ray Computed; Treatment Failure; Treatment Outcome

To investigate the safety and efficacy of nivolumab plus cabozantinib with or without ipilimumab in patients with advanced hepatocellular carcinoma.. In cohort 6 of the multicohort, open-label, phase I/II CheckMate 040 study, patients who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib were randomly assigned 1:1 to nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily (doublet arm); or nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg once daily with ipilimumab 1 mg/kg once every 6 weeks (triplet arm). Primary objectives were safety and tolerability, objective response rate, and duration of response by investigator assessment per RECIST v1.1. Secondary objectives included progression-free survival (by blinded independent central review) and overall survival.. Seventy-one patients were randomly assigned: 36 to the doublet arm and 35 to the triplet arm. After 32.0-month median follow-up, objective response rate (95% CI) was 17% (6 to 33) and 29% (15 to 46) in the doublet and triplet arms, respectively. Median (95% CI) duration of response was 8.3 (6.9 to not estimable) months in the doublet arm and not reached (0.0 to not estimable) in the triplet arm. Median progression-free survival was 5.1 and 4.3 months, and median overall survival was 20.2 and 22.1 months for the doublet and triplet arms, respectively. Grade 3-4 treatment-related adverse events occurred in 50% and 74% of patients and treatment-related adverse events leading to discontinuation were reported for 11% and 23% in the doublet and triplet arms, respectively. There were no treatment-related deaths in either arm.. Nivolumab plus cabozantinib with or without ipilimumab showed encouraging preliminary antitumor activity and had consistent safety profiles with those established for the individual drugs in patients with advanced hepatocellular carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Ipilimumab; Liver Neoplasms; Nivolumab; Sorafenib

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Stomach Neoplasms

Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC.. Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as  ≤ -2.60 score and a grade of 2 as a score of > -2.60 to  ≤ -1.39.. Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46-0.86] and 0.42 [0.32-0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66-1.06] and 0.46 [0.37-0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup.. These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2.. ClinicalTrials.gov number, NCT01908426.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anilides; Bilirubin; Carcinoma, Hepatocellular; Female; Humans; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Pyridines; Retrospective Studies; Serum Albumin; Survival Analysis; Treatment Outcome

Combining multikinase inhibitors (MKIs) with immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC) has a strong biological rationale. Among MKIs, cabozantinib seems an ideal partner for ICIs, playing a potentially synergistic role via a spectrum of immunomodulatory actions.. This paper discusses the preclinical rationale for combining cabozantinib and atezolizumab in advanced HCC. It examines the mechanism of action of these agents and highlights their synergistic activities. The eventual approval of novel combinations for advanced HCC will require careful patient selection and a refinement of study design for future trials. Regarding the search for predictive biomarkers, etiology and extent of disease may predict response to therapy. Moving cabozantinib to first-line, treatment sequencing should consider possible cross-resistance not only to ICIs but also to other MKIs. Finally, the response rates of such combinations may pave the way for their evaluation as peri-operative therapies.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyridines

Patients with hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child-Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child-Pugh B cirrhosis at Week 8.. This was a retrospective analysis of adult patients with previously treated advanced HCC. Child-Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo.. Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child-Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child-Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18-0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25-0.76), and best response was stable disease in 57% versus 23% of patients.. These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child-Pugh B liver function.. NCT01908426.

Topics: Adult; Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Cirrhosis; Liver Neoplasms; Prospective Studies; Pyridines; Retrospective Studies

The CELESTIAL trial (NCT01908426) demonstrated overall survival benefit for cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (aHCC) who had received prior sorafenib treatment. This analysis of CELESTIAL compared the impact of cabozantinib versus placebo on health-related quality of life (HRQoL).. Health status was assessed using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire over the 800-day follow-up period. EQ-5D-5L health states were mapped to health utility scores using reference values for the UK population. Quality-adjusted life years (QALYs) were calculated for each treatment group as the area under the curve for the plot of health utility score over time. The between-treatment group difference in restricted mean QALYs was calculated by generalized linear models and adjusted for baseline differences. A difference of 0.08 in health utility score (or in QALY) was deemed a minimally important difference and to be clinically significant.. At week 5, the difference in mean health utility score between cabozantinib and placebo was -0.097 (95% confidence interval [95% CI]: -0.126, -0.067; p ≤ 0.001). Between-group differences in health utility scores diminished over time and were generally non-significant. The cabozantinib group accrued more QALYs than the placebo group over follow-up. Differences in mean QALYs (cabozantinib minus placebo) were statistically and clinically significant, ranging from +0.092 (95% CI: 0.016, 0.169) to +0.185 (95% CI: 0.126, 0.243) in favour of cabozantinib, depending on the reference value set used.. These HRQoL findings support a positive benefit-risk profile for cabozantinib in previously treated patients with aHCC.

Topics: Anilides; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyridines; Quality of Life

Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma.. COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791.. Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage).. Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.. Exelixis and Ipsen.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyridines; Sorafenib

A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC), but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC including patients outside of traditional resection criteria (NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin negative resection, and 5/12 (42%) patients had major pathologic responses. In-depth biospecimen profiling demonstrated an enrichment in T effector cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders as compared to non-responders, indicating an orchestrated B-cell contribution to antitumor immunity in HCC.

Topics: Anilides; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nivolumab; Pyridines

Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti-PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. ClinicalTrial.gov Registration: NCT03755791.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Drug Interactions; Humans; Liver Neoplasms; Pyridines; Sorafenib

The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes.. Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics.. Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62-1.04] for patients with baseline AFP <400 ng/mL, and 8.5 versus 5.2 months (HR, 0.71; 95% CI, 0.54-0.94) for patients with baseline AFP ≥400 ng/mL. Week 8 AFP response rate was 50% for cabozantinib versus 13% for placebo. In the cabozantinib arm, median OS for patients with and without AFP response was 16.1 versus 9.1 months (HR, 0.61; 95% CI, 0.45-0.84). AFP response was independently associated with longer OS. The optimal cutoff for association with OS in the cabozantinib arm was ≤0% change in AFP at Week 8 [AFP control; HR 0.50 (95% CI, 0.35-0.71)]. HRs for PFS were consistent with those for OS.. Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Anilides; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Placebos; Prognosis; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Reference Values; Young Adult

In the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy.. CELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (<3 months, 3 to <6 months and ≥6 months).. Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for ≥6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS-median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for ≥6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population.. Cabozantinib improved efficacy outcomes versus placebo in the second-line population who had received only prior sorafenib irrespective of duration of prior sorafenib treatment, further supporting the utility of cabozantinib in the evolving treatment landscape of HCC.. NCT01908426.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Male; Middle Aged; Pyridines; Sorafenib; Young Adult

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Disease-Free Survival; Double-Blind Method; Female; Humans; Liver Neoplasms; Male; Protein Kinase Inhibitors; Pyridines; Sorafenib

Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma.. A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate.. At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).. Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .).

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Pyridines; Receptor Protein-Tyrosine Kinases

Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.. Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).. Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.. Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.. NCT00940225.

Topics: Adult; Aged; Anilides; Carcinoma, Hepatocellular; Disease-Free Survival; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sorafenib

Gain-of-function (GOF) mutations of CTNNB1 and loss-of-function (LOF) mutations of AXIN1 are recurrent genetic alterations in hepatocellular carcinoma (HCC). We aim to investigate the functional contribution of Hippo/YAP/TAZ in GOF CTNNB1 or LOF AXIN1 mutant HCCs.. The requirement of YAP/TAZ in c-Met/β-Catenin and c-Met/sgAxin1-driven HCC was analyzed using conditional Yap , Taz , and Yap;Taz knockout (KO) mice. Mechanisms of AXIN1 in regulating YAP/TAZ were investigated using AXIN1 mutated HCC cells. Hepatocyte-specific inducible TTR-CreER T2KO system was applied to evaluate the role of Yap;Taz during tumor progression. Cabozantinib and G007-LK combinational treatment were tested in vitro and in vivo . Nuclear YAP/TAZ was strongly induced in c-Met/sgAxin1 mouse HCC cells. Activation of Hippo via overexpression of Lats2 or concomitant deletion of Yap and Taz significantly inhibited c-Met/sgAxin1 driven HCC development, whereas the same approaches had mild effects in c-Met/β-Catenin HCCs. YAP is the major Hippo effector in c-Met/β-Catenin HCCs, and both YAP and TAZ are required for c-Met/sgAxin1-dependent hepatocarcinogenesis. Mechanistically, AXIN1 binds to YAP/TAZ in human HCC cells and regulates YAP/TAZ stability. Genetic deletion of YAP/TAZ suppresses already formed c-Met/sgAxin1 liver tumors, supporting the requirement of YAP/TAZ during tumor progression. Importantly, tankyrase inhibitor G007-LK, which targets Hippo and Wnt pathways, synergizes with cabozantinib, a c-MET inhibitor, leading to tumor regression in the c-Met/sgAxin1 HCC model.. Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ is an effective treatment against AXIN1 mutant human HCCs.

Topics: Animals; Axin Protein; beta Catenin; Carcinogenesis; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mice; Mutation; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins; Wnt Signaling Pathway

Hepatocellular carcinoma (HCC) is one of the most common cancerous tumors and one of the leading causes of death among cancer-related disorders. Chemotherapy is ineffective in HCC patients, and the number of drugs that are in use is limited. Thus, new molecules are needed that could increase the effectiveness of anti-HCC regimens. Here, we show that AT7519, a CDK inhibitor, exerts positive effects on HCC cells: it inhibits proliferation, migration and clonogenicity. Detailed analysis of the transcriptomes of cells treated with this compound indicated that AT7519 affects a substantial portion of genes that are associated with HCC development and progression. Moreover, we showed that the concomitant use of AT7519 with gefitinib or cabozantinib sensitized HCC cells to these drugs. Thus, our research indicates that AT7519 is worth considering in monotherapy for hepatocellular carcinoma patients or in combination with other drugs, e.g., gefitinib or cabozantinib.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Gefitinib; Humans; Liver Neoplasms

Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy.. We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection.. ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient.. These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.

Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Neoadjuvant Therapy; Nivolumab; Prospective Studies; Transcriptome; Tumor Microenvironment

Multimodal treatment is an important tool to overcome tumor drug resistance. The reactive oxygen species (ROS) generated by photodynamic therapy (PDT) can directly play a killing role on tumor cells, which has the advantages of repeatable treatment and no drug resistance. However, its therapeutic oxygen consumption and destruction of tumor microvessels lead to hypoxia in tumor tissues, and hypoxia leads to overexpression of the receptor tyrosine kinase (c-MET) and vascular endothelial growth factor receptor (VEGFR). Overexpression of these two receptors leads to increased tumor invasiveness and metastasis. The molecularly targeted drug cabozantinib (CAB) has multiple targets, including anti-c-MET and VEGFR, to inhibit the development of hepatocellular carcinoma (HCC). In this study, our team designed a pH-sensitive nanoparticle CAB/Ce6@ZIF-8@PEG-FA (CCZP) loaded with CAB and Ce6, which exerted a multimodal therapeutic effect of PDT and molecularly targeted therapy by laser irradiation, and the PDT-induced overexpression of MET and VEGFR could also be inhibited by the target of CAB, thus reducing the invasive tumor cells metastasis. In summary, CCZP gives full play to the advantages of both drugs, exerting multimodal treatment while reducing HCC invasion and metastasis, providing a safe, potential approach to clinical treatment.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Combined Modality Therapy; Humans; Hydrogen-Ion Concentration; Hypoxia; Liver Neoplasms; Metal-Organic Frameworks; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Vascular Endothelial Growth Factor A

Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC.. Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation.. Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation.. Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.

Topics: Carcinoma, Hepatocellular; Hepatitis B virus; Humans; Liver Neoplasms; STAT3 Transcription Factor

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Topics: Anilides; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Humans; Liver Neoplasms; Pyridines; Sirolimus; Xenograft Model Antitumor Assays

Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a FASN inhibitor, either alone or in combination, for HCC treatment.. The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-programmed death ligand 1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNA sequencing was performed to elucidate the effects of TVB3664 on global gene expression and tumor metabolism. TVB3664 significantly ameliorated the fatty liver phenotype in the aged mice and AKT-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of phosphatase and tensin homolog and MET proto-oncogene, receptor tyrosine kinase (c-MET) overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this murine model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, whereas TVB3664 synergized with cabozantinib to down-regulate multiple cancer-related pathways, especially the AKT/mammalian target of rapamycin pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC-driven HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent murine HCC models.. This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Fatty Acid Synthase, Type I; Fatty Acid Synthases; Fatty Liver; Humans; Liver; Liver Neoplasms; Mammals; Mice; Phosphoric Monoester Hydrolases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridines; Sorafenib; Tensins; TOR Serine-Threonine Kinases

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

Immune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination.. C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival.. The combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P < 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P < 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P < 0.01) and memory/effector T cells (P < 0.05), while lowering the neutrophil-to-lymphocyte ratio (P < 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes.. Cabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.

Topics: Anilides; Animals; Carcinoma, Hepatocellular; Humans; Immunity; Liver Neoplasms; Mice; Mice, Inbred C57BL; Neutrophils; Programmed Cell Death 1 Receptor; Pyridines

Concomitant inhibition of vascular endothelial growth factor (VEGF) and programmed cell death protein 1 (PD-1) or its ligand PD-L1 is a standard of care for patients with advanced hepatocellular carcinoma (HCC), but only a minority of patients respond, and responses are usually transient. Understanding the effects of therapies on the tumor microenvironment (TME) can provide insights into mechanisms of therapeutic resistance.. 14 patients with HCC were treated with the combination of cabozantinib and nivolumab through the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Among them, 12 patients (5 responders + 7 non-responders) underwent successful margin negative resection and are subjects to tissue microarray (TMA) construction containing 37 representative tumor region cores. Using the TMAs, we performed imaging mass cytometry (IMC) with a panel of 27-cell lineage and functional markers. All multiplexed images were then segmented to generate a single-cell dataset that enables (1) tumor-immune compartment analysis and (2) cell community analysis based on graph-embedding methodology. Results from these hierarchies are merged into response-associated biological process patterns.. Image processing on 37 multiplexed-images discriminated 59,453 cells and was then clustered into 17 cell types. Compartment analysis showed that at immune-tumor boundaries from NR, PD-L1 level on tumor cells is significantly higher than remote regions; however, Granzyme B expression shows the opposite pattern. We also identify that the close proximity of CD8. These results demonstrate the feasibility of a novel application of multiplexed image analysis that is broadly applicable to quantitative analysis of pathology specimens in immuno-oncology and provides further evidence that CD163

Topics: Anilides; B7-H1 Antigen; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Humans; Liver Neoplasms; Nivolumab; Pyridines; Spatial Analysis; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyridines

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, and AXL, among others. This drug is considered to exert excellent antitumor effects by inhibiting these targets simultaneously. Significant improvement in the primary endpoint (overall survival or PFS) were observed in patients on CAB in comparison with controls in a phase-III study in patients with renal cell carcinoma, progressed after treatment with anti-angiogenic agents, and in another phase-III study in patients with previously treated, advanced hepatocellular carcinoma. These results led to the approval of CAB in Japan in 2020 as a therapeutic agent for unresectable or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma progressed after cancer chemotherapy, under the trade name of CABOMETYX

Topics: Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Pyridines

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited.. In 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain.. An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed.. Following an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed.. More than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy.. In conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.

Topics: Abdominal Pain; Adult; Anilides; Carcinoma, Hepatocellular; Combined Modality Therapy; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Liver Neoplasms; Liver Transplantation; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Postoperative Complications; Pyridines; Radiofrequency Ablation

Two novel bioisosteres of cabozantinib,

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Mice; Molecular Structure; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Xenograft Model Antitumor Assays

Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.

Topics: Anilides; Animals; Benzoxazoles; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Female; Humans; Liver Neoplasms; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; PTEN Phosphohydrolase; Pyridines; Pyrimidines; Thiazoles; Treatment Outcome; Tumor Burden

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo.. Human HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody.. Cabozantinib treatment led to stable disease in c-Met/β-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/β-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/β-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested.. c-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.

Topics: Anilides; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzoxazoles; Carcinoma, Hepatocellular; Cell Line, Tumor; Female; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Liver Neoplasms, Experimental; Pyridines; Pyrimidines; Tumor Microenvironment

To evaluate the efficacy and safety of cabozantinib in Japanese patients with advanced hepatocellular carcinoma (HCC) who had progressed following one or two lines of systemic therapy including sorafenib. An exploratory evaluation in sorafenib-naïve patients was performed.. In this open-label, single-arm, phase 2 trial, patients received oral cabozantinib 60 mg once daily. The primary endpoint was progression-free survival (PFS) rate at Week 24. Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR, best response of complete/partial response), disease control rate (DCR, objective response or stable disease) and safety.. Thirty-four patients received cabozantinib across 17 centers (prior sorafenib cohort, n = 20; sorafenib-naïve cohort, n = 14). PFS rate at 24 weeks was 59.8% [90% confidence interval (CI) 36.1-77.2%] in the prior sorafenib cohort, 16.7% (90% CI 4.0-36.8%) in the sorafenib-naïve cohort and 40.1% (90% CI 24.8-55.0%) overall. Median PFS was 7.4 months for the prior sorafenib cohort, 3.6 months for the sorafenib-naïve cohort, and 5.6 months overall. OS rate at 6 months was 100.0%, 78.6% and 91.1%, respectively; DCR was 85.0%, 64.3% and 76.5%, respectively. The ORR was 0.0% for both cohorts. All patients required dose modifications due to adverse events, the most common of these were palmar-plantar erythrodysesthesia syndrome and diarrhea. Three patients (8.8%) discontinued due to adverse events other than disease progression.. Cabozantinib 60 mg/day has a favorable benefit/risk profile for Japanese patients with advanced HCC who have previously received one or two lines of systemic anticancer therapy including sorafenib. (Clinical trial registration: NCT03586973).

Topics: Aged; Anilides; Carcinoma, Hepatocellular; Female; Humans; Japan; Liver Neoplasms; Male; Middle Aged; Pyridines; Sorafenib

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

Cabozantinib and ramucirumab are approved for the treatment of adults with hepatocellular carcinoma (HCC) following prior sorafenib treatment; ramucirumab is restricted to use in patients with serum alpha-fetoprotein (AFP) ≥ 400 ng/mL. This matching-adjusted indirect comparison evaluated the efficacy and safety of both drugs after sorafenib in patients with HCC and AFP ≥ 400 ng/mL.. Individual patient data (IPD) from the CELESTIAL trial (cabozantinib) and population-level data from the REACH-2 trial (ramucirumab) were used. To align with REACH-2, the CELESTIAL population was limited to patients who received first-line sorafenib only and had baseline serum AFP ≥ 400 ng/mL. The IPD from CELESTIAL were weighted to balance the distribution of 11 effect-modifying baseline characteristics with those of REACH-2. Overall survival (OS; primary endpoint) and progression-free survival (PFS) were compared for the CELESTIAL (matching-adjusted) and REACH-2 populations using weighted Kaplan-Meier (KM) curves and parametric (OS, Weibull; PFS, log-logistic) modeling. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.. After matching and weighting, baseline characteristics were balanced between populations (REACH-2, N = 292; CELESTIAL, effective sample size = 105). Weighted KM estimates for OS (median [95% CI]) were not significantly different between cabozantinib and ramucirumab (10.6 [9.5-17.3] months versus 8.7 [7.3-10.8] months; p = 0.104), but PFS was significantly longer for cabozantinib than for ramucirumab (5.5 [4.6-7.4] months versus 2.8 [2.7-4.1] months; p = 0.016). Parametric modeling results were consistent with the weighted KM analysis. Rates of some grade 3 or 4 TRAEs were lower with ramucirumab than with cabozantinib; however, TRAE-related discontinuation rates were similar (p = 0.271).. In this MAIC, cabozantinib significantly prolonged median PFS compared with ramucirumab after prior sorafenib treatment in patients with HCC and AFP ≥ 400 ng/mL; rates of some grade 3 or 4 TRAEs were lower with ramucirumab than cabozantinib but related discontinuation rates were not significantly different between treatments.. Clinical trials.gov identifiers: CELESTIAL trial (NCT01908426) and REACH-2 trial (NCT02435433). These slides can be retrieved under Electronic Supplementary Material.

Topics: Adult; alpha-Fetoproteins; Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyridines; Ramucirumab; Sorafenib

We report on a patient with hepatocellular carcinoma (HCC) who developed bone metastasis after surgery. RET amplification, high tumor mutational burden (TMB; TMB ≥10 mutations per megabase), and programmed death-ligand 1 (PD-L1) expression were detected by next-generation sequencing. Oral administration of cabozantinib was initiated. Nivolumab was added after 1 month. The patient responded well to cabozantinib and nivolumab therapy, with tolerated adverse reactions, and achieved progression-free survival of more than 25 months. To the best of our knowledge, this is the first clinical case report in the literature to describe the benefit of cabozantinib and nivolumab treatment in a patient with HCC and RET amplification, high TMB, and positive PD-L1 expression. This study explored the selection of biomarkers for targeted therapy and combination immunotherapy in patients with HCC. KEY POINTS: A patient with metastatic hepatocellular carcinoma (HCC) harboring RET amplification, high tumor mutational burden, and positive programmed death-ligand 1 expression responded well to the combination of cabozantinib and nivolumab therapy with progression-free survival of longer than 25 months. The combination of nivolumab and cabozantinib may be a good option for patients with advanced HCC, especially those with bone metastasis. The efficacy of cabozantinib and immune checkpoint inhibitors suggests the necessity of the combined application of multiple detection technologies, including next-generation sequencing and immunohistochemistry, for patients with HCC. This study explored the selection of biomarkers for targeted therapy and combination immunotherapy for patients with HCC.

Topics: Anilides; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Nivolumab; Proto-Oncogene Proteins c-ret; Pyridines

Cabozantinib was approved by the European Medicines Agency and the Federal Drug Administration as an option for sorafenib-resistant advanced hepatocellular carcinoma, increasing overall survival and progression-free survival compared with placebo. We evaluated the cost-effectiveness of cabozantinib in the second-line setting for patients with an advanced hepatocellular carcinoma from the German statutory health insurance perspective compared with an US scenario using US prices.. A Markov model was developed to compare the costs and effectiveness of cabozantinib with best supportive care in the second-line treatment of advanced hepatocellular carcinoma over a lifetime horizon. Health outcomes were measured in discounted life years and discounted quality-adjusted life years. Survival probabilities were estimated using parametric survival distributions based on CELESTIAL trial data. Utilities were derived from the literature. Costs contained drugs, monitoring and adverse events measured in US Dollars. Model robustness was addressed in univariable, scenario and probabilistic sensitivity analyses.. Cabozantinib generated a gain of 0.18 life years (0.15 quality-adjusted life years) compared with best supportive care. The total mean cost per patient was $56,621 for cabozantinib and $2064 for best supportive care in the German model resulting in incremental cost-effectiveness ratios for cabozantinib of $306,778/life year and $375,470/quality-adjusted life year. Using US prices generated costs of $177,496 for cabozantinib and $4630 for best supportive care and incremental cost-effectiveness ratios of $972,049/life year and $1,189,706/quality-adjusted life year.. Our analysis established that assuming a willingness-to-pay threshold of $163,371/life year (quality-adjusted life year) for the German model and $188,559/life year (quality-adjusted life year) for the US model, cabozantinib is not cost-effective compared with best supportive care. Sensitivity analyses showed that cabozantinib was not cost-effective in almost all our scenarios.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Drug Resistance, Neoplasm; Germany; Humans; Liver Neoplasms; Markov Chains; Pyridines; Quality-Adjusted Life Years; Sorafenib; Survival Analysis; United States

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

Cabozantinib is an oral multikinase inhibitor whose targets include vascular endothelial growth factor receptors, MET, and the TAM family of kinases (TYRO3, AXL, MER). Cabozantinib is approved for patients with advanced hepatocellular carcinoma who have been previously treated with sorafenib, based on improved overall survival and progression-free survival relative to placebo in the phase III CELESTIAL study. During CELESTIAL, the most common adverse events (AEs) experienced by patients receiving cabozantinib included palmar-plantar erythrodysesthesia, fatigue, gastrointestinal-related events, and hypertension. These AEs can significantly impact treatment tolerability and patient quality of life. However, AEs can be effectively managed with supportive care and dose modifications. During CELESTIAL, more than half of the patients receiving cabozantinib required a dose reduction, while the rate of treatment discontinuation due to AEs was low. Here, we review the safety profile of cabozantinib and provide guidance on the prevention and management of the more common AEs, based on current evidence from the literature as well as our clinical experience. We consider the specific challenges faced by clinicians in treating this patient population and discuss factors that may affect exposure and tolerability to cabozantinib.

Topics: Anilides; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Pyridines; Quality of Life; Receptor Protein-Tyrosine Kinases

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

Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. Met interaction with integrins is shown to modulate the downstream signaling to Akt and ERK (extracellular-regulated kinase). In this study, we developed a mechanistically detailed systems biology model of HGF/Met signaling pathway that incorporated specific interactions with integrins to investigate the efficacy of integrin-binding peptide, AXT050, as monotherapy and in combination with other therapeutics targeting this pathway. Here we report that the modeled dynamics of the response to AXT050 revealed that receptor trafficking is sufficient to explain the effect of Met-integrin interactions on HGF signaling. Furthermore, the model predicted patient-specific synergy and antagonism of efficacy and potency for combination of AXT050 with sorafenib, cabozantinib, and rilotumumab. Overall, the model provides a valuable framework for studying the efficacy of drugs targeting receptor tyrosine kinase interaction with integrins, and identification of synergistic drug combinations for the patients.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Computer Simulation; Drug Resistance, Neoplasm; Hep G2 Cells; Hepatocyte Growth Factor; Humans; Integrins; Liver Neoplasms; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Sorafenib; Systems Biology

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2-5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

Topics: Anilides; Antibodies, Monoclonal, Humanized; beta Catenin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Clinical Trials as Topic; Humans; Immunotherapy; Liver Neoplasms; Molecular Targeted Therapy; Mutation; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines

In the CELESTIAL trial for patients with advanced hepatocellular carcinoma (HCC), cabozantinib showed improved survival compared with placebo but comes at a price. We aimed to investigate the cost-effectiveness of cabozantinib for sorafenib-resistant HCC from the payer's perspective of the USA, UK and China.. We developed Markov models to simulate the patients pre-treated with first-line sorafenib following the CELESTIAL trial. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated for the treatment with cabozantinib or best supportive care. The list price for drugs was acquired from the Red Book, the British National Formulary, West China hospital and reported literature. Adverse events, utilities weights, and transition likelihood between states were sourced from the published randomized phase III trial. A willing-to-pay threshold was set $150 000/QALY in the USA, $70 671/QALY (£50 000/QALY) in the UK and $26 481/QALY (3x GDP per capita) in China. Deterministic and probabilistic sensitivity analyses were developed to test the models' uncertainty.. In the base case, treatment with cabozantinib increased effectiveness by 0.13 QALYs, resulting in an ICER vs best supportive care of $833 497/QALY in the USA, $304 177/QALY in the UK and $156 437/QALY in China. The models were most sensitive to assumptions about transitions to progression with both cabozantinib and best supportive care, the utility associated with being progression free. These results were robust across a range of scenarios and sensitivity analyses, including deterministic and probabilistic analyses.. Cabozantinib at its current cost would not be a cost-effective treatment option for patients with sorafenib-resistant HCC from the payer's perspective in the USA, UK or China. Substantial discounts are necessary to meet conventional cost-effectiveness thresholds.

Topics: Anilides; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Humans; Liver Neoplasms; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Renal Cell; Drug Approval; Humans; Kidney Neoplasms; Liver Neoplasms; Pyridines; Thyroid Neoplasms; United States; United States Food and Drug Administration

Topics: Anilides; Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Hypothyroidism; Liver Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyridines; Treatment Outcome

Treatment options are limited for patients with advanced hepatocellular carcinoma (HCC) that progresses after treatment with sorafenib. Cabozantinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, recently showed improved overall survival (OS) compared with placebo in sorafenib-pretreated patients with advanced HCC in the CELESTIAL trial. This study assessed the cost-effectiveness of cabozantinib for second-line treatment of patients with advanced HCC from a US healthcare system perspective.. Cost and utility data were extracted from the CELESTIAL trial and used to determine the cost-effectiveness of cabozantinib compared with placebo plus best supportive care. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained by using cabozantinib compared with placebo plus best supportive care in sorafenib-pretreated HCC.. In the base-case analysis using data from the CELESTIAL trial, the incremental QALY and ICER were 0.067 and $1,040,675 for cabozantinib compared with placebo and best supportive care. OS reported in the CELESTIAL trial (hazard ratio, 0.76; 95% CI, 0.63-0.92) had the strongest association with the ICER. In one-way sensitivity analyses, there were no scenarios in which cabozantinib was cost-effective. In a cost-threshold analysis, cabozantinib would have to be priced at least $50 per pill to be cost-effective considering a willingness to pay of $100,000 per QALY. Although the CELESTIAL trial demonstrated that cabozantinib improves OS compared with placebo in patients with HCC that progresses after treatment with sorafenib, our analysis shows that cabozantinib is not a cost-effective therapy in this scenario.. At current costs, cabozantinib is not cost-effective for second-line therapy of HCC in the United States.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Decision-Making; Clinical Trials, Phase III as Topic; Computer Simulation; Cost-Benefit Analysis; Disease-Free Survival; Drug Costs; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Markov Chains; Models, Economic; Neoplasm Staging; Palliative Care; Patient Selection; Placebos; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Sorafenib

To test the hypothesis that cytoreductive nephrectomy (CN) improves overall survival (OS) of patients with synchronous metastatic renal cell carcinoma (mRCC), who subsequently receive targeted therapies (TT).. We identified 261 patients who received TT for synchronous mRCC with or without prior CN. To achieve balance in baseline characteristics between groups, we used the inverse probability of treatment weighting (IPTW) method. We conducted OS analyses, including IPTW-adjusted Kaplan-Meier curves, Cox regression models, interaction term, and landmark and sensitivity analyses.. Of the 261 patients, 97 (37.2%) received CN and 164 (62.8%) did not. IPTW-adjusted analyses showed a statistically significant OS benefit for patients treated with CN (HR 0.63, 95% CI 0.46-0.83, P = 0.0015). While there was no statistically significant difference in OS at 3 months (P = 0.97), 6 months (P = 0.67), and 12 months (P = 0.11) from diagnosis, a benefit for the CN group was noted at 18 months (P = 0.005) and 24 months (P = 0.004). On interaction term analyses, the beneficial effect of CN increased with better performance status (P = 0.06), in women (P = 0.03), and in patients with thrombocytosis (P = 0.01).. IPTW-adjusted analysis of our patient cohort suggests that CN improves OS of patients with synchronous mRCC treated with TT. On the whole, the survival difference appears after 12 months. Specific subgroups may particularly benefit from CN, and these subgroups warrant further investigation in prospective trials.

Topics: Aged; Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Nephrectomy; Nivolumab; Probability; Prognosis; Proportional Hazards Models; Pyridines; Pyrimidines; Pyrroles; Retrospective Studies; Sex Factors; Sulfonamides; Sunitinib; Survival Rate; Thrombocytosis

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Pyridines

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Pyridines

Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916-25. ©2016 AACR.

Topics: Anilides; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Synergism; Enzyme Activation; Focal Adhesion Kinase 1; Humans; Liver Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Cabozantinib, a small-molecule multitargeted tyrosine kinase inhibitor, has entered into a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). This study assessed the mechanistic effect of cabozantinib on the reversal of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR).. CCK-8 assays and tumour xenografts were used to investigate the reversal of MDR in vitro and in vivo respectively. Substrate retention assays were evaluated by fluorescence microscope and flow cytometry. Western blotting was used to detect protein expression levels. mRNA expression was determined by qPCR. The ATPase activity of P-gp was investigated using Pgp-Glo(™) assay systems. The binding mechanism of cabozantinib to P-gp at the molecular level was evaluated using docking analysis.. Cabozantinib enhanced the cytotoxicity of P-gp substrate drugs in HepG2/adr and HEK293-MDR1 cells but had no effect on non-P-gp substrates. In addition, cabozantinib increased the accumulation of P-gp substrates in HepG2/adr cells but had no effect in HepG2 cells. Furthermore, cabozantinib did not alter the expression of P-gp mRNA or protein but did stimulate the activity of P-gp ATPase. The docking study indicated that cabozantinib and verapamil may partially share a binding site on P-gp. The reversal concentrations of cabozantinib did not affect the expression of MET, AKT and ERK1/2. Significantly, cabozantinib increased the inhibitory efficacy of doxorubicin in P-gp-overexpressing HepG2/adr cell xenografts in nude mice.. Cabozantinib reverses P-gp-mediated MDR by directly inhibiting the efflux function of P-gp, indicating that cabozantinib may help to reverse P-gp-mediated MDR in HCC and other cancer chemotherapy.

Topics: Anilides; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Hepatocellular; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; HEK293 Cells; Hep G2 Cells; Humans; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridines; Random Allocation; Xenograft Model Antitumor Assays

MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.. Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.. High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G1-phase arrest. Cabozantinib inhibited tumor growth in p-MET-positive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.. Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker. Clin Cancer Res; 20(11); 2959-70. ©2014 AACR.

Topics: Anilides; Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins c-met; Pyridines; Sorafenib; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays