Fruquintinib-Induced Cerebellar Hemorrhage in Left-Sided Descending Metastatic Colorectal Adenocarcinoma: A Case Report and Risk Assessment.

Colorectal adenocarcinoma is the most prevalent form of colorectal cancer, representing the majority of cases in the United States. The disease is driven by a series of genetic mutations, including alterations in the adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS), human epidermal growth factor receptor 2 immunohistochemistry 3+ (HER-2 IHC3+), checkpoint kinase 2 (CHEK-2) and tumor protein P53 (TP53) genes, which lead to malignant transformation. While the standard treatment for metastatic colorectal cancer (mCRC) typically involves chemotherapy and targeted therapies, many patients experience disease progression, necessitating the exploration of novel treatments. Fruquintinib, a highly selective vascular endothelial growth factor (VEGFR) inhibitor, has emerged as a promising option for mCRC patients who have exhausted conventional therapies. However, its use is associated with significant bleeding risks, including rare but severe complications such as cerebellar hemorrhage. This case report presents a patient with mCRC who developed a cerebellar hemorrhage shortly after initiating fruquintinib therapy, highlighting the need for careful patient monitoring and individualized risk assessment to mitigate such serious adverse events.

Systemic hypertension with VEGFR inhibitor (axitinib) therapy in cancer patients: A meta-analysis and systematic review of randomized controlled trials.

Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this medication has a significant cardiovascular side effect profile, such as high-grade hypertension. We performed this updated meta-analysis of RCTs to compile cardiovascular adverse events, such as all-grade and high-grade (>3) hypertension, the risk for thrombosis (DVT and PE), and peripheral edema. A systematic search was performed on PubMed, Cochrane, and Embase from inception until October 2023 for studies using axitinib to treat various cancers. Trials with patients randomly allocated for VEGFRi drug therapy with axitinib and reported all-grade hypertension as an outcome were included. Statistical analysis was performed using Cochrane Review Manager to calculate pooled proportions of odds ratios (OR) with a 95 % confidence interval (CI) using the random-effects model, Mantel-Haenszel method. A total of 8 RCTs and 2502 patients were included in the review. Compared with the placebo group, the VEGFRi (Axitinib) therapy group was associated with a higher risk of all-grade and high-grade hypertension, hand-foot syndrome, and fatigue. Furthermore, there was no increased risk of thromboembolism (DVT/PE) or hypothyroidism. However, a lower risk of peripheral edema was noted between the two groups. Screening for patients with preexisting hypertension, identifying risk factors for cardiovascular diseases before the initiation of VEGFRi therapy, and careful monitoring of high-risk patients during VEGFRi therapy, as well as prompt treatment with antihypertensive drugs, will help mitigate the adverse effects. Further evaluation using prospective designs is required to study the clinical significance and develop mitigation strategies.

Nintedanib in Combination With Chemotherapy in the Treatment of Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer remains a major global health challenge, contributing to substantial morbidity and mortality rates. Nintedanib, a tyrosine kinase inhibitor, has demonstrated potential as a treatment for lung cancer. We aim to evaluate nintedanib's efficacy in treating patients with non-small cell lung cancer (NSCLC), depending on the available evidence. Our search for relevant articles was conducted on PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials (RCTs) that involved adult patients with NSCLC up to August 15, 2023. These trials compared the combination of nintedanib and chemotherapy to either placebo plus chemotherapy or chemotherapy alone. Our main outcomes include progression-free survival (PFS) and overall survival (OS). We utilized the Review Manager Software V.5.4 (The Cochrane Collaboration) to analyze all relevant data. Three identified trials, which included 2270 patients, fulfilled the inclusion criteria. Our analysis showed significantly improved PFS (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.71-0.88, P < 0.0001) in patients receiving nintedanib compared to placebo. However, OS was not statistically significant (HR = 0.96; 95% CI 0.88-1.05, P = 0.35). In conclusion, a combination of nintedanib and chemotherapy in treating patients with NSCLC was associated with improved PFS than chemotherapy alone but not with improved OS. Further clinical trials assessing nintedanib in the setting of NSCLC are necessary before any further recommendations can be made.

A protocol of a single arm, prospective, open-label, multicenter, phase II study of ramucirumab and erlotinib in treatment-naïve non-small cell lung cancer patients with EGFR mutation and brain metastases (SPIRAL-BRAIN study).

Background: The combination of erlotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) antibody, is one of the most effective treatments for patients with non-small cell lung cancer (NSCLC) and EGFR mutation. However, little is known about the safety and efficacy of this combination treatment for patients with brain metastases. Methods: This single arm, prospective, open-label, multicenter, phase II study will recruit 32 NSCLC patients with EGFR mutation (except for T790M mutation) and brain metastases (asymptomatic or mild symptoms). Patients will be treated with erlotinib at a dose of 150 mg/body once daily and ramucirumab at a dose of 10 mg/kg once every 2 weeks. The primary endpoint is intracranial overall response rate (iORR) and the secondary endpoints are intracranial disease control rate, intracranial progression-free survival (iPFS), extracranial ORR, extracranial PFS, ORR, overall PFS, overall survival (OS), and safety. The planned number of enrollments was calculated based on a one-sample binomial test (normal approximation) with a two-sided α level of 5% and 80% power, assuming that the expected iORR is 65% and the iORR threshold is 40%. Discussion: A prospective study to confirm the safety and efficacy of the combined erlotinib plus ramucirumab treatment for NSCLC patients with EGFR mutation and brain metastases is ongoing. Trial Registration: Japan Registry of Clinical Trials, jRCTs051220059.

The mechanism of action and biodistribution of a novel EGFR/VEGF bispecific fusion protein that exhibited superior antitumor activities.

Despite the promising clinical benefits of therapies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) with antibodies in various cancers, resistance to these therapies will inevitably develop following treatment. Recent studies suggest that crosstalk between the EGFR and VEGF signaling pathways might be involved in the development of resistance. Therefore, simultaneous blockade of EGFR and VEGF signaling may be able to counteract this resistance and improve clinical outcomes. Here, we devised a fusion protein with two copies of VEGFR1 domain 2 connected to the C-terminus of cetuximab that can simultaneously bind to EGFR and VEGF and effectively inhibit target cell growth mediated by these two pathways. Furthermore, the fusion protein could bring soluble VEGF into target cells for degradation through internalization upon binding to EGFR. Tissue distribution in mice confirmed that the fusion protein effectively accumulated in tumors compared to its mAb counterpart cetuximab. These features resulted in stronger antitumor efficacies in vivo than the combination of bevacizumab and cetuximab. Thus, we provide a promising new strategy for the treatment of EGFR-overexpressing cancers.

Evaluating everolimus for the treatment of breast cancer.

INTRODUCTION: Everolimus is an oral drug that inhibits mTOR with immunosuppressive and antiproliferative characteristics. It is commonly used in association with exemestane in hormone receptor (HR)-positive advanced breast cancer (ABC). AREAS COVERED: The current review summarizes the publications relating to everolimus from clinical research in breast cancer. Everolimus showed treatment efficacy and an acceptable safety tolerance with the prevention of side effects in Phase II/III studies. BOLERO-2 study showed a progression-free survival improvement in patients with HR - positive ABC previously treated with aromatase inhibitors (AI) and leading to its acceptance in this indication. The absence of a post-CDK4/6 inhibitor (CDK4/6i.) study and the arrival of new drugs may raise questions about its current place in the therapeutic strategy. EXPERT OPINION: Everolimus is relevant in the management of HR - positive ABC. Because of its efficacy, acceptable tolerability and the absence of drugs that have shown a greater benefit, it remains a second-line treatment option in HR-positive, HER2 negative (score 0) patients without BRCA mutation or visceral crisis and can be discussed with fulvestrant in second line after CDK4-6i. It is likely that within 5 years this treatment will be replaced in second-line HR-positive breast cancer by new emerging treatments: drug-conjugated antibodies, tyrosine kinase inhibitors or immunotherapy in combination with chemotherapy.

A Retrospective Cohort Study Examining the Effects of Anti-PD-1 Antibody in Combination with Apatinib in Patients Previously Treated for Her2-Negative Advanced Gastric/Gastroesophageal Junction Cancer.

Combining immune checkpoint inhibitors with vascular endothelial growth factor/vascular endothelial growth factor receptor inhibitors is effective in treating a number of solid tumors; however, evidence in advanced gastric/gastroesophageal junction (G/GEJ) cancer is limited. This retrospective study included consecutive patients who received a programmed cell death protein 1 (PD-1) inhibitor plus the vascular endothelial growth factor receptor 2 inhibitor apatinib, second-line or later to treat unresectable advanced or metastatic, histologically proven, human epidermal growth factor receptor 2-negative G/GEJ cancer in a single center between November 1, 2018, and March 31, 2021. Treatment was continued until the disease progressed or the toxicity became intolerable. We examined data from 52 patients. The primary tumor site was the stomach in 29 patients and the GEJ in 23 patients. PD-1 inhibitors administered included camrelizumab (n = 28), sintilimab (n = 18), pembrolizumab (n = 3), and tislelizumab (n = 1), and all patients were given 200 mg every 3 weeks, and toripalimab (240 mg every 3 weeks) and nivolumab (200 mg every 2 weeks) were given to 1 patient each. For 28 days, apatinib 250 mg was administered orally once a day. The objective response rate was 15.4% (95% confidence interval [CI], 6.9-28.1), and the disease control rate was 61.5% (95%CI, 47.0-74.7). After 14.8 months of median follow-up, the median progression-free survival was 4.2 months (95%CI, 2.6-4.8), and the overall survival was 9.3 months (95%CI, 7.9-12.9). Twelve patients underwent grade 3-4 treatment-related adverse events (23.1%). There was no unexpected toxicity or death. This trial demonstrated combination therapy with an anti-PD-1 antibody and apatinib was effective and safe in patients with previously treated unresectable advanced or metastatic G/GEJ cancer.

Using a combination of fruquintinib, raltitrexed, and S-1 as a third-line treatment for metastatic colorectal cancer with co-existence of Hodgkin lymphoma: a case report.

Background: Patients with metastatic colorectal cancer (mCRC) beyond second line treatment have a poor prognosis. Fruquintinib, regorafenib, trifluridine/tipiracil (TAS-102), panitumumab and cetuximab combined with single-agent chemotherapy regimens are currently recommended as third-line therapies for patients exhibiting disease progression. Effective late-line therapies for mCRC are urgently needed. The FRESCO randomized clinical trial (RCT) prompts fruquintinib as a third-line treatment in advanced colorectal cancer (CRC). A phase II study in our center reported the efficacy and safety of S-1 plus raltitrexed for the treatment of chemo-refractory mCRC. The combination of the fruquintinib, raltitrexed, and S-1 has not been reported in mCRC. Case Description: This case report presents a patient with mCRC who received third-line treatment with fruquintinib, raltitrexed, and S-1. A 54-year-old male presenting with hematochezia was admitted to West China Hospital of Sichuan University in June 2017 and underwent surgery for a tumor between the rectum and sigmoid colon. Postoperative pathology identified adenocarcinoma (wild-type RAS/RAF, no PIK3CA mutation), and the patient was diagnosed with mCRC (pathological stage, pT3pN1apM0). The mFOLFOX6 regimen was administered. The patient was subsequently diagnosed with Hodgkin lymphoma in May 2018 and treated with the ABVD regimen after multidisciplinary discussions. Liver metastases (intestinal-type adenocarcinoma) were detected in November 2018, and second-line therapy with the FOLFIRI regimen was initiated in January 2019. Lung metastases were identified in September 2019, so the patient was treated with a combination of raltitrexed, S-1, and fruquintinib. A partial response (PR) was detected in November 2019, and the patient underwent resection of the hepatic lesion on November 5, 2020. Computed tomography (CT) images in November 2021 revealed a stable disease; thus, raltitrexed was discontinued, and S-1 and fruquintinib were maintained. The treatment is still responding until the last follow-up (December 2022). Conclusions: The case was characterized by the simultaneous existence of mCRC and Hodgkin lymphoma, which required management by a multidisciplinary team. Third-line therapy with fruquintinib, raltitrexed, and S-1 achieved a PR that permitted surgical resection and enabled a relatively long progression-free survival. The findings suggest that the three agents regimen might be clinically effective as late-line therapy for mCRC.

Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma.

Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells. Cabozantinib inhibits the growth and metastatic spread of experimental HNSCC in zebrafish and the growth of experimental HNSCC in mice by blocking tumor cell proliferation and angiogenesis. The efficacy of cabozantinib is also confirmed on viable sections of surgically removed specimens of human HNSCC and on a patient who relapses after five lines of treatment. These results suggest that cabozantinib is relevant for the treatment of patients with HNSCC after relapse under radiotherapy and cisplatin.

Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: A multi-center, single-arm, phase 1b trial.

This is a phase Ib study of anlotinib plus a programmed death-ligand 1 (PD-L1) inhibitor TQB2450 for platinum-resistant or -refractory ovarian cancer. Thirty-four patients are enrolled and receive treatment. The objective response rate (ORR) is 47.1%, and the disease control rate is 97.1%. The median duration of response (DOR) has not been reached, and 61.3% of patients have a DOR of at least 8 months. The median progression-free survival (PFS) is 7.8 months, and the median overall survival (OS) has not been reached. The PD-L1-positive group has an ORR of 25.0%, whereas the PD-L1-negative group has an ORR of 92.9%. Treatment-related grade 3 or 4 adverse events (AEs) occur in 70.6% of patients, with the most common being hypertension (29.4%) and palmar-plantar erythrodysesthesia syndrome (29.4%). Anlotinib plus TQB2450 show promising antitumor activity and manageable toxicities in patients with platinum-resistant or -refractory ovarian cancer. A phase 3 randomized controlled trial to further validate our findings is ongoing.

Tivozanib in relapsed or refractory advanced renal cell carcinoma: a focus on US approval.

INTRODUCTION: Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR)-inhibitor designed to, more specifically, bind to the VEGF receptor with fewer off-target interactions with other tyrosine kinase receptors in the treatment of advanced renal cell carcinoma (RCC). AREAS COVERED: Both preclinical and early clinical studies have suggested tivozanib could be a more potent VEGFR inhibitor with less off-target toxicities for patients. After a complicated clinical development process, the drug was approved by the FDA for third- and fourth-line use in relapsed, refractory renal cell carcinoma (RCC) in March of 2021 based on the results of the TIVO-3 trial. However, questions remain regarding the proper incorporation of tivozanib in the current treatment landscape of RCC. EXPERT OPINION: Here, we review the existing literature surrounding tivozanib and comment on its optimal use in current and future clinical practice. We suggest that tivozanib may be considered in relapsed, refractory RCC in the later-line treatment setting following progression on both immune checkpoint inhibitors (ICIs) and nonselective VEGFR-TKIs. We anticipate the application of tivozanib in RCC will continue to evolve as trials exploring tivozanib in combination with ICIs may move this drug earlier in the future treatment landscape of RCC.

Efficacy of sintilimab and fruquintinib combination treatment in the management of microsatellite-stable metastatic colorectal cancer: a case report.

Background: The immune microenvironment of deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) colorectal cancer exhibits better immune activity, and patients with dMMR/MSI-H colorectal cancer benefit from immunotherapy with programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors as a first-line treatment. However, for microsatellite-stable (MSS) colorectal cancer, which accounts for the majority of the cases of colorectal cancer, immunotherapy has yielded little success, especially in cases of patients with advanced colorectal cancer in whom multiple lines of chemotherapy have failed. Hence, safe and effective targeted treatment strategies are urgently needed to achieve greater survival benefits. Case Description: We report a case in which next-generation sequencing (NGS) and immunohistochemistry (IHC) showed that that the patient's molecular characteristics were as follows: MSS, low expression of PD-L1, and high tumor mutation burden (TMB-H). Due to the failure of multiple lines of chemotherapy and severe chemotherapeutic adverse effects, a combined targeted immunotherapy regimen was utilized. After 6 months of treatment, imaging suggested near-complete clinical remission, and at the 18-month follow-up, the patient had a good quality of life and imaging showed no tumor recurrence. Conclusions: This case suggests that a good response to a combined targeted immunotherapy regimen can be achieved in patients with MSS metastatic colorectal cancer, in addition, it also suggests that TMB-H is a predictive biomarker for clinical benefit from immunotherapy in MSS metastatic colorectal cancer.

Recent advancements of antiangiogenic combination therapies in ovarian cancer.

Ovarian cancer is a deadly malignancy with a growing therapeutic armamentarium, though achieving sustained benefit in the clinic remains largely elusive. Through biomarker and genetic analysis, several pathways of resistance and sensitivity to commonly used therapeutics have been identified, expanding the potential of identifying unique drug combinations and indicating new directions for improving clinical outcomes. Here, we review the mechanisms of angiogenic response and antiangiogenic therapy in ovarian cancer, as well as the interactions it exhibits with the immune and DNA damage response pathways. We discuss results from clinical trials examining the combinations of antiangiogenics, PARP inhibitors, and immune checkpoint inhibitors are also discussed, as well as several ongoing trials.

Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment.

The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.

A Review of Drug Therapy in Vestibular Schwannoma.

Vestibular schwannomas (VSs, also known as acoustic neuromas) are benign intracranial tumors commonly managed with observation, surgery, and radiotherapy. There is currently no approved pharmacotherapy for VS patients, which is why we conducted a detailed search of relevant literature from PubMed and Web of Science to explore recent advances and experiences in drug therapy. VSs feature a long course of disease that requires treatment to have minimal long-term side effects. Conventional chemotherapeutic agents are characterized by neurotoxicity or ototoxicity, poor effect on slow-growing tumors, and may induce new mutations in patients who have lost tumor suppressor function, and therefore are unsuitable for treating VSs. Along with the well-investigated molecular pathophysiology of VS and the increasingly accessible technology such as drug repositioning platform, many molecular targeted inhibitors have been identified and shown certain therapeutic effects in preclinical experiments or clinical trials.

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours.

BACKGROUND: Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor. METHODS: Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours. RESULTS: Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets. CONCLUSION: This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed. TRIAL REGISTRATION NUMBER: NCT02264418.

Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

Selective Vascular Endothelial Growth Factor Receptor Inhibitors Provide Limited Benefits for Metastatic Colorectal Cancer: A Meta-Analysis.

BACKGROUND: Metastatic colorectal cancer (mCRC) is one of the most common and deadly cancers worldwide. For most patients diagnosed with mCRC and managed with 5-fluorouracil (5-FU)/leucovorin plus oxaliplatin (FOLFOX), the median survival time is still less than 2 years. Small molecule selective vascular endothelial growth factor receptor (VEGFR) inhibitors have been demonstrated to have strong anti-tumour activity in various cancer models. OBJECTIVE: To demonstrate the efficacy and safety of selective VEGFR inhibitors in the management of mCRC. METHODS: A comprehensive search in PubMed, EMBASE, Web of Science, Ovid MEDLINE, Google Scholar, Springer and Cochrane Central databases was performed for randomized controlled trials (RCTs) focusing on the effect of selective VEGFR inhibitors on mCRC. The primary outcome measures were progression-free survival (PFS) rates, overall survival (OS) rates, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rates (ORRs), disease control rates (DCRs) and adverse effect (AE) rates. The dates of the included studies ranged from the inception of the database to January 15, 2020. RESULTS: Twenty-two RCTs were included. A total of 9362 patients met the inclusion criteria. Compared with placebo, selective VEGFR inhibitors significantly increased the PFS rate, SD, PR and DCR, reduced PD, caused more treatment-emergent adverse events (TEAEs), hypertension, hand-foot skin reaction, diarrhoea, fatigue, and thrombocytopaenia and increased aspartate aminotransferase(AST) concentration. There was no significant difference between selective VEGFR inhibitors and placebo regarding OS rate, CR, ORR, proteinuria, hyperbilirubinaemia or alkaline phosphatase(ALP) concentration. Additionally, compared with FOLFOX4+placebo, FOLFOX4+ selective VEGFR inhibitors, clearly reduced PD, and caused more 3-4 AEs, serious AEs, hypertension, hand-foot syndrome, diarrhoea, nausea, vomiting, decreased appetite, dehydration, fatigue, dizziness, neutropaenia and thrombocytopaenia. For PFS rate, OS rate, CR, PR, SD, ORR, abdominal pain, peripheral sensory neuropathy, asthaenia, anaemia and hypokalaemia rates, there was no significant difference between FOLFOX4+ selective VEGFR inhibitors and FOLFOX4+placebo. However, compared with FOLFOX4+bevacizumab, FOLFOX4+selective VEGFR inhibitors, led to increased hypertension, neutropaenia, fatigue, thrombocytopaenia and asthaenia. There is no clear difference between FOLFOX4+selective VEGFR inhibitors and FOLFOX4+ bevacizumab with regard to PFS rate, OS rate, CR, PR, SD, PD, ORR, diarrhoea, nausea, vomiting, peripheral neuropathy and abdominal pain rates. Selective VEGFR inhibitors+cetuximab increased PFS and PR and reduced PD compared to cetuximab, but there was no statistical difference between the two groups for OS and SD. CONCLUSION: Compared with placebo or cetuximab, selective VEGFR inhibitors alone or combined with cetuximab seemed to be more efficacious for mCRC respectively; however, the effects were not better than FOLFOX4 alone or when combined with bevacizumab for mCRC. Additionally, selective VEGFR inhibitors were not as safe as placebo or FOLFOX4 alone or in combination with bevacizumab in mCRC.

Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration-Time Curve for Metastatic Renal-Cell Carcinoma.

BACKGROUND: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration-time curve from 0 to 12 hours (AUC0-12) for sunitinib-pretreated metastatic renal-cell carcinoma patients. PATIENTS AND METHODS: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0-12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0-12 at steady state according to first-dose AUC0-12. The primary end point was the 6-month progression-free survival rate. RESULTS: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand-foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. CONCLUSION: Individualized dosing of axitinib based on the first-dose AUC0-12 might have promising efficacy and manageable toxicity.

Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study.

BACKGROUND: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. RESULTS: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. CONCLUSIONS: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. TRIAL REGISTRATION NUMBER: NCT00428597.