lenvatinib and Neoplasms

Angiogenesis is an important and interesting scientific subject in the area of malignant tumours. Current research importance and interest are directed in connection to blood microvessels in cancer cell proliferation, tumour growth, and metastasis. Tyrosine kinases have been intensely implicated as therapeutic targets that affect the angiogenic process in tumour growth. In the last decades, targeting angiogenesis has led to achievements in the therapy of different carcinomas by different mechanisms, such as the utilization of anti-angiogenic small molecule receptor tyrosine kinase inhibitors. In the current review, we aim to track the advancements in the total synthesis of three receptor tyrosine kinase inhibitors (pazopanib, regorafenib and lenvatinib). This review surveys different synthetic routes for these three approved drugs (pazopanib, regorafenib and lenvatinib) which were previously published as patents (2014-2021). The purity of medicines is a very important factor during manufacturing so we have decided to review the purification process of these anticancer medicines as well. It should be noted that the different patents may have reported some procedures with different yields and purities for the synthesis of desired drug and their intermediates. In order to simplify the understanding of the contents of this review article, only the best results reported in each of these patents are reported for the synthesis of desired drug and their intermediates.

Topics: Humans; Indazoles; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinolines; Sulfonamides; Tyrosine

Low muscle mass has been associated with worse clinical outcomes in various cancers. This work investigated whether, during tyrosine kinases inhibitors (TKIs) therapy, low muscle mass was associated with treatment toxicity and survival outcomes. A systematic literature search was performed in Pubmed, Web of Science, and Scopus databases from inception to June 2020, based on fixed inclusion and exclusion criteria. Effect sizes were estimated with hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) and heterogeneity was assessed by measuring inconsistency (I

Topics: Gefitinib; Humans; Imatinib Mesylate; Indazoles; Muscle, Skeletal; Neoplasms; Phenylurea Compounds; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Quinolines; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis

Both pembrolizumab and lenvatinib demonstrate antitumor activity and safety in cancers. However, whether their combination is safer and more effective than monotherapies remains unknown. A systematic review was performed to assess the safety and efficacy of pembrolizumab plus lenvatinib versus their respective monotherapies in solid cancers.. PubMed, Embase, and Cochrane Library were searched. Forty-two clinical trials with 8155 patients were included.. The total ≥grade 3 adverse events (AEs) and objective response rates (ORRs) among pembrolizumab plus lenvatinib and pembrolizumab or lenvatinib monotherapies in solid cancers were 68.0% vs 17.7% vs 68.5% and 40.6% vs 20.8% vs 43.3%, respectively. The most common AEs of pembrolizumab plus lenvatinib were hypertension (20-61.1%), fatigue (12-59.1%), diarrhea (9-51.9%), hypothyroidism (25-47%), and proteinuria (8-17%). Good ORRs for combination therapy were observed in renal cell carcinoma (70%), gastric cancer (69%), melanoma (48%), head and neck squamous cell carcinoma (46%), and endometrial cancer (38-53%), while these rates were reported as 27%, 11.6-22%, 26-37%, 14.6-23%, and 11-14.3% for monotherapies, respectively. Longer median progression-free survival (mPFS) and median overall survival (mOS) were observed for hepatocellular carcinoma (mPFS 9.3 months, mOS 22.0 months), renal cell carcinoma (mPFS 19.8 months), gastric cancer (mPFS 7.1 months, mOS not reached), and endometrial cancer (mPFS 7.4 months, mOS 16.7 months).. Compared with their monotherapies, pembrolizumab plus lenvatinib showed more promising antitumor activity and resulted in higher ORRs and significant survival benefits in the above cancers. Toxicities were manageable, with no unexpected safety issues.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Neoplasms; Phenylurea Compounds; Progression-Free Survival; Quinolines; Time Factors

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Infections; Kaplan-Meier Estimate; Neoplasms; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Signal Transduction

In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies-such as sorafenib, regorafenib, sunitinib, and lenvatinib-on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.

Topics: Cachexia; Humans; Molecular Targeted Therapy; Multicenter Studies as Topic; Muscle, Skeletal; Neoplasms; Nutrition Assessment; Nutritional Status; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Randomized Controlled Trials as Topic; Recommended Dietary Allowances; Sorafenib; Sunitinib; Treatment Outcome

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

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

Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1-3 (VEGFR1-3), fibroblast growth factor receptors 1-4 (FGFR-1-4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Clinical Trials as Topic; Combined Modality Therapy; Everolimus; Humans; Infant; Iodine Radioisotopes; Mice; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasms; Paclitaxel; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptors, Growth Factor; Signal Transduction; Thyroid Neoplasms; Thyroidectomy; Xenograft Model Antitumor Assays

Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are resistant. Even when drugs have yielded significant results, improvements in progression-free survival, and, in some cases, overall survival, are modest. Thus, a crucial issue in development of these drugs is the search for predictive biomarkers-tests that predict which patients will, and will not, benefit before initiation of therapy. Development of biomarkers is important because of the need to balance efficacy, toxicity, and cost. Novel combinations of these drugs with other antiangiogenics or other classes of drugs are being developed, and the appreciation that these drugs have immunomodulatory and other modes of action will lead to combination regimens that capitalise on these newly understood mechanisms.

Topics: Angiogenesis Inhibitors; Angiopoietin-1; Biomarkers, Tumor; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Quinazolines; Quinolines; Receptor, TIE-2; Signal Transduction; Sorafenib; Vascular Endothelial Growth Factor A

To systematically review the safety and efficacy of lenvatinib in the treatment of patients, we retrieved all the relevant clinical trials on the adverse events (AEs) and survival outcomes of lenvatinib through PubMed, Medline, Embase, Web of Science and Cochrane Collaboration's Central register of controlled trial. Fourteen eligible studies involving a total of 978 patients were included in our analysis. The most common all-grade AEs observed in patients treated with lenvatinib were hematuria (56.6%), fatigue (52.2%) and decreased appetite (50.5%). The most frequently observed grade ≥3 AEs were thrombocytopenia (25.4%), hypertension (17.7%) and edema peripheral (15.5%). The incidences of both all-grade and high-grade hypertension were significantly increased. Meanwhile, the controlled trial suggested that progression free survival (PFS) was significantly longer in the lenvatinib group than the placebo group. Subgroup analyses showed that mean PFS for renal cell carcinoma was 10.933±1.828 months (95% CI 7.350-14.515, p < 0.001), and that for thyroid cancer was 18.344±0.083 months (95% CI 18.181-18.506, p < 0.001). In conclusion, lenvatinib is an effective agent in thyroid cancer. Early monitoring and effective management of side effects are crucial for the safe use of this drug.

Topics: Antineoplastic Agents; Disease-Free Survival; Fatigue; Hematuria; Humans; Hypertension; Neoplasms; Phenylurea Compounds; Quinolines; Thrombocytopenia; Treatment Outcome

Topics: Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Melanoma; Molecular Targeted Therapy; Mutation; Neoplasms; Phenylurea Compounds; Precision Medicine; Proto-Oncogene Proteins B-raf; PTEN Phosphohydrolase; Quinolines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Translational Research, Biomedical

Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.. Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORR. Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cohort Studies; Endometrial Neoplasms; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasms; Phenylurea Compounds; Quinolines

Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib.. This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available.. Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration-time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850-0.983) but increased it on day 14 to 1.148 (90% CI 0.938-1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753-0.988) but increased it on day 14 to 1.027 (90% CI 0.852-1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%).. Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. CLINICALTRIALS.. NCT02686164.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Cytochrome P-450 CYP3A; Drug Interactions; Female; Half-Life; Humans; Male; Midazolam; Middle Aged; Neoplasms; Phenylurea Compounds; Quinolines

Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of (14)C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

Topics: Adult; Antineoplastic Agents; Carbon Radioisotopes; Feces; Female; Humans; Male; Middle Aged; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Treatment Outcome

This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors.. Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort.. Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC(0-24) and C(max) increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively).. The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Cohort Studies; DNA Mutational Analysis; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Treatment Outcome

This phase 1 study aimed to assess the tolerability, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of lenvatinib capsules in Japanese patients with solid tumors when administered orally up to 24 mg on a once-daily (QD) continuous schedule.. Patients were enrolled in one of the two sequential cohorts (20 or 24 mg) of lenvatinib on a 28-day cycle based on the conventional 3 + 3 dose escalation design. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Tolerability was judged based on dose-limiting toxicities (DLTs) during Cycle 1. The drug was defined as tolerable when the incidence of DLTs was less than 33 %.. Nine patients received lenvatinib [20 mg (n = 3); 24 mg (n = 6)]. No DLTs were observed. The most common AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (89 %), followed by leukopenia, headache, and proteinuria (78 %). The area under the concentration-time curve and maximum observed concentration increased dose proportionally. The PK profiles were similar to those in non-Japanese phase 1 studies. One patient with leiomyosarcoma showed a partial response, and three patients have maintained stable disease for more than 6 months.. The 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors.

Topics: Adult; Area Under Curve; Asian People; Female; Headache; Humans; Japan; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thrombocytopenia; Treatment Outcome

Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.. Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.. Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1α] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1α, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1α levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.. PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.. ClinicalTrial.gov: NCT00280397 (January 20, 2006).

Topics: Angiogenic Proteins; Biomarkers, Pharmacological; Blood Proteins; Disease Progression; Drug Administration Schedule; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Treatment Outcome

The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy.. E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles.. Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks' administration.. E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinolines

E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.. In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.. Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma concentration-time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.. E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Biomarkers, Tumor; Chemokine CXCL12; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelial Cells; Fatigue; Female; Headache; Humans; Hypertension; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Quinolines; Stem Cells; Treatment Outcome

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

Topics: Angiogenesis Inhibitors; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension; Models, Biological; Neoplasms; Phenylurea Compounds; Proteinuria; Quinolines; Urinalysis

Lenvatinib (LT), a first-line molecular targeted therapeutic drug for hepatocellular carcinoma (HCC), has been replacing the status of Sorafenib (SF) as the clinically preferred and irreplaceable treatment for a decade. To overcome the low drug utilization and limited single efficacy of LT, ultrasmall copper sulfide nanocrystals (Cu

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Copper; Gold; Humans; Hydrogen Peroxide; Liver Neoplasms; Metal Nanoparticles; Nanoparticles; Neoplasms; Phototherapy; Theranostic Nanomedicine; Tumor Microenvironment

Microwave (MW) thermal therapy has been developed as an effective clinical strategy that can achieve pronounced antitumor activity and also has the potential to trigger antitumor immunity. However, patients generally face high rates of tumor recurrence following MW treatment, limiting the long-term benefits of such treatment. The combination of MW treatment and immunomodulatory strategies may represent a promising means of reprogramming the immunosuppressive tumor microenvironment (TME) in a manner conducive to lower recurrence rates. In this study, a Lenvatinib-loaded Gd/Fe metal-organic framework (Gd/FeMOF) was designed as a promising approach to enhancing such antitumor immunity. MW-enhanced dynamic Gd/FeMOF sensitization can facilitate high levels of reactive oxygen species production under MW irradiation, resulting in stronger immunogenic tumor cell death. In parallel, the Lenvatinib released from Gd/FeMOF preparations can serve as an immune adjuvant that suppresses programmed death ligand 1 (PD-L1) expression and drives the reprogramming of the immunosuppressive TME. The Gd and Fe present within this MOF preparation also imbue it with magnetic resonance imaging capabilities. Importantly, in vivo animal model experiments confirmed the ability of GdFeMOF treatment to significantly enhance antitumor immunity while protecting against recurrence. Accordingly, this study offers a foundation for promising strategies aimed at the integrated diagnosis and durable treatment of cancer. STATEMENT OF SIGNIFICANCE: High rates of tumor recurrence following MW thermal therapy limit the long-term benefits of such treatment. We found that the administration of Lenvatinib-loaded Gd/FeMOF nanoparticles significantly reduced tumor recurrence after MW thermal therapy. Under MW irradiation, the Gd/FeMOF nanoparticles were found to augment the immune response due to facilitation of the process of immunogenic cell death. In addition, the released Lenvatinib could act as an immune adjuvant to downregulate the expression of PD-L1 and reprogram the immunosuppressive state of the tumor microenvironment, thus further enhancing the immune response. This is significant because MW-induced immune responses are relatively weak and usually fail to effectively prevent tumor recurrence. The combination of MW treatment with an immunomodulatory strategy may solve this problem.

Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; Humans; Microwaves; Neoplasm Recurrence, Local; Neoplasms; Tumor Microenvironment

We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers.. We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N = 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N = 16)].. Patients whose cancers harbored FGF/FGFR alterations (N = 1074) versus those without them (N = 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P = 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P = 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR) = 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well.. FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.

Topics: Fibroblast Growth Factors; Humans; Neoplasms; Phenylurea Compounds; Quinolines; Receptors, Fibroblast Growth Factor

Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease Progression; Humans; Immune Checkpoint Inhibitors; Neoplasm Staging; Neoplasms; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines

Topics: Antineoplastic Agents; Drug Approval; Equivalence Trials as Topic; Humans; Neoplasms; Phenylurea Compounds; Quinolines; Sorafenib; United States; United States Food and Drug Administration

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.

Topics: Aminopyridines; Animals; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Hepatocyte Growth Factor; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Phenylurea Compounds; Piperazines; Proto-Oncogene Proteins c-met; Quinolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytoskeletal Proteins; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms; NIH 3T3 Cells; Oncogene Proteins, Fusion; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinolines; Signal Transduction

The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years.

Topics: Angiogenesis Inhibitors; Animals; Clinical Trials as Topic; Humans; Models, Molecular; Neoplasms; Pyridines; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Structure-Activity Relationship

To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment.. A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred.. Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%).. The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Computer Simulation; Drug Administration Schedule; Female; Humans; Hypertension; Male; Markov Chains; Middle Aged; Models, Biological; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Proteinuria; Quinolines; Receptors, Vascular Endothelial Growth Factor; Research Design; Treatment Outcome

E7080 is an orally active multi-targeted kinase inhibitor whose targets include vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptors (PDGFR). It has been shown to inhibit tumor angiogenesis by targeting endothelial cells. A number of the targets of E7080 are also expressed on tumor cells and here we have looked at the direct effects of E7080 on tumor cell behavior.. Using a panel of human tumor cell lines we determined the effect of E7080 on cell proliferation, migration and invasion. Inhibition of FGFR and PDGFR signaling in the cells was measured.. E7080 had little effect on tumor cell proliferation. However, it blocked migration and invasion at concentrations that inhibited FGFR and PDGFR signaling. Knock-down of PDGFR-β in U2OS osteosarcoma cells also inhibited cell migration which, could not be further inhibited in the presence of E7080. Furthermore, E7080 could not inhibit the migration of a PDGFR negative cell line.. E7080 does not significantly affect tumor cell proliferation but can inhibit their migration and invasion at concentrations that both inhibit its known targets and are achievable clinically.

Topics: Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Immunoblotting; Neoplasm Invasiveness; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor beta; RNA Interference; Signal Transduction