On April 20, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has presented the results of non-clinical research investigating the combination of Eisai’s in-house developed anticancer agent lenvatinib mesylate (lenvatinib) and anticancer agent everolimus at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 107th Annual Meeting (Press release, Eisai, APR 20, 2016, View Source [SID:1234511115]). The presentations concerned an analysis of the mechanism of action that leads to enhanced inhibition of angiogenesis as well as using murine models to demonstrate an anti-tumor effect on renal cell carcinoma.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

As the results of research presented at the AACR (Free AACR Whitepaper) meeting,1 when the combination of lenvatinib (7.5 mg/kg) and everolimus (15 mg/kg), lenvatinib alone (10 mg/kg) or everolimus alone (30 mg/kg) were administered to model mice in which tumor angiogenesis had been induced from overexpression of either vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF), a substantial inhibitory effect on tumor growth was observed in both types of mice that had been administered the combination therapy compared to the higher doses of lenvatinib alone or everolimus alone. As subsequent in vitro studies, in VEGF and FGF stimulated human umbilical vascular endothelial cells, it was observed that lenvatinib inhibits VEGF and FGF receptors while everolimus suppresses the downstream signaling pathways for these two receptors, confirming that enhanced antiangiogenic activity is due to the mechanisms of action of both agents combined. Furthermore, it is suggested that the combination of lenvatinib and everolimus synergistically enhances inhibitory activity against FGF-induced angiogenesis as well.

In separate research findings,2 in a xenograft model where human renal cell carcinoma cell strains had been implanted subcutaneously into mice, when the combination of lenvatinib (10 mg/kg) and everolimus (30 mg/kg), lenvatinib alone (10 mg/kg) or everolimus alone (30 mg/kg) were administered to these mice, pronounced apoptosis in tumor cells was observed only in the group that received combination therapy. Furthermore, a decrease in microvessel density for lenvatinib alone and a decrease in the proportion of proliferative cells for everolimus alone were seen, and both these effects were observed in the combination therapy group. These results suggest that treatment of lenvatinib in combination with everolimus causes a strong antitumor effect by combining the potent antiangiogenic activity of lenvatinib as well as direct antitumor activity of everolimus.

Eisai remains committed to providing further clinical evidence for lenvatinib aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

1. About lenvatinib mesylate (generic name, "lenvatinib", product name: Lenvima)
Lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for lenvatinib in over 40 countries including the United States, Japan, Europe, Korea and Canada as a treatment for refractory thyroid cancer, and is undergoing regulatory review in countries throughout the world including in Asia, Russia, Australia, Brazil and Mexico. More specifically, Eisai has obtained approval for the agent indicated in the United States for treatment for locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively. Meanwhile, Eisai is conducting a global Phase III study of lenvatinib in hepatocellular carcinoma, Phase II studies of lenvatinib in several other tumor types such as endometrial carcinoma and biliary tract cancer, as well as a Phase Ib/II study of lenvatinib in combination with an immune checkpoint inhibitor.

2. About Renal Cell Carcinoma
The number of patients with renal cancer was estimated to be approximately 338,000 worldwide, including approximately 58,000 in the United States, 115,000 in Europe and 17,000 in Japan.3 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney,4 and occurs when malignant cells are found in the lining of the tubules of the kidney. The incidence of renal cell carcinoma in people aged in their late 50s is rising, and is more likely to affect men than women. For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment method is molecular targeted drug therapy, however with low 5-year survival rates, this remains a disease with significant unmet medical need.

Formation of new blood vessels in tumors, a process termed tumor angiogenesis, is a crucial step during oncogenic progression. Blocking tumor angiogenesis is therefore expected to have a profound impact on tumor growth. It took several decades of collective efforts to translate this intriguing idea into tangible clinical benefit. Today, anti-angiogenesis agents represent standard-of-care therapies for multiple types of cancers, and the clinical experience has taught us many lessons about the concept and application of anti-angiogenesis. This Perspective is an attempt to summarize these lessons and how they can be leveraged to improve anti-angiogenesis therapy.
Copyright © 2016 Elsevier Inc. All rights reserved.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd versus Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P=.09); median PFS was longer with EBd (9.7 months) versus Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months versus 9.8 in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) versus 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) versus 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd versus Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd versus Bd alone. ClinicalTrials.govNCT01478048 .
Copyright © 2016 American Society of Hematology (ASH) (Free ASH Whitepaper).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Roniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. Here, we show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas residence times on other CDKs are transient, thus giving rise to a kinetic selectivity of roniciclib. Surprisingly, variation of the substituent at the 5-position of the pyrimidine scaffold results in changes of up to 3 orders of magnitude of the drug-target residence time. CDK2 X-ray cocrystal structures have revealed a DFG-loop adaption for the 5-(trifluoromethyl) substituent, while for hydrogen and bromo substituents the DFG loop remains in its characteristic type I inhibitor position. In tumor cells, the prolonged residence times of roniciclib on CDK2 and CDK9 are reflected in a sustained inhibitory effect on retinoblastoma protein (RB) phosphorylation, indicating that the target residence time on CDK2 may contribute to sustained target engagement and antitumor efficacy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Developing effective vaccines against Ebola virus is a global priority.
To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo).
Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015.
Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 1010 viral particles) or MVA-BN-Filo (1 × 108 median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later.
The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations.
Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses.
In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies.
clinicaltrials.gov Identifier: NCT02313077.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!