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PRELIMINARY PHASE IB CLINICAL STUDY RESULTS FOR LENVATINIB IN COMBINATION WITH PEMBROLIZUMAB IN SELECTED SOLID TUMORS PRESENTED AT ESMO 2016

On October 12, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that a presentation on the results of a Phase Ib clinical study of its in-house developed multiple receptor tyrosine kinase inhibitor lenvatinib mesylate (lenvatinib) in combination with the anti-PD-1 antibody pembrolizumab developed by Merck & Co., Inc (Press release, Eisai, OCT 12, 2016, View Source [SID:SID1234515765]). (Kenilworth, New Jersey, U.S.A.), known as MSD outside the United States and Canada, in patients with selected solid tumors was given at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress held from October 7 to 11. Development of this combination regimen is being conducted jointly under the cooperation of both companies.

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This investigational study is a multicenter, open-label Phase Ib/II clinical study to evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab. In the Phase Ib part of the study, which was conducted to determine and confirm the maximum tolerated dose (MTD), 13 patients with selected solid tumors (8 patients with renal cell carcinoma, 2 patients with endometrial cancer, 2 patients with non-small cell lung cancer and 1 patient with melanoma) that had progressed after treatment with approved therapies or for which there are no standard effective therapies available were administered lenvatinib (either 24 mg or 20 mg daily) and pembrolizumab (200 mg intravenously every three weeks).

According to the latest results of the Phase Ib part of the study as of August 2016, dose-limiting toxicities (DLTs) were reported in 2 of 3 patients in the lenvatinib 24 mg / pembrolizumab 200 mg group. No DLTs were reported in the lenvatinib 20 mg / pembrolizumab 200 mg group (10 patients), and the MTD was confirmed as 20 mg of lenvatinib per day / 200 mg of pembrolizumab every three weeks. The objective response rate, one of the study’s secondary endpoints, was 69.2% (n of 13 patients). Grade 3 or higher Treatment-Emergent Adverse Events (TEAEs) were observed in 69.2% of patients, and no patients had discontinued treatment due to TEAEs. The three most frequently observed adverse events were decreased appetite, diarrhea and fatigue.

Takashi Owa, Ph.D, Chief Medicine Creation Officer of Eisai’s Oncology Business Group, commented "From the results of this study for patients who had progressed after treatment with approved therapies or for which there are no standard effective therapies available, we are encouraged to further explore the combination of lenvatinib and pembrolizumab in the next stage of clinical development." Currently, the Phase II part of the study is underway in the United States, while preparations to initiate a Phase Ib clinical study in Japan are also underway.

Eisai regards oncology as a key therapeutic area and is aiming to discover revolutionary new medicines with the potential to cure cancer. 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.

About lenvatinib mesylate ("lenvatinib", generic name, product names: Lenvima , Kisplyx )
Discovered and developed in-house, 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 as a treatment for refractory thyroid cancer in over 45 countries including in the United States, Japan, in Europe, Korea, Canada, and Mexico, and is undergoing regulatory review in countries throughout the world including South Africa and Malaysia. Specifically, Eisai has obtained approval for the agent indicated in the United States for the treatment of 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.Lenvatinib was also approved in the United States in May 2016 for an additional indication in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. Furthermore, lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe in August 2016. Lenvatinib has been launched in Europe under the brand name Kisplyx for this indication. Meanwhile, Eisai is conducting clinical studies of lenvatinib in several other tumor types such as hepatocellular carcinoma (Phase III), endometrial carcinoma (Phase II), biliary tract cancer (Phase II), and in combination with pembrolizumab for various types of cancer (Phase Ib/II). In addition, Eisai has initiated a Phase III clinical study of lenvatinib in combination with pembrolizumab and everolimus in renal cell carcinoma (first-line therapy).

About the Phase Ib/II Clinical Study (Study 111)

Study 111 is a multicenter, open-label Phase Ib/II clinical study to evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab. In the Phase Ib part of the study, which was to determine and confirm the maximum tolerated dose (MTD), 13 patients with selected solid tumors (8 patients with renal cell carcinoma, 2 patients with endometrial cancer, 2 patients with non-small cell lung cancer and 1 patient with melanoma) who had progressed after treatment with approved therapies or for which there are no standard effective therapies available were administered 24 mg (3 patients) or 20 mg (10 patients) of lenvatinib orally daily as well as 200 mg of pembrolizumab intravenously every three weeks. Objective response rate, overall survival and progression-free survival are also assessed as secondary endpoints. Currently, the Phase II part of the clinical study is underway in the United States.

Adaptimmune Provides Update on Clinical Study Evaluating its SPEAR® T-Cell Therapy Targeting NY-ESO-1 in Ovarian Cancer

On October 12, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that its amended protocol using its NY-ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell therapy in ovarian cancer patients with treatment resistant or refractory metastatic ovarian cancer is now actively recruiting (Press release, Adaptimmune, OCT 12, 2016, View Source [SID:SID1234515760]).

To date, no objective clinical responses have been reported in the ovarian cancer patients who received NY-ESO SPEAR T-cell therapy in the initial iteration of this trial. Of note, these initial patients received a preconditioning regimen which consisted of cyclophosphamide alone, rather than including fludarabine. Data from Adaptimmune’s studies of its NY-ESO SPEAR T-cell therapy in synovial sarcoma patients have indicated the importance of including fludarabine in the preconditioning regimen. The use of fludarabine appears to be required for expansion, response and persistence of transduced cells. As a result, this trial will enroll patients under a revised protocol including a pre-conditioning regimen that includes fludarabine in combination with cyclophosphamide.

"Based on our clinical experience to date, we have amended the protocol for this trial to include both fludarabine and cyclophosphamide in the conditioning regimen," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We hope that, as previously observed in synovial sarcoma, this lymphodepleting regimen will enable anti-tumor immune responses mediated by NY-ESO SPEAR T-cell therapy in these patients with advanced chemotherapy relapsed or refractory ovarian cancer."

This is a Phase I/IIa, open-label study of autologous T-cells genetically engineered with an enhanced affinity NY-ESO-1 T-cell receptor in ovarian cancer patients with the HLA-A*0201, HLA-A*0205, and/or HLA-A*0206 allele and whose tumor expresses the NY-ESO-1 tumor antigen. Though the prevalence of HLA sub-types varies from population to population, the most common in the western world is HLA-A2. Among the HLA-A2 variants, the most prevalent are HLA-A*0201 and HLA-A*0206.

This multi-center study is intended to enroll up to 10 additional patients under the revised protocol, and will assess the safety and tolerability of Adaptimmune’s NY-ESO SPEAR T-cell therapy in patients with treatment resistant or refractory metastatic ovarian cancer expressing the NY-ESO-1 antigen. Secondary objectives will include the assessment of clinical efficacy, measurements of durability of persistence of NY-ESO SPEAR T-cells in the blood, and exploratory tumor biomarker studies, and evaluations of the phenotype and functionality of NY-ESO-1 SPEAR T-cells.

For more information on this clinical trial, visit ClinicalTrials.gov at: View Source (Identifier: NCT01567891).

About Ovarian Cancer
As reported by the American Cancer Society, epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and the country’s fifth most common cause of cancer mortality in women. It is estimated that in 2016 in the United States, 22,280 women will receive a new diagnosis of ovarian cancer, and approximately 14,240 women will die of this disease. Overall, the five-year relative survival rate is 45 percent. If the cancer is detected and treated early, at the localized stage when the cancer is only in the part of the body where it started, the five-year relative survival rate is 92 percent. However, only 15 percent are detected at the localized stage. No treatment is available for patients with refractory or resistant metastatic ovarian cancer.

Celgene and Agios Announce Collaborations with Abbott for Diagnostic Identification of IDH Mutations in AML

On October 12, 2016 Celgene Corporation (NASDAQ:CELG) and Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) reported each company has entered into collaboration agreements with Abbott (NYSE: ABT), a leader in diagnostic technologies, to develop and commercialize companion diagnostic tests on Abbott’s m2000 RealTime System to identify isocitrate dehydrogenase (IDH) mutations in acute myeloid leukemia (AML) patients (Press release, Agios Pharmaceuticals, OCT 12, 2016, View Source [SID1234515759]). Celgene is currently developing enasidenib (AG-221/CC-90007), an IDH2 mutant inhibitor, for the treatment of patients with relapsed or refractory AML who have an IDH2 mutation. Agios is developing AG-120, an IDH1 mutant inhibitor, for the treatment of patients with relapsed or refractory AML who have an IDH1 mutation.

IDH1 and IDH2 mutations occur in approximately 20% of AML patients. An article published online this week in the journal Leukemia (Medeiros, Leukemia 2016) concluded that advances in the understanding of the genetics underlying myeloid malignancies are driving an era of development for targeted treatments such as IDH mutant inhibitors. The authors recommend that IDH mutational analysis should become part of the routine AML diagnostic workup and repeated at relapse to identify patients who may be eligible for targeted investigational treatments currently under clinical study.

"AML is a complex and heterogeneous disease, making it difficult to treat," said Han Myint, M.D., Vice President, Global Medical Affairs, Myeloid for Celgene. "IDH mutations lead to aberrant DNA methylation, causing a block in myeloid differentiation that leads to disease progression. Molecular profiling is important to identify genomic mutations which may have prognostic and potential treatment implications for patients with AML."

Abbott’s m2000rt RealTime System, is a polymerase chain reaction (PCR) instrument designed to enable clinical laboratories to automate PCR and results analysis, simplifying the complex and manual steps often associated with molecular diagnostics. Both Celgene and Agios have incorporated this screening into clinical trial designs, including the recently initiated Phase 3 IDHENTIFY trial comparing enasidenib with conventional therapy in older patients with an IDH2 mutation and relapsed or refractory AML (NCT02577406).

"The field of personalized medicine is advancing at a rapid pace for a broad range of medical conditions, especially within hematology-oncology," said Chris Bowden, M.D., chief medical officer at Agios. "Our collaboration with Abbott will provide a test to help identify AML patients with IDH mutations who are in need of treatment options."

The m2000 system has not been FDA cleared or approved for use with enasidenib or AG-120.

Enasidenib and AG-120 have not been approved for any use in any country.

Daiichi Sankyo and Dana-Farber Cancer Institute Announce Lung Cancer Research Collaboration

On October 12, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and the Dana-Farber Cancer Institute reported a preclinical research collaboration focused on lung cancer (Press release, Daiichi Sankyo, OCT 11, 2016, View Source [SID:SID1234515767]).

A team of scientists led by Pasi A. Jänne, M.D., Ph.D., Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute; Scientific Director, Belfer Center for Applied Cancer Science; and, Professor of Medicine, Harvard Medical School will partner with Daiichi Sankyo on the development of a translational pharmacology package with unique experimental animal and patient derived xenograft models that were established at Dana-Farber Cancer Institute. The collaboration will leverage the translational medicine expertise of the Belfer Center. Financial terms of the agreement were not disclosed.

"We are excited to enter into this unique partnership with Daiichi Sankyo. Working together we can accelerate the development of new therapeutic strategies for patients with lung cancer," said Dr. Jänne.
"Despite several recent significant advances in the treatment of lung cancer with EGFR mutations,many patients still die of this disease, hence our urgency and obligation to pursue swiftly great science," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "By partnering with scientists at Dana-Farber, we are looking to better understand drivers of disease as well as initial and secondary resistance to established targeted treatments with the ultimate goal of identifying a potential new treatment for patients with lung cancer."

Daiichi Sankyo Announces First Patient Enrolled in Phase 3 QuANTUM-First Trial Investigating Quizartinib in Newly-Diagnosed FLT3-ITD+ Acute Myeloid Leukemia

On October 11, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the first patient has been enrolled in the global phase 3 QuANTUM-First study evaluating the oral FLT3-ITD inhibitor quizartinib in patients with newly-diagnosed FLT3-ITD-positive (+) acute myeloid leukemia (AML) (Press release, Daiichi Sankyo, OCT 11, 2016, View Source [SID:SID1234515762]).

QuANTUM-First is a randomized, double-blind, placebo-controlled study evaluating quizartinib in combination with induction and consolidation chemotherapy and as maintenance monotherapy in patients with newly-diagnosed FLT3-ITD+ AML. The primary endpoint of the study is event-free survival. Secondary endpoints include overall survival, complete remission rate, composite complete remission rate and the percentage of subjects achieving a complete remission with no evidence of minimal residual disease.

Approximately 30 percent of patients with AML have a genetic mutation called FLT3-ITD, which is associated with more aggressive disease, resulting in increased relapse rate and reduced overall survival compared to those without this mutation.1FLT3-ITD mutations are more common than FLT3-TKD mutations, which occur in approximately 10 percent of AML patients.1There is controversy as to whether FLT3-TKD mutations carry as poor a prognosis as FLT3-ITD mutations.1Currently, there are no approved targeted treatments for FLT3-ITD+ AML, with little change in the treatment of AML for the past 30 years.2

"It is well established that patients with FLT3-ITD mutated AML have an overall worse prognosis compared to those without this specific mutation," said Harry Erba, MD, PhD, Chair of the QuANTUM-First Steering Committee and Professor of Medicine and Director of the Hematologic Malignancy Program at the University of Alabama at Birmingham. "In this study we are evaluating whether adding quizartinib to standard first-line chemotherapy will help delay or prevent relapse, which in turn may impact overall survival in patients with FLT3-ITD+ AML."

"Given the high unmet need in FLT3-ITD+ AML, we are moving forward with a comprehensive clinical development program investigating the role of quizartinib in multiple lines of treatment including induction and consolidation chemotherapy, maintenance therapy and salvage therapy," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Additionally, we also are looking to combine quizartinib with other investigational agents in our pipeline such as our MDM2 and BRD4 inhibitors where science suggests combining different mechanisms of action may help improve outcomes."

QuANTUM-First is expected to enroll more than 500 patients between 18 and 75 years of age in the Americas, Europe and Asia-Pacific. More information about the study is available at ClinicalTrials.gov or www.QuantumFirstStudy.com.

About Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) is the most common type of acute leukemia accounting for about 33 percent of all new cases of leukemia.3 An aggressive blood and bone marrow cancer, AML causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells. 3 The five-year survival rate of AML is approximately 26 percent, which is the lowest of all leukemias.3

About Quizartinib
Quizartinib is an investigational oral small molecule that potently and selectively inhibits FLT3-ITD (FMS-like tyrosine kinase-3-internal tandem duplication), which is a growth driver of abnormal cells that contribute to the development of AML.4 Quizartinib has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of AML. Quizartinib also has been granted Fast Track Designation by the FDA for the treatment of relapsed/refractory AML. Quizartinib has not been approved by any regulatory authority for uses under investigation.
In addition to QuANTUM-First, a global, randomized, open-label, phase 3 study called QuANTUM-R is evaluating quizartinib as monotherapy in patients with FLT3-ITD+ AML who are refractory to or have relapsed after first-line treatment with or without hematopoietic stem cell transplant (HSCT). The primary objective of QuANTUM-R is to determine whether quizartinib prolongs overall survival compared to salvage chemotherapy, and the secondary objective is to determine event-free survival. The trial is expected to enroll approximately 363 patients age 18 or older in North America, Europe and Asia-Pacific. More information about QuANTUM-R is available at www.QuantumRStudy.com or ClinicalTrials.gov.