On January 30, 2015 Eisai reported that the Phase II part of a Phase I/II clinical trial (Study 205) of its in-house developed anticancer agent lenvatinib mesylate (lenvatinib) in unresectable advanced or metastatic renal cell carcinoma has met its primary endpoint (Press release Eisai, JAN 30, 2015, View Source [SID:1234501422]).

The second part of Study 205 was an open-label, multicenter study of lenvatinib alone, and in combination with the anticancer agent everolimus, in patients with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted treatment. 153 patients were randomized in a 1:1:1 ratio to one of three treatment arms to receive either lenvatinib
(18 mg) plus everolimus (5 mg), lenvatinib alone (24 mg), or everolimus alone (10 mg) to compare the safety and efficacy of these three regimens.

From the preliminary results of the study, both lenvatinib plus everolimus and the lenvatinib alone groups prolonged progression free survival (PFS), the study’s primary endpoint, compared to everolimus alone, and the lenvatinib plus everolimus group in particular showed a highly statistically significant improvement. The most common treatment-related adverse events reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite, fatigue, nausea, and hypertension, and in the lenvatinib alone group were diarrhea, nausea, decreased appetite, hypertension, fatigue, and vomiting. Detailed results of the study will be presented at an academic conference in the near future.

Renal cell carcinoma is the most common form of cancer to affect the kidneys. For metastatic or advanced 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 needs. According to the result
s of this study, lenvatinib plus everolimus showed superior PFS over everolimus alone which is recommended by the National Comprehensive Cancer Network guidelines as a 2nd-line therapy for unresectable advanced or metastatic renal cell carcinoma. Currently, no combination therapy for this indication has been approved in any major country worldwide. Eisai will share these study results with regulatory authorities to discuss further steps.

Lenvatinib is an oral molecular targeted agent that selectively inhibits the activities of several different molecules including VEGFR, FGFR, RET, KIT and PDGFR, involved in angiogenesis and tumor proliferation. It is the first compound that has been confirmed through X-ray crystal structural analysis to possess a novel binding mode (Type V) to VEGFR2. Furthermore, lenvatinib exhibits rapid and potent inhibition of kinase activity, according to kinetic analysis. Currently, Eisai has already submitted regulatory applications for lenvatinib seeking indication approval for thyroid cancer to health authorities firstly in Japan, the United States and the EU, and is filing subsequent applications in other countries worldwide. Eisai has also initiated a global Phase III trial of lenvatinib in hepatocellular carcinoma and Phase II studies of lenvatinib in several other tumor types are also underway.

On January 29, 2015 Pharmacyclics reported that the U.S. Food and Drug Administration (FDA) has granted single-agent IMBRUVICA (ibrutinib) regular (full) approval in all lines of therapy as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM), a rare, indolent type of B-cell lymphoma (Press release Pharmacyclics, JAN 29, 2015, View Source [SID:1234501415]). This is the fourth indication for IMBRUVICA, an oral therapy, which received FDA Breakthrough Therapy Designation for this indication in February 2013. IMBRUVICA is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

“Because there has never been an FDA-approved treatment for Waldenstrom’s macroglobulinemia since it was first identified over 70 years ago, doctors had to rely on therapies borrowed from similar cancers to treat these patients,” Steven P. Treon, M.D., Ph.D., Director of the Bing Center for Waldenstrom’s Macroglobulinemia at the Dana-Farber Cancer Institute and Associate Professor at Harvard Medical School, Boston, Mass., and lead investigator of the WM trial data submitted to the FDA for this approval. “I am truly grateful to the FDA for recognizing this need and for approving IMBRUVICA, and I thank those scientists whose hard work and dedication helped discover the genetic cause of this disease and identified ibrutinib as a targeted therapy, and those clinicians at several leading medical centers who diligently enrolled the clinical trial showing that IMBRUVICA is a safe and highly effective therapy for patients with Waldenstrom’s macroglobulinemia.”

“The FDA’s approval of IMBRUVICA for Waldenstrom’s macroglobulinemia marks a significant milestone for patients living with this rare disease and has the potential to positively impact the lives of a number of patients,” said Carl Harrington, President of the International Waldenstrom’s Macroglobulinemia Foundation, who also is a patient living with WM.
The approval is based on results from a multi-center, Phase II study that evaluated the efficacy and tolerability of IMBRUVICA in 63 patients with previously treated WM. In this study, IMBRUVICA demonstrated a response rate of 62% according to an Independent Review Committee. Very good partial responses (VGPR) of 11% and partial responses (PR) of 51% were observed. These responses were maintained and the median duration of response (DOR) has not been reached, with a range of 2.8+ to 18.8+ months.
“IMBRUVICA has demonstrated its effectiveness in patients living with Waldenstrom’s macroglobulinemia who, until now, did not have an FDA-approved standard-of-care therapy,” said Thorsten Graef, M.D., Ph.D., Head of Hematology at Pharmacyclics. “This approval is a proud moment for our Pharmacyclics and Janssen teams and would not have been possible without the dedication and support of our patients, clinical investigators and the FDA’s recognition of IMBRUVICA as a breakthrough therapy for these patients.”

WM (a clinically recognized subset of lymphoplasmacytic lymphoma, or LPL) is a slow-growing and rare blood cancer that most commonly originates from B cells, a type of white blood cell (lymphocyte) that develops in the bone marrow.2 In the United States, approximately 1,000 to 1,500 people are diagnosed each year,3 with the median age at diagnosis being 60 to 70 years of age.4 WM occurs as the result of a malfunction in the healthy lifecycle of a B cell, causing the cell to become malignant and reproduce at an abnormal rate. The malignant B cells produce large amounts of an abnormal type of antibody protein called immunoglobulin M (IgM). Excess IgM causes the blood to thicken and causes many of the symptoms of WM.2
Consistent with the previous label, the most commonly occurring adverse reactions in WM patients treated with IMBRUVICA ( > 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients.
In addition, the warnings and precautions for IMBRUVICA were updated and reflect the most current safety knowledge based on ongoing clinical investigation and commercial use.

On January 29, 2015 Celldex Therapeutics and Bristol Myers-Squibb reported the initiation of a Phase 1/2 dose escalation and cohort expansion study examining the investigational combination of varlilumab, Celldex’s CD27 targeting investigational immune-activating antibody and Bristol-Myers Squibb’s immunotherapy Opdivo (nivolumab) (Press release Bristol-Myers Squibb, JAN 29, 2015, View Source [SID:1234501409]). The study will be conducted in adult patients with advanced non-small cell lung cancer (NSCLC), metastatic melanoma (MEL), colorectal cancer (CRC), ovarian cancer, and head and neck squamous cell carcinoma (SCCHN). Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. This study will evaluate the safety and tolerability of the combination and address the hypothesis that the combination of these two mechanisms enhance the anti-tumor activity compared to either agent alone. Celldex is responsible for conducting the study and development costs will be shared.

The Phase 1 dose-escalation portion of the study will assess the safety and tolerability of varlilumab at doses ranging from 0.1 to 10 mg/kg when administered with Opdivo (3mg/kg). Following dose escalation, a Phase 2 portion of the study will include 5 disease specific cohorts, with either 18 (CRC, SCCHN, ovarian) or 35 (NSCLC and MEL) patients in each cohort. Patients will be treated with varlilumab until intolerance, disease progression or completion of up to 4 cycles. There is no limit on the duration of treatment with Opdivo. The primary objective of the Phase 2 study is overall response rate. Secondary objectives include pharmacokinetics assessments, determining the immunogenicity of varlilumab when given in combination with Opdivo and further assessing the anti-tumor activity of combination treatment, including duration of response, time to response, progression-free survival and overall survival.

On January 27, 2015 Amgen and its subsidiary Onyx Pharmaceuticals reported on the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Kyprolis (carfilzomib) for Injection to seek approval for the treatment of patients with relapsed multiple myeloma who have received at least one prior therapy (Press release Amgen, JAN 27, 2015, View Source [SID:1234501397]). In the U.S., the sNDA is designed to support the conversion of accelerated approval to full approval and expand the current approved indication. In the European Union (EU), Kyprolis received orphan drug designation and the MAA has been granted accelerated assessment.

The sNDA and MAA are based on data from the Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of Patients with Relapsed Multiple MyEloma) trial and other relevant data.

“Multiple myeloma is an incurable blood cancer that often becomes resistant to treatment, underscoring the need for new therapeutic options that provide deep and durable responses to extend the time patients live without their disease progressing,” said Pablo J. Cagnoni, M.D., president, Onyx Pharmaceuticals, Inc. “The U.S. and EU submissions support our goal of bringing Kyprolis to patients with relapsed multiple myeloma.”

Orphan designation is granted by the EMA for medicines intended for the treatment, prevention or diagnosis of a disease that is life threatening and has a prevalence in the EU of no more than five in 10,000. The intended medicine must aim to provide significant benefit to those affected by the condition.

Kyprolis is in a class of drugs called proteasome inhibitors and was granted accelerated approval by the FDA in 2012. Kyprolis is also approved for use in Argentina, Israel and Mexico.