On June 1, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its subsidiary in the Philippines HI-Eisai Pharmaceutical Inc., has received approval for a new indication for its in-house discovered anticancer agent Halaven (eribulin mesylate) for the treatment of soft tissue sarcoma (Press release, Eisai, JUN 1, 2016, View Source [SID:1234512912]). Halaven is the first and only single agent to demonstrate a statistically significant overall survival (OS) benefit in a Phase III trial in patients with advanced, recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma). The Philippines is the second country in Asia in which Halaven has been approved for the soft tissue sarcoma indication following approval in Japan, the United States and Europe.

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In a Phase III study (Study 309)1 comparing the efficacy and safety of Halaven versus dacarbazine in patients with locally advanced, recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen, Halaven demonstrated a statistically significant extension in the study’s primary endpoint of OS over the comparator treatment dacarbazine. In this study, the most common treatment-emergent adverse events (incidence greater than or equal to 25%) in patients treated with Halaven were neutropenia, fatigue, alopecia, nausea, and peripheral neuropathy, which was consistent with the known side-effect profile of Halaven.

Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissue (including fat, muscle, nerves, fibrous tissues and blood vessels). The worldwide annual incidence of soft tissue sarcoma is around 2-3 out of every 100,000 people. Halaven was approved for the treatment of patients with advanced soft tissue sarcoma in the United States, Japan and Europe in January, February and May 2016, respectively. Applications seeking approval for use in the treatment of soft tissue sarcoma are currently under review in countries and territories including Malaysia, Taiwan, Hong Kong, Singapore, and Thailand. Furthermore, Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

Halaven is a halichondrin class microtubule dynamics inhibitor with a distinct binding profile. Recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.2 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate. 3

Since the launch of Halaven as a treatment for breast cancer in the Philippines in August 2013, Eisai has been striving to further contribute to patients including obtaining additional approval in September 2014 for treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments. Eisai Co., Ltd. No.16-38 June 1, 2016

Together with providing Halaven for patients with soft tissue sarcoma in the Philippines, Eisai is working to submit applications seeking approval for an indication covering soft tissue sarcoma throughout Asia. Furthermore, Eisai remains committed to maximizing the clinical value as well as exploring the potential clinical benefits of Halaven 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 Halaven

Halaven is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally Halaven is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Halaven is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.2 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.3

Halaven was first approved in November 2010 in the United States as a treatment for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries worldwide, including Japan and countries in Europe, the Americas and Asia. In Japan, Halaven has been approved to treat inoperable or recurrent breast cancer and was launched in the country in July 2011. In addition, Halaven has been approved in countries in Europe and Asia indicated as a treatment for patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.

Regarding soft tissue sarcoma, Halaven was approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen in January 2016, approved in Japan for the treatment of soft tissue sarcoma in February 2016, and approved in Europe for the treatment of adult patients with unresectable liposarcomas who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease in May 2016. Applications seeking approval for use in the treatment of soft tissue sarcoma are currently under review in Switzerland, Russia, Australia, Brazil, Malaysia, Taiwan, Hong Kong, Singapore, and Thailand. Furthermore, Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

About Soft Tissue

Sarcoma Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissue (including fat, muscle, nerves, fibrous tissues and blood vessels). The worldwide annual incidence of soft tissue sarcoma is around 2-3 out of every 100,000 people. Approximately 12,000 patients in the United States and 29,000 patients in Europe are diagnosed with soft tissue sarcoma each year. According to a patient survey conducted by Japan’s Ministry of Health, Labour and Welfare, there are approximately 4,000 patients with soft tissue sarcoma in Japan. As the structures where the tumors originate are diverse, there are various types of soft tissue sarcoma, and the most common types include leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. While treatment of soft tissue sarcoma is focused on curative surgery, if the stage of the disease is advanced, treatment then becomes a combination of chemotherapy and radiation therapy. As outcomes are poor for patients with advanced disease, it remains a disease with significant unmet medical need.

About Study 3091

Conducted primarily in Europe and the United States, Study 309 was a multicenter, open-label, randomized Phase III study comparing the efficacy and safety of Halaven versus dacarbazine in 452 patients (aged 18 or over) with locally advanced, recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen. Patients received either Halaven (1.4 mg/m2 administered intravenously on Day 1 and Day 8) or dacarbazine (850–1200 mg/m2 administered intravenously on Day 1) every 21 days until disease progression.

From the results for the study, Halaven demonstrated a statistically significant extension in the study’s primary endpoint of overall survival (OS) over the comparator treatment dacarbazine (Halaven median OS: 13.5 months vs dacarbazine median OS: 11.5 months; Hazard Ratio (HR) 0.77 [95% CI=0.62-0.95], p=0.0169). Furthermore, in the study’s secondary endpoints, there was no statistically significant difference found between Halaven and dacarbazine in either progression-free survival (PFS) (median PFS: 2.6 months in both arms) or progression-free rate at 12 weeks (PFR12wks) (Halaven PFR12wks: 33% vs dacarbazine PFR12wks: 29%). In this study, the most common treatment-emergent adverse events (incidence greater than or equal to 25%) in patients treated with Halaven were neutropenia, fatigue, alopecia, nausea, and peripheral neuropathy, which was consistent with the known side-effect profile of Halaven.

On June 01, 2016 Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective therapeutics for the treatment of cancer, reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s Investigational New Drug (IND) application for CA-170 (Press release, Curis, JUN 1, 2016, View Source [SID:1234512911]). CA-170 is a first-in-class orally available small molecule that has been designed to target and inhibit the immune checkpoints, Programmed Death Ligand-1 (PD-L1) and V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA).

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"The acceptance of CA-170’s IND by the FDA marks an important milestone in the advancement of immuno-oncology therapy," said Ali Fattaey, Ph.D., Curis’s president and CEO. "The last few years have seen the successful development and commercial launch of multiple checkpoint inhibitors to treat a broad range of human cancers. However, all checkpoint inhibitors developed thus far have been monoclonal antibodies, with similar pharmacokinetic properties, and can only be administered by IV infusion. Today, the FDA has cleared us to test the first small molecule checkpoint inhibitor, CA-170, that will be taken orally by cancer patients. We envision that the pharmacokinetic properties of a small molecule will likely provide an advantage in dosing flexibility of a checkpoint inhibitor, either as a monotherapy or in combination with other cancer treatment regimens. We believe that, if successful, CA-170 can provide a compelling treatment alternative for patients and physicians."

CA-170 is an orally available, small molecule designed to selectively target and inhibit both PD-L1 and VISTA checkpoint regulators of immune activation. Preclinical data have demonstrated that CA-170 can induce effective proliferation and cytokine production by T cells in culture that are specifically suppressed by PD-L1 or VISTA. In addition, CA-170 demonstrated in vivo anti-tumor activity similar to anti-PD-1 or anti-VISTA antibodies in multiple mouse tumor models and appeared safe to administer based on toxicology studies.

On June 1, 2016 Bayer and the U.S. National Surgical Adjuvant Breast and Bowel Project (NSABP), a leading clinical trials cooperative group, are collaborating on a new Phase III study to investigate Stivarga (regorafenib) as an additional adjuvant therapy in colon cancer (Press release, Bayer, JUN 1, 2016, View Source [SID:1234512910]). The ARGO trial will investigate regorafenib as a single agent for the adjuvant treatment of Stage IIIB and IIIC colon cancer following completion of standard adjuvant chemotherapy. In this stage, the tumor has started to invade the wall of the colon, but not yet spread to other distant organs.

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"In 2016, more than 134,000 adults in the United States will be diagnosed with colorectal cancer. Two-thirds of these cases, or more than 95,000, will be cancers of the colon," said Norman Wolmark, MD, Chairman of the Foundation. "Despite receiving adjuvant chemotherapy, patients with stage IIIB and IIIC colon cancer have about a 40% risk of developing metastatic disease, meaning that the disease has spread from the colon to distant organs. Given the anti-metastatic effects of regorafenib demonstrated pre-clinically and the treatment benefits in the metastatic setting of colorectal cancer, we are keen to explore if it could also help patients at earlier stages of the disease."

The Phase III study ARGO, a randomized, double-blind, placebo-controlled study, will be conducted by NSABP, with Bayer offering consultation as well as financial support. If positive, Bayer may use the results for submission of marketing authorization of Stivarga in this earlier stage of the disease.

"We are excited to be collaborating with NSABP to further explore the potential of regorafenib in an earlier line of treatment for patients with colon cancer, one of the most common forms of cancer worldwide," said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "We believe that by partnering with those on the front line of patient care, we will be in a position to deliver additional therapeutic options to treating physicians and their patients."

Regorafenib is approved under the trade name Stivarga in 90 countries worldwide, including the United States, Europe, and Japan for the treatment of metastatic CRC. The approval of regorafenib was based on data from the pivotal Phase III CORRECT (Colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial. Full results from the CORRECT study were published in January 2013 in The Lancet.

About the ARGO Study
The Phase III study ARGO (A Phase III Randomized Placebo-Controlled Study Evaluating ReGOrafenib Following Completion of Standard Chemotherapy for Patients with Stage III Colon Cancer) will investigate whether providing oral regorafenib monotherapy in the adjuvant setting after standard chemotherapy increases disease-free survival (DFS) in patients with Stage IIIB/IIIC colorectal cancer. The secondary study endpoints include overall survival (OS) and safety. The trial will enroll approximately 1,100 patients from the U.S. who will be randomized in a 1:1 ratio to receive either 120 mg regorafenib or placebo for a planned duration of two years.

About Colon Cancer
The colon is part of the body’s digestive system, which is called the gastrointestinal system. Most colon cancers begin as a growth or a polyp on the inner lining of the colon, a part of the large intestine. Some types of polyps can develop into cancer over the course of several years. The cancer occurs when cells in the body begin to grow out of control.

Colon cancer is often grouped with rectal cancer because the two diseases share many common features. However, treatment approaches may differ for colon and rectal cancers, especially in the earlier stages.

Worldwide, colon and rectal cancers make up the third most common cancer in men and women combined. In 2012, there were an estimated 1.3 million new cases, and that number is expected to increase to 1.6 million by 2020.

About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that targets various kinases involved in tumor growth and progression – angiogenesis, oncogenesis and the tumor microenvironment. In preclinical studies, regorafenib inhibits several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis (the growth of new blood vessels). In addition to VEGFR 1-3 it also inhibits various oncogenic and tumor microenvironment kinases including TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression.

Regorafenib is approved under the brand name Stivarga in 90 countries for the treatment of mCRC and in more than 70 countries for the treatment of metastatic gastrointestinal stromal tumors (GIST). In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

About the National Surgical Adjuvant Breast and Bowel Project
The National Surgical Adjuvant Breast and Bowel Project (NSABP) is a clinical trials cooperative group supported since its inception by the National Cancer Institute (NCI).
Since its beginning the NSABP has enrolled more than 110,000 women and men in clinical trials in breast and colorectal cancer. Headquartered in Pittsburgh, Pennsylvania, the NSABP has research sites at nearly 1000 major medical centers, university hospitals, large oncology practice groups, and health maintenance organizations in the United States, Canada, Puerto Rico, Australia, and Ireland. In addition to federally sponsored studies, the NSABP also conducts research supported by other resources.