On August 7, 2017 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical-stage pharmaceutical company focused on discovering and developing novel small molecule drugs directed against tumor metabolism and tumor immunology targets for the treatment of cancer, reported the initiation of a randomized Phase 2 trial of CB-839, the company’s glutaminase inhibitor, combined with AFINITOR (everolimus)‎ in patients with clear cell renal cell carcinoma (Press release, Calithera Biosciences, AUG 7, 2017, View Source [SID1234520057]).

“Despite the advances in the treatment of renal cell carcinoma, there remains significant unmet need for patients who have progressed following treatment with an anti-PD1 and/or tyrosine kinase inhibitors,” said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. “The initiation of this study marks an important milestone for our company, as it is the first randomized trial of CB-839 that we believe has the potential for U.S Food and Drug Administration (FDA) registration and approval. In recognition of the lack of treatment options available to patients with renal cell carcinoma, the FDA has granted Fast Track Designation to CB-839 in this setting.”

The randomized, double-blind, placebo controlled trial is designed to evaluate the safety and efficacy of CB-839 in combination with everolimus versus placebo with everolimus in approximately 250 patients with metastatic, clear cell renal cell carcinoma (RCC) patients who have been treated with at least two prior lines of systemic therapy including a VEGFR-targeting tyrosine kinase inhibitor and at least one of either CABOMETYX (cabozantinib) or an active PD-1/PD-L1 inhibitor. Patients will be randomized in a 2:1 ratio. The primary endpoint is progression free survival assessed by an independent review committee; overall survival will be assessed as a secondary endpoint. The multicenter, international study will be conducted at multiple sites in the United States, Europe and Canada. Clinical trial sites have been activated and the study is open for enrollment. For a listing of clinical sites and additional details about the clinical trial, please see www.clinicaltrials.gov (NCT03163667).

CB-839 takes advantage of the pronounced dependency many cancers have on the nutrient glutamine for growth and survival. CB-839 inhibits glutaminase, an enzyme required by cancer cells to utilize glutamine effectively, resulting in inhibition of tumor growth. In 2017, RCC is estimated to be diagnosed in approximately 63,990 people in the United States, according to the National Cancer Institute. Clear cell is the most common form of kidney cancer, comprising 70-75% of cases. Most patients with clear cell RCC lack the tumor suppressor gene VHL, making them more dependent on glutamine due to a loss of ability to make fatty acids from glucose1,2,3. Since the mTOR inhibitor everolimus impairs the use of glucose by cancer cells, the combination of CB-839 with everolimus induces dual metabolic inhibition.

On August 7, 2017 Bayer reported the European Commission (EC) has granted marketing authorization for Stivarga (regorafenib) for the treatment of adult patients with HCC who have been previously treated with Nexavar (sorafenib) (Press release, Bayer, AUG 7, 2017, View Source [SID1234520056]). Stivarga is the first and only treatment that has demonstrated a significant improvement in overall survival (OS) in second-line HCC. This marks the third major approval in five months for Stivarga, with the product also gaining approval in the U.S. and Japan for second-line treatment of HCC in April and June, respectively.

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"Until now, there was no effective second-line systemic treatment option for liver cancer patients and their treating physicians in Europe. With the EU approval of Stivarga in HCC, the outlook could significantly improve for patients with HCC, as they have now for the first time, a treatment plan with two approved therapies involving the use of Stivarga directly after Nexavar," said Dr. Jordi Bruix, lead investigator for the RESORCE trial, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Spain.

The approval is based on data from the international, multicenter, placebo-controlled Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma; NCT 01774344] trial, which investigated patients with HCC whose disease had progressed during treatment with Nexavar. In the trial, regorafenib plus best supportive care (BSC) was shown to provide a statistically significant and clinically meaningful improvement in OS versus placebo plus BSC (10.6 vs. 7.8 months, respectively, (HR 0.63; 95% CI 0.50-0.79; p<0.0001)), which translates to a 37% reduction in the risk of death over the trial period. Adverse events observed in the RESORCE trial were generally consistent with the known safety profile of regorafenib. The most common treatment-emergent adverse events were hand-foot skin reaction, diarrhea, fatigue and hypertension.

"Liver cancer is often diagnosed late and difficult to treat, but the EU approval of Stivarga for HCC marks the first treatment advance for patients in nearly a decade. Bayer continues to support the liver cancer community and is committed to ongoing research in the field, as well as continuing to pursue additional regulatory filings for Stivarga across the world," said Robert LaCaze, Executive Vice President and Head of the Oncology Strategic Business Unit at Bayer.

Liver cancer is often more difficult to treat than other cancers with an annual mortality rate of 48,000 in the EU. Globally, it is the second leading cause of cancer-related deaths.

Additional regulatory filings for Stivarga in HCC are under review in other countries around the world, including China. The product was approved in the U.S. and Japan for second-line treatment of HCC in April and June, respectively. Stivarga is already approved in more than 90 countries worldwide, including the U.S., Japan, China and countries in the EU, for the treatment of metastatic colorectal cancer. Stivarga is also approved in more than 80 countries globally, including the U.S., Japan, China and countries in the EU, for the treatment of metastatic gastrointestinal stromal tumors.

About Hepatocellular Carcinoma
Hepatocellular carcinoma, or HCC, is the most common form of liver cancer representing approximately 70-85 percent of liver cancer worldwide. Liver cancer is the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally. More than 780,000 cases of liver cancer are diagnosed worldwide each year (52,000 in the European Union, 501,000 in the Western Pacific region and 30,000 in the United States) and the incidence rate is increasing. In 2012, approximately 746,000 people died of liver cancer including approximately 48,000 in the European Union, 477,000 in the Western Pacific region and 24,000 in the United States.
 
About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R).

In the EU, Stivarga is indicated as monotherapy 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, and for the treatment of adult patients with HCC who have been previously treated with sorafenib.

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 Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative cancer treatments. The oncology franchise at Bayer currently includes three oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways, with the potential to impact the way that cancer is treated.