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Bayer Receives Positive CHMP Opinion for regorafenib for the Second-Line Systemic Treatment of Liver Cancer (for specialized target groups only)

On June 23, 2017 Bayer reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended regorafenib for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with Nexavar (sorafenib) (Press release, Bayer, JUN 23, 2017, View Source [SID1234519658]). Regorafenib is the first and only treatment that has demonstrated a significant improvement in overall survival in second-line HCC patients who previously had no other options. The final decision of the European Commission on the marketing authorization is expected in the coming months. The anti-cancer medication from Bayer is already approved under the brand name Stivarga in more than 90 countries worldwide for the treatment of metastatic colorectal cancer (CRC), including countries of the EU, and in more than 80 countries globally for the treatment of metastatic gastrointestinal stromal tumors (GIST), including countries of the EU. The product recently gained approval in the U.S. for second-line treatment of HCC and additional regulatory filings for Stivarga in HCC are under review in countries around the world, including China.

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"Liver cancer is one of the leading cancer-related causes of death in Europe. Nexavar, as the first and only approved systemic treatment for HCC, has been a major advance in this field, but effective second-line treatment options are urgently needed for patients," said Robert LaCaze, Executive Vice President and Head of the Oncology Strategic Business Unit at Bayer. "The positive opinion for regorafenib in Europe is great news for patients as it supports our efforts to make this treatment available to as many patients as possible in the second-line HCC setting and offers a treatment plan with two therapies that both have shown to improve overall survival."

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

The positive opinion 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 overall survival (OS) versus placebo plus BSC (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. The median OS was 10.6 vs. 7.8 months for regorafenib and the placebo groups, respectively. Adverse events observed in the trial were generally consistent with the known safety profile of regorafenib. The most common treatment-emergent adverse events (regorafenib vs. placebo group) were hand–foot skin reaction (53% vs. 8%), diarrhea (41% vs. 15%), fatigue (40% vs. 32%) and hypertension (31% vs. 6%).

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).

Regorafenib is approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU, China and Japan for the treatment of metastatic colorectal cancer (mCRC). The product is also approved in over 80 countries, including the U.S., countries of the EU, China and Japan, for the treatment of metastatic gastrointestinal stromal tumors (GIST). It was recently approved in the U.S. for second-line treatment of HCC. Additional regulatory filings for Stivarga in HCC are under review in countries around the world, including China.

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.

AVEO Oncology Announces Positive CHMP Opinion for Tivozanib as a Treatment of Advanced Renal Cell Carcinoma

On June 23, 2017 AVEO Oncology (NASDAQ:AVEO) reported that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has recommended FOTIVDA (tivozanib) for approval as a treatment for patients with advanced renal cell carcinoma (RCC) (Press release, AVEO, JUN 23, 2017, View Source [SID1234519657]). The CHMP’s recommendation is now referred to the European Commission (EC). The EC, which typically adheres to the recommendation of the CHMP, but is not obligated to do so, is expected to make its final decision in about 67 days. If approved by the EC, marketing authorization for tivozanib will be granted in all 28 countries of the European Union, Norway, Iceland and Liechtenstein. EUSA Pharma, a specialty pharmaceutical company with a focus on oncology and oncology supportive care, is the European licensee for tivozanib.

"A positive opinion from the CHMP is a critical step in our goal of obtaining regulatory approval of tivozanib as a treatment for RCC," said Michael Bailey, president and chief executive officer of AVEO. "Tivozanib’s unique tolerability profile together with the longest progression free survival reported in a Phase 3 first line RCC study, have the potential to fill an unmet patient need for better tolerated treatment in this disease. Further, we believe this tolerability profile could enable immune-oncology combinations such as those in the Phase 1/2 TiNivo study, which combines the PD-1 inhibitor Opdivo (nivolumab) with tivozanib and recently advanced to Phase 2."

Mr. Bailey concluded: "If the European Commission grants marketing approval for tivozanib, it would trigger a $4 million research and development reimbursement payment from EUSA, and AVEO will also be eligible for up to $12 million in additional milestones from EUSA based on member state reimbursement and regulatory approvals. These payments would add significant resources to our balance sheet as we work toward the anticipated readout of our U.S. pivotal trial in third-line RCC, the TIVO-3 trial, in the first quarter of 2018."

Under the terms of their December 2015 agreement, EUSA Pharma has agreed to pay AVEO up to $394 million in future research and development funding and milestone payments, assuming successful achievement of specified development, regulatory and commercialization objectives, as well as a tiered royalty ranging from a low double-digit up to mid-twenty percent on net sales of tivozanib in the agreement’s territories. Thirty percent of milestone and royalty payments received by AVEO, excluding research and development funding, are due to Kyowa Hakko Kirin (KHK) as a sublicensing fee in Europe. In the United States, the royalty obligation to KHK ranges from the low- to mid-teens on net sales.

RCC is the most common form of kidney cancer,i which accounts for an estimated 49,000 deaths in Europe each year.ii It is expected to be one of the fastest increasing cancers over the next ten years.iii Tyrosine Kinase Inhibitor (TKI) vascular endothelial growth factor (VEGF) inhibitors are the standard of care treatment for advanced RCC in Europe, however, patients on current treatments can often experience significant side effects.iv,v If approved for use in the European Union, tivozanib would be indicated for use in adult patients with advanced RCC who are VEGFR and mTOR pathway inhibitor-naïve and are either untreated or who have failed prior therapy with interferon-alpha (IFN-α) or interleukin-2 (IL-2).

About Tivozanib

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.

Faslodex (fulvestrant) receives positive CHMP opinion for use in 1st-line hormone receptor-positive advanced breast cancer

On June 23, 2017 AstraZeneca reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending the marketing authorisation of Faslodex (fulvestrant) for the treatment of hormone receptor-positive (HR+), locally-advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on anti-oestrogen therapy (Press release, AstraZeneca, JUN 23, 2017, View Source [SID1234519656]).

The CHMP recommendation is based on pivotal data from the Phase III FALCON trial, where Faslodex 500mg demonstrated superiority over anastrozole 1mg in the treatment of locally-advanced or metastatic breast cancer in post-menopausal women who had not received prior hormonal-based medicine for HR+ breast cancer.

The FALCON data show that the delay in disease worsening or death (median progression-free survival, PFS) was 2.8 months longer with Faslodex than anastrozole. The median PFS was 16.6 months in the Faslodex arm compared with 13.8 months in the anastrozole arm. Aromatase inhibitors such as anastrozole are the current standard of care for the 1st-line treatment for postmenopausal women with HR+ advanced breast cancer.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "Faslodex has long been an effective medicine for women with advanced breast cancer in later lines of treatment and we are pleased that the CHMP has recognised its potential as a first-line option. Faslodex is also being tested in combination with over 19 different medicines, which is testament to its well-established safety and efficacy profile with over 15 years of patient evidence since its first launch in 2002."

The safety and tolerability profile was in line with current experience with Faslodex and anastrozole. The most-commonly reported adverse events (AEs) in the Faslodex and anastrozole arms were arthralgia (16.7% vs. 10.3%), hot flush (11.4% vs. 10.3%) and nausea (10.5% vs. 10.3%).

Faslodex is the only hormone medicine for advanced breast cancer that slows tumour growth by binding to and degrading the oestrogen receptor – a key driver of breast cancer progression in some women. It is widely approved for the treatment of HR+ advanced breast cancer in postmenopausal women with disease progression following anti-oestrogen medicine.

The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union (EU). The final decision will be applicable to all 28 EU member countries plus Iceland, Norway and Liechtenstein.

NOTES TO EDITORS

About FALCON

The FALCON (Fulvestrant and AnastrozoLe COmpared in hormonal therapy-Naïve advanced breast cancer) trial is a Phase III, randomised, double-blind, multicentre trial comparing the antitumour effects and tolerability profile of a 500mg dose of Faslodex plus placebo with a 1mg dose of anastrozole plus placebo, in postmenopausal women with HR+, locally-advanced or metastatic breast cancer who have not been treated previously with any hormonal medicine.

The FALCON trial was designed on the basis of positive results from the Phase II FIRST trial, which demonstrated a median overall survival nearly six months longer with Faslodex compared to anastrozole.

About Advanced Breast Cancer

Advanced/metastatic breast cancer refers to Stage III and IV breast cancer. Stage III disease may also be referred to as locally-advanced breast cancer, while metastatic disease is the most-advanced stage of breast cancer (Stage IV), and occurs when cancer cells have spread beyond the initial tumour site to other organs of the body outside the breast. Since there is no cure for the disease, the goal of current treatment is to delay disease worsening or death.

About Faslodex

Faslodex (fulvestrant) is indicated for the treatment of postmenopausal women with oestrogen receptor-positive (ER+), locally-advanced or metastatic breast cancer with disease relapse on or after adjuvant anti-oestrogen treatment, or disease progression on treatment with an antioestrogen.

In the US, Faslodex is also approved, in combination with palbociclib, for the treatment of women with HR+, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine. Faslodex represents a hormonal treatment approach that helps to slow tumour growth by blocking and degrading the oestrogen receptor – a key driver of disease progression.

About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody-Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

ArQule Presents Preclinical Data for BTK Inhibitor, ARQ 531, at the 22nd Annual Congress of the European Hematology Association (EHA)

On June 23, 2017 ArQule, Inc. (Nasdaq: ARQL) reported that preclinical data for ARQ 531 in diffuse large B-cell lymphoma (DLBCL) in vitro and in vivo tumor models was presented at EHA (Free EHA Whitepaper) Congress in Madrid, Spain (Press release, ArQule, JUN 23, 2017, View Source [SID1234519655]). ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK).

The presentation titled "ARQ 531, A Reversible BTK Inhibitor, Demonstrates Potent Anti-Tumor Activity in ABC-DLBCL and GCB-DLBCL" can be viewed at View Source

ARQ 531 Poster Presentation Highlights

Preclinical data suggests ARQ 531 has the potential for broad clinical utility in a wide range of hematological malignancies and lymphomas.
The signaling pathways evaluated show a distinct kinase inhibition profile that could be advantageous in treating lymphomas.
ARQ 531, unlike other BTK inhibitors, has activity in both ABC-DLBCL and GCB-DLBCL preclinical models.
A phase 1 trial with ARQ 531 in patients with B-cell malignancies refractory to other therapeutic options, including ibrutinib, is planned to commence by the third quarter of 2017.
"This data further strengthens a very comprehensive preclinical package for ARQ 531," said Dr. Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "While targeting ibrutinib resistant patients will be an initial, fast-to-market strategy for the clinical development of ARQ 531, the data presented at EHA (Free EHA Whitepaper) clearly demonstrate the potential clinical utility of the drug beyond ibrutinib refractory cancers."

B-cell malignancies, like chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, DLBCL and mantle cell lymphoma are driven by BTK. The only approved BTK inhibitor, ibrutinib, is irreversible and makes a covalent bond with the C481 residue of the targeted protein. Although ibrutinib has demonstrated excellent responses in patients with elevated B-cell receptor signaling, clinical resistance has been observed, and the BTK C481S mutation is emerging as a predominant mechanism of resistance. As a reversible inhibitor, ARQ 531 does not require interaction with the C481 residue, a binding site essential for irreversible ibrutinib binding to BTK, thus positioning ARQ 531 as a targeted therapy for patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.

About BTK and ARQ 531

ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies ARQ 531 has demonstrated high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to initiate a phase 1 trial by the third quarter of 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.

Acceleron Provides Updated Results from Phase 2 Studies of Luspatercept in Beta-Thalassemia at the 22nd Congress of the European Hematology Association

On June 23, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a clinical stage biopharmaceutical company focused on the discovery, development, and commercialization of innovative therapeutics to treat serious and rare diseases, reported preliminary results from the ongoing Phase 2 study of luspatercept in patients with beta-thalassemia during an oral presentation at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Madrid, Spain (Press release, Acceleron Pharma, JUN 23, 2017, View Source [SID1234519653]). Luspatercept is being developed to treat a range of hematologic diseases including beta-thalassemia, myelodysplastic syndromes (MDS), and myelofibrosis as part of a global collaboration between Acceleron and Celgene.

"With beta-thalassemia patients now remaining on study for over two years, we continue to be highly encouraged by luspatercept’s long-term efficacy results and safety profile," said Habib Dable, President and Chief Executive Officer of Acceleron. "Combined with the rapid completion of enrollment in the BELIEVE Phase 3 trial, the program’s momentum continues to build alongside our enthusiasm to potentially transform the treatment of beta-thalassemia patients globally."

Phase 2 Results

A total of 32 transfusion-dependent beta-thalassemia patients have been treated with therapeutic dose levels of luspatercept in the ongoing study.

69% (22 of 32) achieved a reduction in red blood cell (RBC) transfusion burden of at least 33% in any 12-week treatment interval as compared to baseline.
A 12-week fixed interval analysis was conducted to review RBC transfusion reduction during weeks 13 to 24 and weeks 37 to 48 compared to the baseline 12-week period pre-treatment in order to evaluate durability of response. The ongoing BELIEVE Phase 3 trial will use this 12-week fixed interval analysis for evaluating the proportion of patients achieving at least a 33% reduction in RBC transfusion burden.

50% (12 of 24 patients with 6-20 units RBC / 24 weeks estimated pre-treatment) achieved a reduction in RBC transfusion burden of at least 33% in the fixed 12-week interval from weeks 13 to 24 as compared to baseline.
46% (11 of 24 patients with 6-20 units RBC / 24 weeks estimated pre-treatment) achieved a reduction in RBC transfusion burden of at least 33% in the fixed 12-week interval from weeks 37 to 48 as compared to baseline.
A total of 31 non-transfusion-dependent beta-thalassemia patients have been treated with therapeutic dose levels of luspatercept in the ongoing study.

71% (22 of 31) achieved a clinically meaningful increase in hemoglobin of at least 1.0 g/dL compared to baseline (mean increase over 12 weeks).
There are patients who remain on luspatercept with clinically meaningful increases in hemoglobin and reductions in RBC transfusion burden for up to 24 months.

Phase 2 Safety Summary

A total of 64 beta-thalassemia patients have been treated with luspatercept in the ongoing Phase 2 studies (all dose levels).

The majority of adverse events (AEs) were Grade 1 or 2. The most common related AEs (occurring in ≥ 10% of patients) were bone pain, headache, myalgia, arthralgia, musculoskeletal pain, asthenia, injection site pain, and back pain.
Grade 3 AEs probably related to study drug were bone pain (n=3), asthenia (n=2) and headache (n=1).
There were no serious AEs related to study drug.
"Beta-thalassemia remains an area of critical medical need for many patients around the world," said Michael Pehl, President, Hematology/Oncology for Celgene. "These longer-term results continue to illustrate the potential for luspatercept to affect transfusion dependence and hemoglobin levels, making a meaningful impact for patients with this serious blood disease."

Luspatercept is an investigational product that is not approved for use in any country.

The BELIEVE trial, a global Phase 3 study of luspatercept in transfusion-dependent beta-thalassemia patients, is fully enrolled and top-line results are expected in mid-2018.

The EHA (Free EHA Whitepaper) beta-thalassemia presentation is available under the Science page of the Company’s website at www.acceleronpharma.com/.

About the Phase 2 Study

Data from two open-label Phase 2 studies were presented at the conference: the base study in which patients received treatment with luspatercept for three months and the ongoing long-term safety extension study in which patients may receive treatment with luspatercept for up to an additional five years. In both the three-month base study and the long-term extension study, red blood cell (RBC) transfusion-dependent patients (≥ 4 units RBC / 8 weeks) and non-transfusion-dependent patients ( < 4 units RBC / 8 weeks) were enrolled and treated with open-label luspatercept, dosed subcutaneously once every three weeks.

The primary outcome measure of the three-month base study was the proportion of patients who have an erythroid response, defined as 1) a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of RBC transfusions) in non-transfusion dependent patients, or 2) ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion-dependent patients. The primary outcome for the long-term extension study is to evaluate the long-term safety and tolerability of luspatercept.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the transforming growth factor-beta superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept regulates late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoiesis stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the "MEDALIST" study) and in patients with beta-thalassemia (the "BELIEVE" study). For more information, please visit www.clinicaltrials.gov.