On July 20, 2015 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on oncology with an emphasis on the treatment of primary and metastatic liver cancers, reported that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) has granted Orphan Drug Designation for melphalan for the treatment of cholangiocarcinoma (Press release, Delcath Systems, JUL 20, 2015, View Source [SID:1234506537]).

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The OOPD is tasked with evaluating the scientific and clinical data submissions from sponsors to identify and designate products as promising for rare diseases and to further advance scientific development of such promising medical products.

Orphan drug designation provides certain exclusivity benefits, tax credits for certain research and a waiver of the New Drug Application user fee. Cholangiocarcinoma is recognized by the FDA as an orphan disease, usually defined as a condition that affects fewer than 200,000 people nationwide.

Intrahepatic cholangiocarcinoma (ICC), a sub-category of cholangiocarcinoma, is a tumor in the bile duct that arises within the liver. It is the second most common primary liver tumor and represents approximately 15% of new HCC cases diagnosed annually. Surgical resection, the standard of care, is not possible for an estimated 80% to 90% of patients diagnosed with ICC.

The Company recently announced the expansion of its global Phase 2 clinical study in primary liver cancer (HCC) to include an ICC cohort, which is investigating the safety and efficacy of Melphalan/HDS treatment in patients with unresectable ICC confined to the liver. The study is being conducted at the same hospitals in Europe participating in the Company’s Phase 2 HCC trial, and is expected to enroll 11 patients. The ICC cohort will evaluate tumor response (objective response rate) as measured by modified Response Evaluation Criteria in Solid Tumor (mRECIST), and will assess progression-free survival and safety. Additional analyses will be conducted to characterize the systemic exposure of melphalan administered by Melphalan/HDS, as well as to assess patient-reported clinical outcomes, or quality-of-life.

"We are pleased with the receipt of orphan drug designation for melphalan in the treatment of patients with cholangiocarcinoma as it is a key milestone that supports our broader regulatory and development strategy for our Melphalan/Hepatic Delivery System (Melphalan/HDS) as a therapy for primary and metastatic liver cancers," said Jennifer Simpson, Ph.D., M.S.N., C.R.N.P., President and Chief Executive Officer of Delcath. "ICC is a disease of significant unmet medical need and our Melphalan/HDS treatment may offer clinical benefit for ICC patients who face limited treatment options."

On July 20, 2015 Bristol-Myers Squibb Company (NYSE:BMY)reported that an open-label, randomized Phase III study evaluating Opdivo (nivolumab) versus everolimus in previously-treated patients with advanced or metastatic renal cell carcinoma (RCC) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving Opdivo compared to the control arm (Press release, Bristol-Myers Squibb, JUL 20, 2015, View Source [SID:1234506536]).

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The company looks forward to sharing these data with health authorities soon.

"The results of CheckMate -025 mark the first time an Immuno-Oncology agent has demonstrated a survival advantage in advanced renal cell carcinoma, a patient group that currently has limited treatment options," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Through our Opdivo clinical development program, we aim to redefine treatment expectations for patients with advanced RCC by providing improved survival."

CheckMate -025 investigators are being informed of the decision to stop the comparative portion of the trial. Bristol-Myers Squibb is working to ensure that eligible patients will be informed of the opportunity to continue or start treatment with Opdivo in an open-label extension as part of the company’s commitment to providing patient access to Opdivo, and characterizing long-term survival. The company will complete a full evaluation of the final CheckMate -025 data and work with investigators on the future presentation and publication of the results.

About CheckMate -025

CheckMate -025 is a Phase III, open-label, randomized study of Opdivo versus everolimus in previously-treated patients with advanced or metastatic clear-cell renal cell carcinoma. The trial randomized 821 patients to receive either nivolumab 3 mg/kg intravenously every two weeks or everolimus 10 mg tablets by mouth daily until documented disease progression or unacceptable toxicity. The primary endpoint is overall survival. Secondary endpoints include objective response rate and progression-free survival.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80 percent to 90 percent of all cases. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. Globally, the five-year survival rate for those diagnosed with metastatic, or advanced kidney cancer, is 12.1 percent.

Immuno-Oncology at Bristol-Myers Squibb

Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.

To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as Immuno-Oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining Immuno-Oncology agents that target different pathways in the treatment of cancer.

Bristol-Myers Squibb is committed to advancing the science of Immuno-Oncology, with the goal of changing survival expectations and the way patients live with cancer.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the U.S. Food and Drug Administration (FDA) as a monotherapy in two cancer indications. On March 4, 2015, Opdivo received FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In the U.S., Opdivo is also indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

IMPORTANT SAFETY INFORMATION


Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

On July 20, 2015 BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) reported an update on the ABRAZO Phase 2 study of its poly ADP-ribose polymerase (PARP) inhibitor, talazoparib (formerly referred to as BMN 673) for the treatment of patients with deleterious germline BRCA 1 or BRCA 2 mutations and locally advanced and/or metastatic breast cancer (Press release, BioMarin, JUL 20, 2015, View Source [SID:1234506535]).

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The company announced that the ABRAZO Phase 2 trial has met the study’s protocol-specified threshold for documented tumor reduction (using the RECIST response rate criteria) in order to warrant expanding enrollment in the study from 70 to 140 patients. The ABRAZO study includes two cohorts of patients with BRCA mutated metastatic breast cancer. The first cohort consists of patients who have initially responded to a platinum-containing regimen then progressed, while the second cohort consists of patients who have received more than two prior chemotherapy regimens for metastatic disease. The protocol-specified expansion criteria requires that a minimum of five responses per cohort, of up to 35 patients, be observed in order to expand the study. The minimum of 5 responses was seen prior to full enrollment in each cohort.

The ABRAZO study is the first study treating BRCA breast cancer patients with a PARP inhibitor monotherapy that has demonstrated activity in patients who are in a salvage setting defined as having failed at least two prior chemotherapy regimens for metastatic disease. In addition, this is the first reported data showing tumor reduction from a PARP inhibitor in BRCA breast cancer patients previously treated with a platinum regimen. The trial, now targeting enrollment of a total of 140 patients, is expected to be fully enrolled in the first quarter of 2016 with results expected by year end 2016. These interim results of the ABRAZO study are planned to be presented at an upcoming medical meeting in 2016.

"We are pleased to have met our protocol-specified criteria in the ABRAZO Phase 2 trial allowing us to expand enrollment and complete the study," said Hank Fuchs, M.D., Chief Medical Officer at BioMarin. "If successful, single agent efficacy in a salvage setting potentially could support registration, adoption and use by patients who have exhausted therapeutic options. We also are thrilled to have seen anti-tumor activity in patients previously treated with platinum regimens. This is an unprecedented finding in BRCA metastatic breast cancer, which may provide a further treatment option for these patients."

The company also updated guidance for completion of enrollment of the pivotal EMBRACA study, which the company now estimates to be in the first half of 2016. EMBRACA is a Phase 3, open-label, 2:1 randomized trial to compare the safety and efficacy of oral PARP inhibitor talazoparib versus protocol-specific physician’s choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations. Prior guidance had been for enrollment of 430 patients by year end 2015. Since study initiation, a newly completed review of published data suggests that the median progression-free survival (PFS) is lower than originally estimated for the control arm in this patient population, and that fewer than the originally estimated 430 patients may need to be enrolled in order to achieve the targeted hazard ratio.

ABRAZO Trial Design

This is a Phase 2, 2-Stage, 2-Cohort Study of oral PARP inhibitor talazoparib (BMN 673) in patients with locally advanced and/or metastatic breast cancer with germline BRCA mutations.

The purpose of this study is to evaluate the safety and efficacy of talazoparib (BMN 673) in patients with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease:

Cohort 1) Subjects who have previously responded (PR or CR) to a platinum-containing regimen for metastatic disease with disease progression > 8 weeks following the last dose of platinum

Cohort 2) Subjects who have received more than two prior chemotherapy regimens for metastatic disease and no prior platinum therapy for metastatic disease

EMBRACA Trial Design

This is a Phase 3, open-label, 2:1 randomized trial to compare the safety and efficacy of oral PARP inhibitor talazoparib (BMN 673) versus protocol-specific physician’s choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.

The primary objective of the study is to compare progression-free survival (PFS) of subjects treated with talazoparib (BMN 673) as a monotherapy relative to those treated with protocol-specific physician’s choice. The secondary objectives are to evaluate objective response rate (ORR) and overall survival (OS). Exploratory objectives are to evaluate duration of response (DOR) and health-related quality of life.

About Hereditary Breast Cancer with BRCA Mutation

BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer. A woman’s risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation. Men with these mutations also have an increased risk of breast cancer. Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers.

Source: National Cancer Institute at the National Institutes of Health View Source

On July 20, 2015 Adaptimmune Therapeutics plc (Nasdaq: ADAP), a clinical stage biopharmaceutical company focused on the use of T-cell therapy to treat cancer, reported that data from its Phase I/II study of its affinity enhanced T-cell receptor (TCR) therapeutic targeting the NY-ESO-1 cancer antigen in patients with multiple myeloma has been published in Nature Medicine (Press release, Adaptimmune, JUL 20, 2015, View Source [SID:1234506534]).

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The paper entitled NY-ESO-1 Specific TCR Engineered T-cells Mediate Sustained Antigen-specific Antitumor Effects in Myeloma by Drs. Aaron P. Rapoport, Edward Stadtmauer and Gwendolyn Binder-Scholl et al. describes the persistence and tumor trafficking, antitumor effect and safety profile of Adaptimmune’s NY-ESO TCR therapeutic (ADAP NY-ESO TCR) in 20 patients with advanced multiple myeloma. The paper became available through advance online publication on July 20, 2015, and will appear in the August 2015 print edition of Nature Medicine.

This is the first published study of lentiviral vector mediated TCR gene expression in humans. Novel findings include encouraging clinical responses, prolonged duration of persistence of TCR engineered cells and continued expression of the TCR on the cell surface; which is a departure from previously published studies in TCR gene therapy. In addition, high levels of IL-6 were detected, without serious cytokine release syndrome, which is in contrast to the side effects observed with multiple antibody-based CD19 immunotherapeutics to date. Clinical response rates were higher than expected for the patient population enrolled, and evidence supporting the expected mechanism of action of the TCR engineered cells was found.

"We believe these are significant data for Adaptimmune and for the cancer gene therapy field," commented Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "The trial showed that autologous transduced cells can be safely administered to patients with advanced myeloma in the context of stem cell transplantation, and that the transduced cells persist for a prolonged period of time. There was also encouraging evidence of antitumor effect which supports further investigation of cell and gene therapy in myeloma."

The publication describes results of a Phase I/II trial to evaluate the safety and activity of autologous T-cells engineered to express an affinity-enhanced T-cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. All enrolled patients had symptomatic myeloma with active disease, representing an advanced stage population. Five patients (25 percent) had prior autologous stem cell transplant (ASCT) and 12 (60 percent) with cytogenetic abnormalities, including seven categorized as high-risk. After autologous stem cell collection, patients were conditioned with high-dose melphalan followed two days later by autologous stem cell infusion (ASCT). Patients received ADAP NY-ESO TCR (an average of 2.4 billion NY-ESOc259 -engineered CD3 T-cells) two days after ASCT.

Clinical Results
Encouraging clinical responses were observed in 16 patients (80 percent) in the study: Of the 20 patients, 14 patients (70 percent) had a near complete response or complete response, and another two had a very good partial response (VGPR) by three months post treatment. According to the authors, this compares favorably to the expected response frequencies following ASCT or double sequential (tandem) ASCT where response rates are typically less than 40 percent in patients without high risk disease.
Persistence and the manufacturing method

Persistence of gene modified cells in the patients was prolonged. In this study, 19/20 patients continued to have gene marked cells detectable in blood at six months post infusion, and long term persistence of engineered cells in the peripheral blood was detectable in 90 percent of patients who reached two years follow up. Continued TCR expression was detected at two years, which suggested gene silencing was not occurring. Engineered T-cells also trafficked to sites of tumor; a majority of patients (15/20) underwent marrow biopsy for response assessment at day 100; 14/15 had detectable engineered cells. Previous studies with engineered T-cells (Burns et al., 2009; Robbins et al., 2014) reported no demonstrated persistence and expression beyond one month.

The method of T-cell manufacture may be key to enabling persistence; CD3/CD28 costimulation was used to manufacture cells in this study, and as well as in CAR studies for CD19 and HIV by the coauthors, and all of these studies demonstrate long term persistence of gene marked cells. This technology induces activation of the T-cell receptor through CD3 and simultaneous costimulation to the T-cells though the CD28 receptor. This selects for younger T-cells and also helps to program them for prolonged expansion. Adaptimmune holds an exclusive license from ThermoFisher (formerly Life Technologies Corporation) for methods of expanding and activating T-cells transduced with engineered T-cell receptors (TCR), including use of the ThermoFisher DynaBeads CD3/CD28 technology.

Tolerability Profile
Infusions were well-tolerated without clinically apparent cytokine release syndrome (CRS), or macrophage activation syndrome (MAS), despite high IL-6 levels. The observation of safety is a significant finding; CRS and MAS have been reported as significant safety concerns in multiple antibody-based CD19 immunotherapeutics to date. This differentiated safety profile may be related to physiological signaling and/or the antigen target and expression levels.

Anti-tumor activity
To evaluate antigen-specific anti-tumor activity of the engineered T-cells, RNA transcript levels in marrow specimens were quantitatively measured for NY-ESO-1 and LAGE-1, as well as CD138 as a measure of myeloma/plasma cell burden. Relative to levels at enrollment, loss of NY-ESO-1 and LAGE-1 transcripts was observed in 12/15 patients at day 100, and in 11/13 at day 180. At day 100, 3/15 patients had detectable levels of NY-ESO-1 and LAGE-1 transcripts. Notably, disease relapse was correlated with antigen escape (loss of NY-ESO and Lage expression in 2/10 cases) or loss of engineered T-cells (8/10 patients).

"These data suggest that treatment with enhanced NY-ESO-1/LAGE-1 TCR-engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma," said Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine and the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center. "This study establishes a strong foundation for further research in cellular immunotherapy of myeloma. We hope to investigate additional combination approaches to boost the durability and function of the engineered T-cells to achieve even longer and deeper clinical responses."

"This is the first report of TCR engineered T-cell therapy that has shown durable persistence in patients," said Dr. Carl June, Richard W. Vague Professor in Immunotherapy, Department of Pathology and Laboratory Medicine, University of Pennsylvania. "These data are encouraging for the TCR platform, which I believe will be an important technology due to its ability to target intracellular antigens."

About Multiple Myeloma
Multiple myeloma is a cancer formed by malignant plasma cells. Normal plasma cells are found in the bone marrow and are an important part of the immune system, which is made up of several types of cells that work together to fight infections and other diseases. Multiple myeloma is characterized by several features, including low blood counts, bone and calcium problems, infections, kidney problems, monoclonal gammopathy, and others; and by the proliferation of these plasma cells within bone marrow. The American Cancer Society estimates that approximately 26,850 new cases will be diagnosed in the United States in 2015. Average five-year survival rates are estimated to be less than 45 percent with survival rates depending on factors such as age, stage of diagnosis and suitability for auto-SCT, which is used as part of the treatment for eligible patients with multiple myeloma. Despite recent therapeutic advances, multiple myeloma remains an incurable but treatable cancer. Patients are typically treated with repeat rounds of combination therapy with the time intervals to relapse becoming shorter with each successive line of therapy. The majority of patients eventually have a relapse which cannot be further treated.

On July 20, 2015 Exelixis reported positive top-line results from the primary analysis of METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in 658 patients with metastatic renal cell carcinoma (RCC) who have experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI) (Press release, Exelixis, JUL 20, 2015, View Source [SID:1234506521]).

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The trial met its primary endpoint of demonstrating a statistically significant increase in progression-free survival (PFS) in the first 375 randomized patients as determined by an independent radiology committee (IRC). Cabozantinib reduced the risk of disease progression or death by 42 percent compared to the everolimus arm (hazard ratio [HR]=0.58, 95 percent CI 0.45-0.75, p<0.0001).

Data pertaining to overall survival (OS) in the entire study population of 658 patients, a secondary endpoint of the trial, were immature at the data cutoff. A prespecified interim analysis, triggered by the primary analysis for PFS, showed a trend in OS favoring cabozantinib (HR = 0.67, unadjusted 95 percent CI 0.51 – 0.89; p=0.005). At the time of the interim analysis, the pre-specified p-value of 0.0019 to achieve statistical significance was not reached. The trial will continue to the final analysis of OS anticipated in 2016.

METEOR’s primary analysis included a review of serious adverse event (SAE) data. Based on this analysis, the frequency of SAEs of any Grade regardless of causality was approximately balanced between study arms. The rate of treatment discontinuation due to adverse events was low (10%) in both study arms.

Detailed results of the trial will be submitted for presentation at an upcoming medical conference.

In April 2015, cabozantinib received Fast Track designation by the U.S. Food and Drug Administration (FDA) for the potential treatment of advanced RCC patients who have received one prior therapy. Based on the outcome of METEOR, Exelixis plans to complete regulatory filings in the United States and European Union in early 2016.

"We are eager to offer new treatment options for patients with metastatic RCC, particularly in the second-line setting where the most commonly utilized therapies have demonstrated a uniformly modest progression-free survival benefit," said Toni K. Choueiri, M.D., clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and METEOR’s principal investigator. "The magnitude of the improvement in PFS observed with cabozantinib compared to everolimus in the METEOR trial is an exciting and important development — it suggests an opportunity to improve care and outcomes for patients with metastatic RCC."

"The positive top-line results from METEOR represent strong progress for the kidney cancer community and for Exelixis, bringing us one step closer to our shared goal of delivering a new and meaningfully differentiated therapeutic option for the many metastatic RCC patients in need," said Michael M. Morrissey, Ph.D., the company’s president and chief executive officer. "With these data now in hand, Exelixis’ highest corporate priority becomes the submission of U.S. and EU regulatory filings, which we intend to complete in early 2016."

Dr. Morrissey continued, "Delivering these top-line results for METEOR is one of multiple clinical development and regulatory milestones that we have planned for this year. These milestones collectively have the potential to significantly enhance the opportunities before us and bring value to the multiple stakeholders we serve. We look forward to sharing the detailed results of METEOR with the oncology community at an upcoming medical conference, and we thank all of the patients, families, investigators, and clinical staff who made the trial possible."

Conference Call and Webcast

Exelixis’ management will host a conference call to discuss the METEOR results beginning at 8:30 a.m. EDT/ 5:30 a.m. PDT today, July 20, 2015. To join the call, participants may dial 877-358-0169 (domestic) or 706-679-2029 (international) and provide the conference call passcode 90168151 to join by phone. To listen to a live webcast of the conference call, visit the Event Calendar page under Investors & Media at www.exelixis.com.

An archived replay of the webcast will be available on the Event Calendar page under Investors & Media at www.exelixis.com for at least thirty days. An audio-only phone replay will be available until 11:59 p.m. EDT on July 22, 2015. Access numbers for the phone replay are: 855-859-2056 (domestic) and 404-537-3406 (international); the passcode is 90168151.

About the METEOR Phase 3 Pivotal Trial

METEOR is an open-label, event-driven trial with the primary endpoint of progression-free survival (PFS). The target enrollment for METEOR was 650 patients, and 658 patients were ultimately randomized. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily, and were stratified based on the number of prior VEGF receptor TKI therapies received, and on commonly applied RCC risk criteria developed by Motzer et al. No cross-over was allowed between the study arms.

The trial protocol specified that the primary analysis of PFS would be conducted among the first 375 patients randomized. This design was employed to ensure sufficient follow up and a PFS profile that would not be primarily weighted toward early events. Such disproportionate weighting of events was a potential risk if the entire study population required for the secondary endpoint analysis of OS had also served as the population for the primary analysis of PFS. The analysis of PFS was event-driven, and was designed to observe 259 events, providing 90% power to detect a HR of 0.67 (assuming a median PFS of 5 months for the everolimus arm and 7.5 months for the cabozantinib arm). Enrollment of the first 375 patients was completed in June 2014 and the median follow-up for these patients was 13.4 months at the time of the data cut off for the primary analysis for PFS.

Secondary endpoints for METEOR include OS and objective response rate. The secondary endpoint of OS assumes a median of 15 months for the everolimus arm and 20 months for the cabozantinib arm. The study was designed to observe 408 deaths in the entire intent-to-treat population of 650 planned patients, providing 80% power to detect a HR of 0.75. An interim analysis of OS at the 2-sided 0.0019 level per the Lan-DeMets O’Brien-Fleming alpha-spending function was planned at the time of the primary analysis for PFS, if the trial met the primary PFS endpoint.

About Metastatic Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the United States.1 Clear cell renal cell carcinoma is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon) until the introduction of targeted therapies into the RCC setting a decade ago. In the second and later-line setting, which encompasses approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two therapies have been approved for the treatment of patients who have received prior VEGF receptor TKIs. However, despite the availability of several therapeutic options, currently approved agents have shown little differentiation in terms of efficacy and have demonstrated only modest PFS benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET, and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype, and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL, and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

COMETRIQ (cabozantinib) is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.
COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
Wound complications have been reported with COMETRIQ.
COMETRIQ treatment results in an increase in hypertension.
Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.
Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.
Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.