On December 10, 2015 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and granted Priority Review for a supplemental New Drug Application (sNDA) for Pfizer’s breast cancer medication, IBRANCE (palbociclib) (Press release, Pfizer, DEC 10, 2015, View Source [SID:1234508526]).

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If approved, the sNDA would expand the approved use of IBRANCE to reflect findings from the Phase 3 PALOMA-3 trial, which evaluated IBRANCE in combination with fulvestrant versus fulvestrant plus placebo in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+, HER2-) metastatic breast cancer, regardless of menopausal status, whose disease progressed after endocrine therapy, including those with and without prior treatment for their metastatic disease. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is April 2016.

"We look forward to continuing to work with the FDA to add the robust Phase 3 data set from the PALOMA-3 trial to the available data in the IBRANCE label," said Liz Barrett, global president and general manager, Pfizer Oncology. "Since FDA approval in February, more than 18,000 women have been treated with IBRANCE by approximately 5,000 prescribers in the U.S. With approval of this indication, we hope to expand the role of IBRANCE in combination with endocrine therapy for the treatment of HR+, HER2- metastatic breast cancer and to serve even more patients with this first-in-class medicine."

If Pfizer’s sNDA is approved, the updated IBRANCE label would comprise results from two metastatic breast cancer trials in which IBRANCE in combination with an endocrine therapy improved progression-free survival (PFS) compared to endocrine therapy alone, PALOMA-1 and PALOMA-3.

Based on the results of the PALOMA-1 trial, IBRANCE was approved by the FDA in February 2015 for use in combination with letrozole as a treatment for postmenopausal women with estrogen receptor-positive (ER+), HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.1 This indication is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the ongoing confirmatory trial, PALOMA-2. The most frequently reported adverse event for IBRANCE plus letrozole in PALOMA-1 was neutropenia. For more information on the serious and most common side effects of IBRANCE plus letrozole, please see Important IBRANCE Safety Information at the end of this release.

The sNDA seeks to expand approved use of IBRANCE based on the PALOMA-3 trial results. PALOMA-3 enrolled 521 patients, 350 of whom received the combination of IBRANCE plus fulvestrant. Pfizer announced in April 2015 that the trial was stopped early due to efficacy based on an assessment by an independent Data Monitoring Committee (DMC). The results were presented as a late-breaker at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and were published in The New England Journal of Medicine in June 2015. The adverse events observed with IBRANCE in combination with fulvestrant in PALOMA-3 were generally consistent with their respective known adverse event profiles.

In November 2015, the combination of IBRANCE plus fulvestrant was added to the National Comprehensive Cancer Network Guidelines as a Category 1 recommendation for the treatment of women with HR+, HER2- metastatic breast cancer who have progressed on endocrine therapy or premenopausal women receiving ovarian suppression with a luteinizing hormone-releasing hormone (LHRH) agonist.

About IBRANCE (palbociclib)

IBRANCE is an oral, first-in-class inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. CDKs 4 and 6 are key regulators of the cell cycle that trigger cellular progression.1,2

IBRANCE is approved by the FDA for use in combination with letrozole as a treatment for postmenopausal women with ER+, HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.1 The effectiveness of IBRANCE in these patients is based on a study that measured PFS.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The confirmatory Phase 3 trial, PALOMA-2, is fully enrolled. IBRANCE has also received regulatory approval in Albania, Chile and Macau. In the European Union, the Marketing Authorization Application for IBRANCE, which is based on results from the PALOMA-1 and PALOMA-3 trials, is currently under review with the European Marketing Agency.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur.

Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the first two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate.

Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE.

Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone.

Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%).

General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously.

Patients should be encouraged to take their dose at approximately the same time each day.

Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided.

Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

On December 10, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of discovering, developing and commercializing novel immuno-oncology product candidates, including both cellular immunotherapy and checkpoint inhibitor platforms, to improve the lives of patients with cancer, reported that this month it reached the enrollment goal for NLG2101, a randomized Phase 2 study of indoximod in combination with taxane chemotherapy for patients with metastatic breast cancer. Indoximod is a small-molecule indoleamine 2,3-dioxygenase (IDO) pathway inhibitor that has the potential to disrupt mechanisms by which tumors evade the immune system (Press release, NewLink Genetics, DEC 10, 2015, View Source [SID:1234508524]).

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"We believe that IDO is an increasingly important target in immuno-oncology, and that targeting the IDO pathway will be a critical component of future immuno-oncology combination therapies," said Charles Link, Jr., M.D., Chairman and CEO of NewLink Genetics. "Completing enrollment in the clinical trial for this combination chemoimmunotherapy is an important step forward in evaluating indoximod in breast cancer."

IDO pathway inhibitors are a class of immune checkpoint inhibitors akin to the recently developed antibodies targeting CTLA-4, PD-1, and PD-L1 that represent potential breakthrough approaches to cancer therapy. The IDO pathway regulates immune response by suppressing T-cell activation, which enables local tumor immune escape. Recent studies have demonstrated that the IDO pathway is active in many cancers, both within tumor cells as a direct defense against T-cell attack and also within antigen presenting cells in tumor draining lymph nodes, whereby this pathway promotes peripheral tolerance to tumor associated antigens (TAAs). When hijacked by developing cancers in this manner, the IDO pathway may facilitate the survival, growth, invasion and metastasis of malignant cells whose expression of TAAs might otherwise be recognized and attacked by the immune system.

NewLink Genetics has a number of active programs directed at synthesizing inhibitors to the IDO pathway and, additionally, the company has discovered novel tryptophan-2,3-dioxygenase (TDO) specific inhibitors. IDO pathway inhibitors such as indoximod are designed to be used in combination with other therapeutic agents to maximize the body’s immune response against tumors. In addition, NewLink Genetics has entered into an exclusive worldwide license and collaboration agreement with Genentech, a member of the Roche Group, for the development of GDC-0919, which is currently in Phase 1 clinical development in patients with recurrent or advanced solid tumors.

About the NLG2101 Trial

NLG2101 is a Phase 2, 1:1 randomized study evaluating indoximod in 154 patients with ER/PR +/- and HER2- metastatic breast cancer who have not received any prior chemotherapy in the metastatic setting. The primary endpoint of NLG2101 is progression-free survival after treatment with docetaxel 75 mg/m2 or paclitaxel 80 mg/m2 with or without indoximod.

On December 10, 2015 Eli Lilly and Company (NYSE: LLY) and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported another immuno-oncology collaboration that will evaluate abemaciclib (LY2835219), Lilly’s cyclin-dependent kinase (CDK) 4 and 6 inhibitor, and Merck’s KEYTRUDA (pembrolizumab) in a Phase I study across multiple tumor types. Based on the Phase I trial results, the collaboration has the potential to progress to Phase II trials in patients who have been diagnosed with either metastatic breast cancer or non-small cell lung cancer (NSCLC) (Press release, Merck & Co, DEC 10, 2015, View Source [SID:1234508522]).

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Lilly is the sponsor of the Phase I study, and of any subsequent Phase II studies, per the terms of the agreement. Enrollment is scheduled to begin in early 2016. Financial details of the collaboration were not disclosed.

Lilly’s abemaciclib is a cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting CDK4 and CDK6. Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.

"With our active Phase III program underway for abemaciclib in both metastatic breast cancer and non-small cell lung cancer, we are committed to uncovering every opportunity to help these patients – and this includes exploring abemaciclib in combination with immunotherapy," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "We’re encouraged by our productive immuno-oncology collaborations with Merck, through its affiliates, and coming together for another clinical trial is a natural evolution of our scientific collaboration."

"We look forward to continuing our collaboration with Lilly on this combination study with KEYTRUDA and abemaciclib," said Eric Rubin, M.D., vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "Strategic collaborations such as this one reinforce the commitment we have to bringing new combination treatments to the forefront for people with cancer."

NOTES TO EDITORS

About Abemaciclib

Cyclin-dependent kinases play a key role in regulating cell cycle progression. In many cancers, uncontrolled cell growth arises from a loss of control in regulating the cell cycle due to increased signaling from CDK4 and CDK6. Lilly’s abemaciclib (LY2835219) is a cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting CDK4 and CDK6, and in cell-free enzymatic assays has been shown to be most active against Cyclin D1/CDK4. Results from preclinical and early-stage clinical studies support the further evaluation of abemaciclib for the treatment of human cancers – including breast cancer and lung cancer – in which aberrant CDK4 and CDK6 pathways enhance cancer cell growth.

Abemaciclib is in Phase III development with two trials in HR+ breast cancer patients, as well as a Phase III trial in lung cancer.

On December 10, 2015 ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo, Inc. reported that the phase 3 METIV-HCC trial for tivantinib in second-line hepatocellular carcinoma (HCC) has completed accrual (Press release, ArQule, DEC 10, 2015, View Source [SID:1234508521]).

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In addition, the planned interim analysis, which is triggered when 60 percent of events occur, is expected to take place early in the second quarter of 2016.

The METIV-HCC trial is a biomarker-driven, double-blind, placebo-controlled, pivotal phase 3 trial where patients are randomized 2:1 comparing tivantinib to best supportive care. The trial is conducted under a Special Protocol Assessment and has accrued more than 300 HCC patients with MET-high tumors only, as determined by an immunohistochemistry test. The trial is being conducted in western countries by Daiichi Sankyo and ArQule with a primary endpoint of overall survival. The planned interim analysis for Data Monitoring Committee (DMC) review was designed with an early stop for superiority.

"We are pleased to have fully accrued the METIV-HCC trial prior to year-end," said Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "HCC is a disease with high unmet need and with no approved therapy for second-line treatment. It has been very encouraging to see a growing body of evidence supporting the phase 3 clinical evaluation of tivantinib in MET-high populations through a recent presentation at the International Liver Cancer Association conference."

"We would like to thank all the patients, investigators and clinical sites for partnering with us to achieve this important milestone," said Mahmoud Ghazzi, M.D., Ph.D, President and Global Head of Development for Daiichi Sankyo. "The completion of planned patient enrollment into METIV-HCC is an important step forward in the development of a potential new targeted treatment for patients with advanced HCC, who currently have limited options."

About Hepatocellular Carcinoma (HCC)
Liver cancer is the sixth most common cancer globally with 782,000 new cases in 2012 and is the second most common cause of cancer-related death with 745,000 deaths in 2012.
HCC accounts for about 90 percent of primary liver cancers. 2 Cirrhosis, chronic hepatitis B and C and smoking are recognized worldwide as factors increasing the risk of HCC.

About MET and Tivantinib (ARQ 197)
Tivantinib is an orally administered, selective inhibitor of MET, a receptor tyrosine kinase, which is currently in phase 2 and phase 3 clinical trials. In healthy adult cells, MET can be present in normal levels to support natural cellular function, but in cancer cells, MET can be inappropriately and continuously activated. When abnormally activated, MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The activation of certain cell signaling pathways, including MET, has also been associated with the development of resistance to anti-EGFR (epidermal growth
factor receptor) antibodies such as cetuximab and panitumumab.

Pre-clinical data have demonstrated that tivantinib inhibits MET activation in a range of human tumor cell lines and shows anti-tumor activity against several human tumor xenografts. In clinical trials to date, treatment with tivantinib has been generally well tolerated
and has shown clinical activity in a number of tumors studied. Tivantinib has not yet been approved for any indication in any country.

In December 2008, ArQule and Daiichi Sankyo signed a license, co-development and cocommercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan. In November 2015, ArQule exercised its co-commercialization option for tivantinib in the U.S. A co-commercialization agreement is expected to be finalized in the first quarter of 2016.

On December 10, 2015 Argos Therapeutics Inc. (Nasdaq:ARGS) ("Argos"), an immuno-oncology company focused on the development and commercialization of fully individualized immunotherapies for the treatment of cancer based on the Arcelis technology platform, reported its independent data monitoring committee (IDMC) has recommended the continuation of the company’s pivotal phase 3 ADAPT clinical trial of AGS-003 for the treatment of metastatic renal cell carcinoma (mRCC) based on results of the committee’s second planned interim data analysis (Press release, Argos Therapeutics, DEC 10, 2015, View Source [SID:1234508520]).

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"The ADAPT phase 3 trial to evaluate AGS-003 in front line mRCC, the largest global trial ever performed in newly diagnosed, unfavorable risk mRCC patients, continues to progress nicely," said Dr. Figlin, the Steven Spielberg Family chair in hematology oncology, professor of medicine and biomedical sciences at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and the principal investigator for the ADAPT trial. "We anticipate that we are approaching the mid-point for the expected number of events and look forward to the next interim review of the trial data in approximately six months."

AGS-003 is a fully individualized immunotherapy that captures mutated and variant antigens that are specific to each patient’s tumor and is designed to induce an immune response targeting that patient’s tumor antigens. In an open-label phase 2 study, treatment with AGS-003 plus sunitinib yielded a median overall survival of more than 30 months in newly diagnosed, unfavorable (intermediate and poor) risk mRCC patients. The randomized phase 3 ADAPT trial evaluating AGS-003 plus standard targeted therapy enrolled a total of 462 mRCC patients and has a primary endpoint of overall survival. AGS-003 is Argos’ most advanced Arcelis-based product candidate.

"We are excited by the IDMC’s recommendation to continue with the trial," said Jeffrey D. Abbey, president and chief executive officer of Argos. "This is an important step for the ADAPT trial and for the clinical development of AGS-003."

Conference Call and Webcast Details

Argos executive management will host a conference call with Dr. Figlin beginning at 5:00pm EST on Thursday, December 10, 2015 to discuss the IDMC recommendation to continue the trial, and to answer questions.

To participate by telephone, please dial (855) 433-0930 (Domestic) or (484) 756-4271 (International). The conference ID number is 4042406. A live and archived audio webcast can be accessed through the Investors section of the Company’s website at www.argostherapeutics.com. The archived webcast will remain available on the Company’s website for 12 months following the call.

About the Arcelis Technology Platform

Arcelis is a fully individualized immunotherapy technology that captures mutated and variant antigens that are specific to each patient’s disease. It is designed to overcome immunosuppression by producing a durable memory T-cell response without adjuvants that may be associated with toxicity. The technology is potentially applicable to a wide range of different cancers, and is designed to overcome many of the manufacturing and commercialization challenges that have impeded other personalized cancer immunotherapies. The Arcelis process uses only a small tumor or blood sample and the patient’s own dendritic cells, which are optimized from cells collected by a single leukapheresis procedure. The proprietary process uses RNA isolated from the patient’s disease sample to program dendritic cells to target disease specific antigens. The activated, antigen-loaded dendritic cells are then formulated into the patient’s plasma and administered via intradermal injection.