On June 17, 2019 Pfizer Inc. (NYSE: PFE) and Array BioPharma Inc. (NASDAQ: ARRY) reported that they have entered into a definitive merger agreement under which Pfizer will acquire Array, a commercial stage biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule medicines to treat cancer and other diseases of high unmet need. Pfizer has agreed to acquire Array for $48 per share in cash, for a total enterprise value of approximately $11.4 billion (Press release, Array BioPharma, JUN 17, 2019, View Source [SID1234537105]). The Boards of Directors of both companies have approved the merger.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This press release features multimedia. View the full release here: View Source

Array’s portfolio includes the approved combined use of BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) for the treatment of BRAFV600E or BRAFV600K mutant unresectable or metastatic melanoma. The combination therapy has significant potential for long-term growth via expansion into additional areas of unmet need and is currently being investigated in over 30 clinical trials across several solid tumor indications, including the Phase 3 BEACON trial in BRAF-mutant metastatic colorectal cancer (mCRC).

In the U.S., colorectal cancer is the third most common type of cancer in men and women. An estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year.1BRAF mutations are estimated to occur in up to 15% of colorectal cancer cases and represent a poor prognosis for these patients.

"Today’s announcement reinforces our commitment to deploy our capital to bring breakthroughs that change patients’ lives while creating shareholder value," said Albert Bourla, chief executive officer of Pfizer. "The proposed acquisition of Array strengthens our innovative biopharmaceutical business, is expected to enhance its long-term growth trajectory, and sets the stage to create a potentially industry-leading franchise for colorectal cancer alongside Pfizer’s existing expertise in breast and prostate cancers."

In addition to the combination therapy for BRAF-mutant metastatic melanoma, Array brings a broad pipeline of targeted cancer medicines in development, as well as a portfolio of out-licensed potentially best-in-class and/or first-in-class medicines, which are expected to generate significant royalties over time.

"We are incredibly proud that Pfizer has recognized the value Array has brought to patients and our remarkable legacy discovering and advancing molecules with great potential to impact and extend the lives of patients in critical need," said Ron Squarer, Array chief executive officer. "Pfizer shares our commitment to patients and a passion for advancing science to develop even more options for individuals with unmet needs. We’re excited our team will have access to world-class resources and a broader research platform to continue this critical work."

In May 2019, Array announced results from the interim analysis of the Phase 3 BEACON mCRC trial: The second-or-third-line treatment with the BRAFTOVI triplet combination (BRAFTOVI + MEKTOVI + cetuximab) showed statistically significant improvement in overall response rate and overall survival compared to the control group, reducing the risk of death by 48%. The triplet combination could be the first chemotherapy-free, targeted regimen for patients with BRAF-mutant mCRC. Array intends to submit these data for regulatory review in the United States in the second half of 2019.

"We are very excited by Array’s impressive track record of successfully discovering and developing innovative small-molecules and targeted cancer therapies," said Mikael Dolsten, Pfizer chief scientific officer and president, Worldwide Research, Development and Medical. "With Array’s exceptional scientific talent and innovative pipeline, combined with Pfizer’s leading research and development capabilities, we reinforce our commitment to advancing the most promising science, regardless of whether it is found inside or outside of our labs."

Upon the close of the transaction, Array’s employees will join Pfizer and continue to be located in Cambridge, Massachusetts and Morrisville, North Carolina, as well as Boulder, Colorado, which becomes part of Pfizer’s Oncology Research & Development network in addition to La Jolla, California and Pearl River, New York.

Pfizer expects to finance the majority of the transaction with debt and the balance with existing cash. The transaction is expected to be dilutive to Pfizer’s Adjusted Diluted EPS by $0.04 -$0.05 in 2019, $0.04 -$0.05 in 2020, neutral in 2021, and accretive beginning in 2022, with additional accretion and growth anticipated thereafter. Pfizer will provide any appropriate updates to its current 2019 guidance in conjunction with its third quarter 2019 earnings release.

Under the terms of the merger agreement, a subsidiary of Pfizer will commence a cash tender offer to purchase all outstanding shares of Array common stock for $48 per share in cash for a total enterprise value of approximately $11.4 billion. The closing of the tender offer is subject to customary closing conditions, including regulatory approvals and the tender of a majority of the outstanding shares of Array common stock (on a fully-diluted basis). The merger agreement contemplates that Pfizer will acquire any shares of Array that are not tendered into the offer through a second-step merger, which will be completed promptly following the closing of the tender offer. Pfizer expects to complete the acquisition in the second half of 2019.

Pfizer’s financial advisors for the transaction were Guggenheim Securities, LLC, and Morgan Stanley & Co. LLC, with Wachtell, Lipton, Rosen & Katz acting as its legal advisor. Centerview Partners served as Array’s exclusive financial advisor, while Skadden, Arps, Slate, Meagher & Flom LLP served as its legal advisor.

Conference Call

Pfizer Inc. invites investors and the general public to view and listen to a webcast of a live conference call with investment analysts at 9:00 a.m. EDT on Monday, June 17, 2019.

To view and listen to the webcast visit Pfizer’s web site at www.pfizer.com/investorsor directly at View Source Information on accessing and pre-registering for the webcast will be available at www.pfizer.com/investors beginning today. Participants are advised to pre-register in advance of the conference call.

You can listen to the conference call by dialing either (855) 895-8759 in the United States or Canada or (503) 343-6044 outside of the United States and Canada. The password is "Analyst Call." Please join the call five minutes prior to the start time to avoid operator hold times.

Pfizer Inc.: Breakthroughs that change patients’ lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com. In addition, to learn more, please visit us on www.Pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

On June 16, 2019 Shanghai Fosun Pharmaceutical (Group) Co., Ltd.("Fosun Pharma; stock code: 600196.SH, 02196.HK)), a leading healthcare group in China reported that its investigational drug ORIN1001 has received Fast Track designation (FTD) from U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed, refractory and metastatic breast cancer (including triple-negative breast cancer [TNBC]) (Press release, Fosun Pharma, JUN 16, 2019, View Source [SID1234556449]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

ORIN1001 is an investigational first-in-class small molecule drug that has a novel molecular target, novel mechanism of action and novel chemical structural class and identity, and is independently developed by Fosun Orinove, a subsidiary of Fosun Pharma. The new drug is for the treatment of advanced solid tumors and relapsed refractory metastatic breast cancer. As of May 2019, Fosun Pharma has invested RMB 45.47 millions in this investigational drug.

Established in July 2017 by Fosun Pharma and a team of American scientists, Fosun Orinove focuses on cancer cell metabolism-related small molecule anticancer drugs, and has set up R&D locations both in Suzhou and Los Angeles.

Dr. Qingping Zeng, CEO of Fosun Orinove said, "The fast track designation of ORIN1001 reflects a recognition for our R&D aspirations of getting novel therapeutics to patients and addressing unmet medical needs. The molecular target is related to a stress mitigation mechanism for diseased cells, and has commonality for various therapeutic indications. We will accelerate ORIN1001 development in multiple indications in the near future and reach the global market expeditiously."

Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious or life-threatening disease or condition and fill an unmet medical need. A therapeutic that receives Fast Track designation may be eligible for frequent communication with the FDA, priority review, potential accelerated approval according to data, and rolling submission, which allows a company to submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.

Dr. Aimin Hui, the Senior Vice President and Chief Medical Officer of Fosun Pharma said, "We are thrilled to treat cancer patients in the United States and receive FDA Fast Track Development Program designation within six months since initial IND submission. It implies that the research and development for innovative medicine and globalization at Fosun Pharma is moving to a new stage."

Breast cancer is one of the major cancer-caused deaths for women nowadays. TNBC refers to breast cancer tumors that do not express the estrogen receptor (ER), progesterone receptor (PR) and Her2/neu, and is diagnosed more frequently in younger and premenopausal women under 40 years old. TNBC accounts for about 15 to 25% of breast cancer patients, and because of the high heterogeneity of its tumor cells, triple-negative breast cancer has very high invasiveness, recurrence rate and metastasis. Due to the lack of effective targeted therapy, there is a huge unmet clinical need for TNBC.

"Receipt of FDA Fast Track designation has marked another innovative breakthrough of Fosun Pharma in oncology treatment area." Executive Director and Co-President of Fosun International, Chairman of Fosun Pharma, Mr. Chen Qiyu said, "In the future, we’ll continue to innovate in unmet medical needs, to find treatment for refractory diseases, and to provide more accessible, more qualified, and more affordable products and services to global patients."

Cancer severely threats human health. Tradition treatment could hardly curing cancer. In recent years, Fosun Pharma continues to expand investment on innovation and oncology research, and has layout on small molecular innovative drugs, biologics and cellular immunotherapy. Now, Fosun Pharma owns a rich pipeline, with more than 30 projects on clinical development stage in oncology. In February 2019, its independent innovative product HLX01(trademark: 汉利康) which is developed by Henlius, Fosun Pharma’s biologics platform has been approved by NMPA as the first biosimilar in China. It helps to increase the accessibility of high-quality biosimilar, and would benefit more lymphoma patients. Facing with unmet medical needs, Fosun Pharma also introduces a number of advanced and cutting-edge products and technologies via corporate cooperation and license-in. Fosun Kite’s first product FKC876 was accepted in the clinical trial and registration review of the NMPA, with an aim to provide advanced treatment to Chinese cancer patients. In the future, Fosun Pharma will leverage on the advantages and stick to independent innovation and internationalization benefiting from industry and market opportunities, to contribute better and more affordable medicines for society.

On June 16, 2019 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported updated interim efficacy and safety data from the ongoing, pivotal Phase 2 HORIZON trial (Press release, Oncopeptides, JUN 16, 2019, View Source [SID1234537103]). The oral presentation was included in the "Novel strategies in multiple myeloma" session and was led by Professor Paul G. Richardson, Professor of Medicine at Harvard Medical School and Clinical Program Leader, Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute in Boston, Massachusetts, USA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation will be available on the company webpage under: www.oncopeptides.com / Investors & media / Presentations / 2019 EHA (Free EHA Whitepaper)

Comment from CEO Jakob Lindberg
"HORIZON is an all-comer trial for patients with very advanced multiple myeloma. A majority of patients have extra medullary disease (EMD) as well as high-risk cytogenetics. Notably patients with EMD at relapse have limited response from treatment in clinical trials even in the era of modern therapies. In light of this patient population, the response rate of 28% coupled with the manageable side effect profile in HORIZON is very encouraging and indicates that melflufen plus dexamethasone can offer these patients a reasonable treatment alternative. These data form the basis of the upcoming New Drug Application (NDA) submission that we are currently preparing for accelerated approval of melflufen for the treatment of patients with triple-class refractory multiple myeloma" said Jakob Lindberg, CEO of Oncopeptides.

Overall Conclusions – HORIZON Presentation
At the time for the data cut-off, May 6th, 35 out of the 121 patients included were still on treatment.
The Overall Response Rate (ORR) was 28% and the Clinical Benefit Rate (CBR) was 40%, 36% of patients had receved 3+ treatment regimens over the last 12 months.
Extra-medullary disease patients had an ORR of 29%.
The majority of patients 86%, achieved disease stabilization (SD or better)
The median Progression Free Survival (PFS) was 4.0 months in the ongoing study.
Treatment was generally well tolerated with manageable toxicity, nonhematologic AEs were infrequent and the rate of discontinuation due to AEs was low.
Comment from Professor Paul G. Richardson
"The number of patients with resistant myeloma characterized by extra-medullary disease and high-risk cytogenetics is increasing, despite recent advances, and there is a real need for additional treatment options based on new mechanisms of action. Melflufen continues to demonstrate promising activity and manageable toxicity in the relapsed and refractory setting, and in particular amongst patients who are triple-class refractory " said Paul Richardson, MD, the RJ Corman Professor of Medicine at Harvard Medical School and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, USA.

About the OP-106 HORIZON study
Patient recruitment in the HORIZON study is ongoing. The interim data presented at EHA (Free EHA Whitepaper) is based on a data cut-off dated May 6th 2019 with 121 patients treated. 108 patients had recivied two or more cycles of treatment. The goal is to include 150 patients in the study. The patients in the study are refractory to pomalidomide and/or daratumumab after failing on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

More information can be found at: View Source;rank=2

Summary of the OP-106 HORIZON interim data
The study continues to develop positively in this heavily pretreated patient group. Melflufen continues to demonstrate promising activity in patients that have stopped responding to lenalidomide and PI based regimens and subsequently become resistant to salvage therapy based on daratumumab and/or pomalidomide.

The median age of the patients was 64 years. 62% of patients in the study had high-risk cytogenetics, 29% of patients were ISS stage III and 60% of the patients had extramedullary disease (EMD). The median number of prior lines of therapy was five and the median time since initial diagnosis was 6.2 years.

All patients in the study were investigator assessed as non-responsive or non-tolerant to IMiDs and PIs.

91% of patients were double class refractory (IMiD + PI) and 79% anti-CD38 mAb refractory. 74% of the patients were triple class (IMiD + PI + Anti-CD38 mAb) refractory and 59% were alkylator refractory. 98% of the patients were refractory in last line of therapy.

Efficacy
Analysis of the interim efficacy results showed an ORR of 28% and that 86% of the patients achieved disease stabilization (SD or better), see table below.

8 pts did not have available response information at data cutoff; 2 pts response evaluable, PI exposed, but refractoriness to PI subject to confirmation, so excluded from subgroup analysis
One pt with sCR also confirmed as MRD negative (10-6 sensitivity), with ongoing progression-free period of 13.6 mos
Median time to response 1.2 mos
CBR, clinical benefit rate; CR, complete response; MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good PR.

For patients with extra-medullary disease the ORR was 29% as described in the table below.

Safety and tolerability
At time of data cut-off, treatment-related SAEs occurred in 20% of patients, most commonly febrile neutropenia (5%) and thrombocytopenia (2%). The overall incidence of nonhematologic AEs was low.

Discontinuation rate because of AEs was 20%. There were no treatment-related deaths. Six patients (6%) experienced treatment-related bleeding: grade 1 in four patients, grade 3 in two patients.

For further information, please contact:
Jakob Lindberg, CEO of Oncopeptides
E-mail: [email protected]
Telephone: +46 8 615 20 40

Rein Piir, Head of Investor Relations at Oncopeptides
E-mail: [email protected]
Cell phone: +46 70 853 72 92

The information in the press release is information that Oncopeptides is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person above, on June 16, 2019 at 08.45 (CET).

About melflufen
Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. It belongs to the novel class Peptidase Enhanced Cytotoxics (PEnC), which is a family of lipophilic peptides that exhibit increased activity via peptidase cleavage and have the potential to treat many cancers. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and immediately cleaved by peptidases to deliver an entrapped hydrophilic alkylator payload. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the peptidase cleavage, and induces irreversible DNA damage and apoptosis. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

On June 16, 2019 Amgen (NASDAQ:AMGN) reported the five-year overall survival (OS) analysis from the single-arm, Phase 2 BLAST study that evaluated BLINCYTO (blinatumomab) in patients with minimal residual disease (MRD)-positive acute lymphoblastic leukemia (ALL) (Press release, Amgen, JUN 16, 2019, View Source;p=RssLanding&cat=news&id=2401504 [SID1234537102]). The study found that with a median follow-up of 59.8 months, the median OS for BLINCYTO-treated patients was 36.5 months (95 percent CI: 22 months – not estimable [NE]). More than half of patients who achieved a complete MRD response following the first cycle of BLINCYTO treatment were alive at five years. These results from the largest prospective trial ever conducted in MRD-positive ALL were presented today during an oral presentation at the 24th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"As the only CD19-targeted immuno-oncology therapy with five-year survival data, BLINCYTO continues to demonstrate compelling results for ALL patients," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We are proud of the science behind our BiTE technology. These data in an MRD-positive ALL patient population give us increased confidence in the clinical benefit of BLINCYTO, especially when these patients are treated earlier."

The Phase 2 open-label BLAST study enrolled 116 patients with MRD-positive Philadelphia chromosome-negative (Ph-) B-cell precursor ALL in first or subsequent complete hematologic remission after at least three intensive chemotherapy blocks of treatment. Of the 116 enrolled patients, OS was evaluated for 110 patients with less than five percent leukemic blasts, including 74 patients who received hematopoietic stem cell transplantation (HSCT) in continuous complete remission (CCR) after BLINCYTO treatment.

Results presented at EHA (Free EHA Whitepaper) showed that in 84 patients who achieved a complete MRD response (had no measurable MRD), median OS was not reached (95 percent CI: 29.5 months – NE) compared to 14.4 months for those who had measurable MRD (n=23; 95 percent CI: 3.8 – 32.3 months). Among patients with MRD in first complete remission (CR1), median OS was not reached for those who achieved a complete MRD response (95 percent CI: 29.5 months – NE) versus 10.6 months (95 percent CI: 2.7 – 39.7 months) for those who did not achieve complete MRD response (n=13; p=0.008).

"The presence of MRD is a strong predictor of relapse in patients with B-cell precursor ALL," said Nicola Gökbuget, M.D., principal investigator for the BLAST study and head of the German Multicenter Study Group for Adult ALL in Frankfurt, Germany. "Results from the final follow-up of the BLAST trial at five years demonstrate that early achievement of complete molecular remission with BLINCYTO is associated with prolonged survival."

Safety results among MRD-positive patients were consistent with the known safety profile of BLINCYTO.

MRD refers to the presence of cancer cells that remain detectable, despite a patient having achieved complete remission by conventional assessment.1 The presence of MRD is broadly considered the most important independent prognostic factor in ALL.2-8 MRD is only measurable through the use of highly sensitive testing methods that detect cancer cells in the bone marrow with a sensitivity of at least one cancer cell in 10,000 cells – versus about one in 20 with a conventional microscope-based evaluation.1,9,10

BLINCYTO, a bispecific CD19-directed CD3 T cell BiTE (bispecific T cell engager) molecule, is the first approved molecule from Amgen’s BiTE immuno-oncology platform, and the first and only therapy to receive regulatory approval globally for the treatment of MRD.

About the BLAST Study
The BLAST study is the largest prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, single-arm, Phase 2 study that evaluated the efficacy, safety and tolerability of BLINCYTO in adult patients with MRD-positive B-cell precursor ALL in complete hematologic remission after three or more cycles of intensive chemotherapy. Patients received continuous intravenous infusion of BLINCYTO 15 μg/m2/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment and could undergo HSCT at any time after the first cycle, if eligible. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). Results from the primary analysis BLAST study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in 2015 and published in Blood in 2018. Additional secondary endpoints included incidence and severity of adverse events, OS, time to hematological remission and duration of complete MRD response. Survival follow-up visits for assessment of hematological RFS and OS took place every six months until completion of a five-year period after treatment start with BLINCYTO. Three-year OS data results from the BLAST study were also featured in an oral presentation during the 60th ASH (Free ASH Whitepaper) Annual Meeting & Exposition on Dec. 3, 2018.

About ALL and MRD
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.11,12 Poor outcomes have been observed in patients who achieve first or second complete hematologic remission but are persistently MRD-positive, which currently remains detectable at the molecular level after treatment.1,8 For more information about MRD, please visit AmgenOncology.com.

About BiTE Technology
BiTE (Bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage patients’ own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells with the goal of eliminating detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has the goal of off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing more than a dozen BiTE molecules across a broad range of solid and hematologic malignancies, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell BiTE (bispecific T cell engager), immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration in 2014, and carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. In the U.S., BLINCYTO is also approved for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent. This indication is approved under accelerated approval based on MRD response rate and hematological RFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In the European Union (EU), BLINCYTO is indicated for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor ALL and for the treatment of Ph- CD19-positive B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.

BLINCYTO is now approved in 57 countries, including all member countries in the EU and European Economic Area, Canada, Japan and Australia.

Important EU BLINCYTO (blinatumomab) Safety Information

This product is subject to additional monitoring in the EU. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in clinical studies of patients with B-precursor ALL (N = 843). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumour lysis syndrome (0.7%). The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%).

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor patients for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL. Interrupt or discontinue BLINCYTO for evidence of CRS, as outlined in the PI.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment, and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms of neurological toxicity and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia, infusion related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increase (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO.

About Amgen Oncology
Amgen Oncology is searching for and finding answers to incredibly complex questions that will advance care and improve lives for cancer patients and their families. Our research drives us to understand the disease in the context of the patient’s life – not just their cancer journey – so they can take control of their lives.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

At Amgen, we are driven by our commitment to transform the lives of cancer patients and keep them at the center of everything we do.

On June 15, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported positive data from the Phase I/II STARTRK-NG study, evaluating the investigational medicine entrectinib in children and adolescents with recurrent or refractory solid tumors with and without neurotrophic tyrosine receptor kinase (NTRK), ROS1 or anaplastic lymphoma kinase (ALK) gene fusions (Press release, Nerviano Medical Sciences, JUN 15, 2019, View Source [SID1234537210]). The study showed entrectinib shrank tumors (objective response rate; ORR) in all children and adolescents who had NTRK, ROS1 or ALK fusion-positive solid tumors (11 of 11 patients), including two patients achieving a complete response. Of the 11 patients, five patients with primary high-grade tumors in the central nervous system (CNS) had an objective response, including one patient with a complete response. The safety profile of entrectinib was consistent with that seen in previous analyses. Data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Sunday, June 2, 2019, from 8:00 – 8:12 a.m. CDT (Abstract 10009), and was part of today’s official ASCO (Free ASCO Whitepaper) presscast.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are encouraged by the results we have seen with entrectinib in children with pediatric and adolescent cancers, including those with tumors in the brain," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "The STARTRK-NG study underscores the importance of combining comprehensive genomic profiling with targeted therapies and supports our approach to providing people with personalized medicines developed specifically for their type of cancer."

Additional data for entrectinib across different tumor types and patient populations will also be presented at ASCO (Free ASCO Whitepaper), highlighting the company’s unique approach to personalized healthcare through advances in targeted therapies, diagnostics and data analytics:

Initial results from an integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials evaluating the efficacy of entrectinib in adults with solid tumors and CNS metastases will be presented on Saturday, June 1, 2019, in a poster session from 3:00 – 4:30 p.m. CDT (Abstract 3017).
Results from a real-world data study evaluating time-to-treatment discontinuation and progression-free survival as endpoints for comparative efficacy analysis of clinical trials of entrectinib and crizotinib for the treatment of people with ROS1-positive non-small cell lung cancer (NSCLC) will be presented during a poster session on Sunday, June 2, 2019, from 8:00 – 11:00 a.m. CDT (Abstract 9070).
The FDA recently granted Priority Review for entrectinib for both the treatment of pediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or as an initial therapy when there are no acceptable standard therapies, and for the treatment of people with metastatic ROS1-positive NSCLC. These NDAs are based on results from the integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the STARTRK-NG study. The FDA is expected to make a decision on approval by August 18, 2019.

About the STARTRK-NG study

STARTRK-NG is a Phase I/II open-label dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without NTRK, ROS1 or ALK fusions. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using Response Assessment in Neuro-Oncology (RANO) for CNS tumors, Response Evaluation Criteria in Solid Tumors (RECIST), and Curie score (CS) for neuroblastoma. The study enrolled 29 children and adolescents aged 4.9 months through 20 years (median age of 7 years) who had recurrent or refractory solid tumors, and 28 were evaluated for response. Of the 28 children and adolescents evaluated, 11 children were identified to have tumors with NTRK, ROS1 or ALK fusions and one with ALK F1174L-mutated neuroblastoma. A summary of the results are included below.

Complete responses were observed in two patients with tumors harboring NTRK and ALK fusions: one with an NTRK fusion-positive primary CNS tumor and one with an ALK fusion-positive inflammatory myofibroblastic tumor. Another complete response was observed in one neuroblastoma patient with an ALK F1174L mutation.
Partial responses were observed in nine patients, three unconfirmed at the time of the clinical cut-off date, across NTRK, ROS1 and ALK fusion-positive primary CNS (n=4) and extracranial (n=5) solid tumors.
Median duration of therapy for confirmed fusion-positive responders was 10.51 months (3.8 to 17.7 months), and median time to response was 1.89 months (1 to 1.9 months).
The safety profile of entrectinib was consistent with that seen in previous analyses. Treatment-related adverse events were most frequently National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2, leading to discontinuation in 6.9 percent of patients.
About NTRK fusion-positive cancer

Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumor-agnostic, meaning they are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About entrectinib

Entrectinib (RXDX-101) is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions. Entrectinib is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.