Pipeline Review Check

On December 7, 2017 Sandoz, a division of Novartis and the global leader in biosimilars, reported data demonstrating the pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of proposed biosimilar pegfilgrastim as compared to the reference biologic, Neulasta*[1] (Press release, Novartis, DEC 7, 2017, View Source [SID1234522450]). The Phase I study, conducted in healthy volunteers, confirmed that Sandoz biosimilar pegfilgrastim matches the reference biologic in terms of PK, PD, safety and immunogenicity profiles[1]. The data were presented during the 2017 San Antonio Breast Cancer Symposium.

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"At Sandoz, we are committed to developing high-quality biosimilar and generic medicines that provide the oncology community with treatment options to help manage their patients," said Mark Levick, MD PhD, Global Head of Development, Biopharmaceuticals, Sandoz, "And it starts with following the science. These findings add to the totality of evidence supporting our proposed biosimilar pegfilgrastim."

Sandoz biosimilar pegfilgrastim is currently under review by the European Medicines Agency (EMA) for use in the same indication as the reference biologic. Pegfilgrastim is a long-acting formulation of filgrastim (granulocyte colony-stimulating factor [G-CSF])[2].

About the study
Study participants were randomized to receive a single 6 mg subcutaneous injection of biosimilar pegfilgrastim or reference medicine on Day 0[1]. After dosing, study participants underwent a 4-week assessment period followed by a 8-week washout period before crossing over to receive the other medicine, and were assessed for a further 4-weeks[1].

The results demonstrated that Sandoz proposed biosimilar pegfilgrastim matched the reference medicine in the PK and PD comparisons as primary endpoints, in terms of absolute neutrophil count (maximum effect attributed to study medication) (95% CI: [0.97, 1.02]) and maximum serum concentration of study medication after administration (90% CI: [1.03, 1.19])[1]. Secondary endpoints of safety and immunogenicity were comparable between both groups[1].

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved generic or biosimilar products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that, if approved, such generic or biosimilar products will be approved for all indications included in the reference product’s label. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; the particular prescribing preferences of physicians and patients; competition in general, including potential approval of additional generic or biosimilar versions of such products; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; litigation outcomes, including intellectual property disputes or other legal efforts to prevent or limit Sandoz from selling its products; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

Lilly Reports Top-Line Results from CYRAMZA® (ramucirumab) Phase 3 Study in First-Line Advanced Gastric Cancer

On December 5, 2017 Eli Lilly and Company (NYSE: LLY) reported top-line results from its Phase 3 RAINFALL study of CYRAMZA (ramucirumab) in combination with cisplatin and capecitabine or 5-FU (5-fluorouracil) in the first-line treatment of patients with HER2-negative metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (Press release, Eli Lilly, DEC 8, 2017, View Source [SID1234522477]). The trial met its primary endpoint of progression-free survival (PFS) but did not improve overall survival (OS), a secondary endpoint. The results will be submitted for presentation at a future medical meeting.

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The safety profile observed in the RAINFALL study was consistent with what has been previously observed for ramucirumab. Grade ≥3 adverse events occurring at a rate of five percent or greater and that were higher on the ramucirumab-plus-cisplatin-and-capecitabine/5-FU arm compared to the placebo-plus-cisplatin-and-capecitabine/5-FU arm were hypertension, hand-foot syndrome, and fatigue.

"While we hoped that the positive PFS outcome would have translated into an OS benefit, these RAINFALL results highlight the challenges associated with improving outcomes for people with advanced gastric cancer," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "This is underscored by the fact that there have been no major advances over standard chemotherapy in the first-line HER2-negative gastric cancer treatment setting in the last decade."

Dr. Garraway added, "Lilly is deeply committed to patients with this aggressive disease, and CYRAMZA remains a standard of care in the second-line treatment paradigm for advanced gastric cancer patients around the world. We thank the patients, their caregivers and investigators for their support of and participation in the RAINFALL study."

The company does not intend to seek regulatory approval based on the results of the RAINFALL study. The outcome of RAINFALL does not have any impact on current ramucirumab approvals.

After becoming the first FDA-approved agent to treat advanced gastric cancer after prior chemotherapy in 2014 based on two pivotal Phase 3 studies, ramucirumab is now a standard of care in this setting around the world. This is supported by global and local treatment guidelines, including NCCN, JGCA and ESMO (Free ESMO Whitepaper).

Overall, there have been six positive Phase 3 trials of ramucirumab to date. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer – three of the world’s leading causes of cancer-related death. An ongoing Phase 3 trial in advanced urothelial carcinoma has also met its primary endpoint of PFS; those initial data were presented at the ESMO (Free ESMO Whitepaper) 2017 Congress and OS data are expected in mid-2018. Two other ongoing Phase 3 studies of ramucirumab – in hepatocellular carcinoma and EGFR-positive non-small cell lung cancer – are ongoing, with expected data readouts in 2018.

Notes to Editors

About RAINFALL
RAINFALL is a global, randomized, double-blinded, placebo-controlled Phase 3 study of ramucirumab in combination with cisplatin and capecitabine as a first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Study participants unable to take capecitabine (tablets) were given 5-fluorouracil (5-FU).

Initiated in 2015, the study enrolled 645 patients across 19 countries in North America, Asia (Japan), Europe and Latin America. The primary endpoint of the RAINFALL trial is progression-free survival and key secondary endpoints include: overall survival; objective response rate; and safety.

About Gastric Cancer
Gastric cancer, also known as stomach cancer, is a major global health problem. Globally, it is the fifth most common cancer in the world, with one million new cases annually.1 Gastric cancer originates in the stomach. Cancer cells typically develop slowly and symptoms often do not appear until the disease is advanced and has already spread to other organs such as the liver, lungs and bones.2,3 Stomach cancer is the third leading cause of cancer deaths in the world, resulting in 723,000 deaths each year.1 The five-year survival rate for stomach cancer is 31 percent and five percent for advanced cases.4

Stomach cancer is much more common in the Far East than in the Western world.1 In the U.S., it is estimated that approximately 28,000 people will be diagnosed with stomach cancer and nearly 11,000 people will die from this type of cancer in 2017.5 In Japan, the incidence of stomach cancer is high. Of all cancers in Japan, stomach cancer is the second most common and it is the second-leading cause of cancer-related deaths, affecting approximately 108,000 people and killing approximately 52,000.

About Angiogenesis and VEGF Protein
Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.

Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from linking to the blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Ramucirumab is being investigated in a broad global development program that has enrolled more than 10,000 patients across more than 70 trials worldwide. There are several studies underway or planned to investigate ramucirumab as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types.

Ramucirumab is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. Ramucirumab inhibited angiogenesis in an in vivo animal model.

INDICATIONS

Gastric Cancer
CYRAMZA, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND
IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal
hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently
discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal
perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who
experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting
the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound
healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient
develops wound healing complications.
Warnings and Precautions

Hemorrhage

In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3. In study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.
Arterial Thromboembolic Events (ATEs)

Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.
Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
Infusion-Related Reactions (IRRs)

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.
Gastrointestinal Perforations

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for placebo plus docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.
Impaired Wound Healing

CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.
Clinical Deterioration in Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported at a rate of < 0.1% in clinical studies with CYRAMZA. Discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome

In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to < 2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels > 3 g over 24 hours or in the setting of nephrotic syndrome.
Thyroid Dysfunction

Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients.
Embryofetal Toxicity

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.
Most Common Adverse Reactions—Single Agent

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).
The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA-treated patients vs placebo in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).
Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.
Most Common Adverse Reactions—Combination With Paclitaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).
The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).
Most Common Adverse Reactions—Combination With Docetaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; < 1% vs < 1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs < 1%), thrombocytopenia (13% vs 5%; 3% vs < 1%), lacrimation increased (13% vs 5%; < 1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
In patients ≥65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA in study 3 were infusion-related reaction (0.5%) and epistaxis (0.3%).
For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).
Most Common Adverse Reactions—Combination With FOLFIRI

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus FOLFIRI and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs < 1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; < 1% vs 0%), proteinuria (17% vs 5%; 3% vs < 1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs < 1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors.
The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).
Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH was observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.
Drug Interactions

No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38.
Use in Specific Populations

Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.
Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.
Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.
Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing.

RB-P-HCP ISI 16FEB2017

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.

VistaGen Therapeutics Expands Stem Cell Patent Portfolio with New U.S. Patent on Methods for Producing Blood Cells, Platelets and Bone Marrow Stem Cells with Potential to Treat Autoimmune Disorders and Cancer

On December 8, 2017 VistaGen Therapeutics Inc. (NASDAQ: VTGN), a clinical-stage biopharmaceutical company focused on developing new generation medicines for depression and other central nervous system (CNS) disorders, reported that the U.S. Patent and Trademark Office (USPTO) has issued U.S. Patent No. 9,834,754 related to methods for producing, from human pluripotent stem cells (hPSCs), hematopoietic precursor stem cells, which are stem cells that give rise to all of the blood cells and most of the bone marrow cells in the body (Press release, VistaGen Therapeutics, DEC 8, 2017, View Source [SID1234522475]). VistaGen holds an exclusive license to this patent from the University Health Network (UHN).

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The technology covered by the issued U.S. patent has the potential to impact both direct and supportive therapy for autoimmune disorders and cancer, with CAR-T cell applications, and foundational technology which may provide approaches for producing bone marrow stem cells for bone marrow transfusions.

Dr. Gordon Keller, Director of the McEwen Centre for Regenerative Medicine in Toronto, one of the world’s leading centers for stem cell and regenerative medicine research and part of the University Health Network (UHN), discovered the stem cell technology covered by this patent.

Talazoparib Significantly Extends Progression-Free Survival in Phase 3 EMBRACA Trial of Patients with Metastatic Breast Cancer

On December 8, 2017 Pfizer Inc. (NYSE:PFE) reported that the Phase 3 EMBRACA trial in patients with germline (inherited) BRCA1/2-positive (gBRCA+) locally advanced and/or metastatic breast cancer (MBC) demonstrated superior progression-free survival (PFS) in patients treated with talazoparib, compared to patients who received physician’s choice standard of care chemotherapy (Press release, Pfizer, DEC 8, 2017, View Source [SID1234522470]). Median PFS was 8.6 months (95% CI: 7.2, 9.3) for patients treated with talazoparib and 5.6 months (95% CI: 4.2, 6.7) for those treated with chemotherapy [HR: 0.54 (95% CI: 0.41, 0.71), p<0.0001]. This represents a 46% reduction in the risk of disease progression. In addition, the proportion of patients achieving a complete or partial response (objective response rate) in the talazoparib group was more than twice that of the control arm (62.6% for talazoparib vs. 27.2% for chemotherapy [OR: 4.99 (95% CI: 2.9-8.8), p<0.0001]). Talazoparib is an investigational, oral, dual-mechanism poly ADP ribose polymerase (PARP) inhibitor that is taken once daily. The data will be presented today as an oral presentation at the 2017 San Antonio Breast Cancer Symposium.

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"Patients with germline BRCA-positive breast cancer are typically diagnosed at a younger age than those with nonhereditary breast cancer, and there are no therapies specifically approved for them outside of current standard of care therapies," said Jennifer Litton, MD, lead investigator and associate professor in the breast medical oncology department of The University of Texas MD Anderson Cancer Center. "EMBRACA supports the potential of talazoparib to give these patients additional time without disease progression, compared to chemotherapy."

Pfizer will be discussing these data from EMBRACA, the largest Phase 3 trial performed to date of a PARP inhibitor in patients with gBRCA+ MBC, with worldwide health authorities. There are currently limited treatment options for patients with this molecular subtype.

"Results from the EMBRACA study are very encouraging and a great example of precision drug development. By enrolling only patients with germline BRCA-positive metastatic breast cancer, treatment with talazoparib reduced the risk of disease worsening by nearly half, compared with current standard of care chemotherapy. This includes heavily pretreated patients, those with hormone receptor-positive disease and those who had a history of brain metastases," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development.

The results of the EMBRACA trial also showed that the PFS benefit with talazoparib was consistent across prespecified subgroups, including hormone receptor (HR) status (triple negative [TNBC] or hormone receptor-positive [HR+]), BRCA mutation (1 or 2), prior chemotherapy (whether patients had none or up to three chemotherapies before talazoparib), and history of central nervous system (CNS) metastases. There also was a statistically significant delay in the time to clinically meaningful deterioration in global health status/quality of life with talazoparib versus chemotherapy (HR 0.38 [95% CI 0.26-0.55], p<0.0001), as measured by the EORTC QLQ-C30, a cancer-specific, patient-reported quality of life questionnaire.

Adverse events (AEs) observed with talazoparib were consistent with findings from previous trials. The most common AEs observed with talazoparib (any grade in at least 15% of patients) were anemia (52.8%), fatigue (50.3%), nausea (48.6%), neutropenia (34.6%), headache (32.5%), thrombocytopenia (26.9%), alopecia (25.2%), vomiting (24.8%), diarrhea (22%), constipation (22%), decreased appetite (21.3%), back pain (21%) and dyspnea (17.5%). The incidence of serious AEs was 31.8% in the talazoparib arm and 29.4% in the chemotherapy arm. Discontinuations due to AEs occurred in 7.7% of patients in the talazoparib arm and 9.5% of patients in the chemotherapy arm.

In addition to EMBRACA, talazoparib demonstrated promising activity in patients with gBRCA+ MBC in the Phase 2 ABRAZO trial. Patients in ABRAZO had either been previously treated with platinum-based chemotherapy or were heavily pretreated with at least three prior lines of non-platinum-based chemotherapy.1

About EMBRACA

EMBRACA is a global Phase 3, open-label, randomized, parallel, 2-arm trial of talazoparib versus protocol-specific physician’s choice of standard single-agent chemotherapy (PCT [capecitabine, eribulin, gemcitabine or vinorelbine]) in gBRCA+ patients who may have received up to three prior cytotoxic chemotherapy regimens for locally advanced and/or metastatic breast cancer. Patients enrolled had a diagnosis of TNBC or HR+/HER2-negative breast cancer. The trial randomized (2:1) 431 patients to receive talazoparib (1.0 mg) once daily or PCT.

About Germline BRCA1/2-Positive Breast Cancer

BRCA1 and BRCA2 are human genes that produce proteins involved in DNA repair. When either of these genes is altered or mutated, DNA repair may not progress correctly. This can lead to the development of certain types of cancer such as breast cancer.2,3,4 BRCA mutations can be hereditary (germline) or occur spontaneously (sporadic).2 Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers.5,6 Up to 65 percent of women who inherit a BRCA mutation will develop breast cancer by age 70.2 Epidemiologic studies indicate that individuals with gBRCA+ status are diagnosed with breast cancer at a median age of 40-45, which is approximately 20 years younger than the overall breast cancer population.7

About Talazoparib

Talazoparib is an investigational anti-cancer compound called a PARP (poly ADP ribose polymerase) inhibitor. Preclinical studies suggest that talazoparib is highly potent and has a dual mechanism of action, with the potential to induce tumor cell death by blocking PARP enzyme activity and trapping PARP on the sites of DNA damage. Talazoparib is currently being evaluated in advanced gBRCA+ breast cancer as well as other cancer types with deficiencies in DNA damage repair (DDR). It is also being studied in DDR-deficient prostate cancer and in combination with immunotherapy in various tumor types. Talazoparib has not been approved by any regulatory authorities for the treatment of any disease.

Dr. Richard Chen, Chief Scientific Officer, Personalis, Inc. to Present Data and Discuss Tumor Immuno-genomics and Personalized Vaccines Solutions at 2017 Neoantigen Summit

On December 8, 2017 Personalis, Inc., a leading provider of advanced genomic sequencing and analytics to support the development of personalized cancer vaccines and other next-generation cancer immunotherapies, reported that the company’s Chief Scientific Officer (CSO), Dr. Richard Chen, will be speaking at the upcoming Neoantigen Summit, being held in Boston, MA from November 14-16, 2017 (Press release, Personalis, DEC 8, 2017, View Source [SID1234522469]).

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The presentation entitled, "From Sample to Neoantigens for Vaccines: Key Challenges and Solutions" will cover topics including:

cfDNA Neoantigens: dealing with tumor heterogeneity
Improving neoantigen identification
Elaborating tumor microenvironment (TME), immuno-modulators and vaccine response biomarkers
Overcoming poor sample quality and quantity for NGS sequencing
Addressing sequencing coverage gaps that can harbor neoantigens
Validation and regulatory issues on the way to commercialization
Central to this presentation will be Personalis’ ACE ImmunoID Platform. The platform enables the comprehensive characterization of a tumor’s immuno-genomics including neoantigens, the tumor microenvironment, HLA, immuno-modulators and mechanisms of tumor escape to aid rational vaccine design.

"We are continuing to innovate to help our customers build safe, effective, and scalable personalized cancer vaccines. In this talk we will discuss how our ACE ImmunoID platform has been designed to overcome key challenges in personalized cancer vaccine development process starting from a tumor sample to neoantigen identification and rational vaccine design," said Dr. Richard Chen, CSO at Personalis.

Personalis will also be exhibiting during the Neoantigen Summit. Representatives will be available to answer questions about the company’s neoantigen identification and immuno-genomics capabilities.