On November 28, 2017 Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE) reported that the Phase III JAVELIN Gastric 300 trial did not meet its primary endpoint of superior overall survival (OS) with single-agent avelumab* compared with physician’s choice of chemotherapy (Press release, Pfizer, NOV 28, 2017, View Source [SID1234522288]). The trial investigated avelumab as a third-line treatment for unresectable, recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma patients whose disease progressed following two prior therapeutic regimens, regardless of programmed death ligand-1 (PD-L1) expression. The safety profile of avelumab was consistent with that observed in the overall JAVELIN clinical development program.

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"Gastric cancer in the third-line setting is a particularly hard-to-treat and heterogeneous disease, and importantly, this was the first trial conducted with a checkpoint inhibitor compared to an active chemotherapy comparator rather than placebo in a global patient population," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany, which operates as EMD Serono in the US and Canada. "Data from this study will provide valuable information for physicians treating this late stage disease. We remain committed to our ongoing gastric cancer program with avelumab including the JAVELIN Gastric 100 study in the first-line switch maintenance setting."

"Gastric cancer is a leading cause of cancer death globally with clear unmet needs, and the results provide important insights as we continue to investigate the role of avelumab for the treatment of gastric cancer," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "With approvals for two cancers in 2017, our companies have made tremendous progress with avelumab on behalf of patients this year, and we are confident that our broad clinical development program in both monotherapy and combinations across a range of cancers will continue to bring new potential treatment options to patients."

The JAVELIN Gastric 300 data will be further examined in an effort to better understand the results and will also be submitted for presentation at an upcoming medical congress. The outcome of JAVELIN Gastric 300 does not have any impact on current avelumab approvals.

JAVELIN Gastric 300 is a Phase III, multicenter, international, randomized, open-label clinical trial investigating avelumab plus best supportive care versus physician’s choice of protocol-specified chemotherapy (paclitaxel or irinotecan monotherapy) plus best supportive care in patients with unresectable, recurrent or metastatic gastric or GEJ adenocarcinoma whose disease has progressed following two prior therapeutic regimens. The trial enrolled 371 patients from 147 sites in Asia, Australia, Europe, North America and South America. The primary endpoint was OS.

The avelumab gastric clinical development program also includes JAVELIN Gastric 100, a multicenter, randomized, open-label Phase III study evaluating avelumab as first-line maintenance therapy following induction chemotherapy in unresectable, locally advanced or metastatic gastric or GEJ cancer. The trial will continue as planned.

*Avelumab is under clinical investigation for treatment of gastric/GEJ cancer and has not been demonstrated to be safe and effective for this indication. There is no guarantee that avelumab will be approved for gastric/GEJ cancer by any health authority worldwide.

About Gastric/Gastroesophageal Junction Cancer
Globally, gastric cancer is the fifth most common cancer but the third most common cause of cancer death.[1],[2] In 2012, there were approximately 950,000 new cases and 723,000 deaths worldwide.[3] Of these cancers, 90 to 95 percent were adenocarcinomas.[4] Incidence varies by country, with higher rates seen in Central/Eastern Europe, Eastern Asia and South America.[5] Survival in advanced disease is poor and generally less than one year.[6] Globally, there is no recommended therapeutic approach for patients who progress after two lines of therapy for recurrent or metastatic gastric cancer.

About Avelumab
Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.[7]-[9] Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[9]-[11] In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US
The FDA granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information from the US FDA Approved Label
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Please see full US Prescribing Information and Medication Guide available at View Source

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US
Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance is jointly developing and commercializing avelumab and advancing Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab, as a monotherapy, as well as combination regimens, and is striving to find new ways to treat cancer.

All Merck KGaA, Darmstadt, Germany, Press Releases are distributed by e-mail at the same time they become available on the Merck KGaA, Darmstadt, Germany, Website. Please go to View Source to register online, change your selection or discontinue this service.

On November 28, 2017 CytomX Therapeutics, Inc. (Nasdaq:CTMX) reported that Bristol-Myers Squibb has received acceptance of the Investigational New Drug application (IND) from the U.S. Food and Drug Administration (FDA) for a CTLA-4-directed Probody therapeutic (Press release, CytomX Therapeutics, NOV 28, 2017, View Source;p=RssLanding&cat=news&id=2318842 [SID1234522282]). CTLA-4, the clinically validated target of the Bristol-Myers Squibb checkpoint inhibitor Yervoy (ipilimumab), is the first target to advance into the clinic under the companies’ strategic collaboration formed in May 2014. The IND acceptance results in a $10 million milestone payment to CytomX.

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"Immune checkpoint inhibitors are making a profound impact in the treatment of people with cancer," said Sean McCarthy, D.Phil., president and chief executive officer of CytomX Therapeutics. "By localizing antibody binding and therapeutic activity to the tumor microenvironment, our goal with Probody therapeutics is to deliver the same or potentially greater potency as first-generation checkpoint inhibitors, while reducing unwanted side effects. We are excited to see the CTLA-4 Probody advancing into the clinic and look forward to additional progress in our foundational alliance with Bristol-Myers Squibb."

About the Collaboration
In March 2017, Bristol-Myers Squibb and CytomX Therapeutics expanded their 2014 worldwide collaboration to discover, develop and commercialize novel therapies using CytomX‘s proprietary Probody platform taking total upfront payments to CytomX to $275 million. The collaboration provides Bristol-Myers Squibb with the opportunity to select up to ten oncology targets and two non-oncology targets. To date, Bristol-Myers Squibb has selected five oncology targets under the collaboration, including CTLA-4. CytomX is eligible to receive additional preclinical payments and development, regulatory and sales milestone payments totaling up to $4.7 billion across all 12 collaboration targets, as well as tiered royalties from mid-single digit to low-double digits on net sales of each product commercialized by Bristol-Myers Squibb.

On November 28, 2017 Purdue Pharma (Canada) reported that AKYNZEO (netupitant/palonosetron hydrochloride) capsules are now available to Canadian cancer patients for the prevention of chemotherapy-induced nausea and vomiting (CINV) (Press release, Purdue Pharma, NOV 28, 2017, View Source [SID1234522278]).

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AKYNZEO (netupitant/palonosetron hydrochloride) capsules received Notice of Compliance (NOC) from Health Canada on September 28, 2017 and is the first approved fixed dose combination oral agent that targets two critical signalling pathways associated with CINV by combining netupitant, an NK1 receptor antagonist, and palonosetron, a 5-HT3 receptor antagonist, in a single capsule for the prevention of CINV[i].

The effects of chemotherapy can vary from patient to patient and CINV is often a common side effect that can occur during a patient’s chemotherapy treatment. If left uncontrolled, CINV may lead to dehydration, electrolyte imbalances, loss of appetite, fatigue and a reduced quality of life[ii].

David Pidduck, President and CEO, Purdue Pharma (Canada), commented: "Cancer, an upsetting and often overwhelming diagnosis for patients and their families, requires safe and effective therapies that not only attempt to save patient lives, but also increase their quality of life. We are proud to bring AKYNZEO to market in Canada. We believe it is an important and novel treatment in cancer supportive care that will offer physicians and their patients a new option to help mitigate the distressing effects of chemotherapy-induced nausea and vomiting."

Purdue Pharma (Canada) has been granted from Helsinn Healthcare S.A. (hereafter "Helsinn"), a Swiss Group focused on building quality cancer care, the exclusive right to register, market, promote, distribute and sell AKYNZEO in Canada. Helsinn will retain clinical development activities, as well as the manufacture and supply of AKYNZEO to Purdue Pharma (Canada).

– END –

About AKYNZEO

AKYNZEO (netupitant/palonosetron hydrochloride), in combination with dexamethasone, is indicated for once per-cycle treatment in adult patients for the prevention of acute delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy as well as for the prevention of acute nausea and vomiting associated with moderately emetogenic cancer therapy that is uncontrolled by a 5-HT3 receptor antagonist alone. It is the first approved fixed dose oral combination agent that targets two critical signaling pathways associated with CINV by combining netupitant, an NK1 receptor antagonist, and palonosetron, a 5-HT3 receptor antagonist, in a single capsule for the prevention of CINV. The most common adverse events reported with AKYNZEO in clinical trials were headache (3.6%), constipation (3.0%) and fatigue (1.2%)i.

AKYNZEO has been recommended under the antiemetic guidelines of the National Comprehensive Cancer Network (NCCN), an alliance of the world’s leading cancer centers, both in Highly Emetogenic Chemotherapy (HEC) and Moderately Emetogenic Chemotherapy (MEC). It is also recommended in the Clinical Practice Guidelines from the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) as one of the therapeutic options to facilitate the application of antiemetic standard of care for patients receiving HEC regimens by preventing nausea and vomiting in both the acute and delayed phases following chemotherapy treatment.

Purdue Pharma (Canada) will be the sole distributor for AKYNZEO in Canada under terms of the current commercialization contract with Helsinn Group. AKYNZEO is already approved in 47 countries including the US, EU, Switzerland and Australia.

Please consult the Product Monograph posted at www.purdue.ca for complete administration and safety information.

On November 28, 2017 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a clinical stage biotechnology company focused on developing targeted cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that Eurofins Lancaster Laboratories, a leading Contract Manufacturing Organization that PharmaCyte selected to prepare its Master Cell Bank (MCB), has successfully completed its independent growth evaluation of the cells that PharmaCyte will use in its Cell-in-a-Box-based pancreatic cancer therapy (Press release, PharmaCyte Biotech, NOV 28, 2017, View Source [SID1234522277]). This is a significant step in preparing for PharmaCyte’s pancreatic cancer clinical trial.

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Commenting on the cell testing, PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said, "The satisfactory completion of this important work by Eurofins is good news. Now the door is open for Eurofins to grow the cells that will be necessary to populate our Master Cell Bank. We have authorized Eurofins to begin production of the MCB. Once that is completed, the MCB will be shipped to Austrianova for encapsulation into what will ultimately become our clinical trial product."

This vital step in the overall product development process has been achieved using the optimal cell culture medium, which has only recently become available. The growth evaluation of the cells is a necessary pre-step to produce the MCB, which is required to comply with FDA guidelines. During the process, Eurofins independently confirmed Austrianova’s selection of cell culture medium for optimal cell growth as well as the growth kinetics of the cells themselves. The cells from the MCB will go on to become the "engine" of the Cell-in-a-Box encapsulated cell product for the treatment of pancreatic cancer.

"We are pleased to be working with Eurofins, who has been both professional and interactive, during this process leading up to what will be the creation of PharmaCyte’s Master Cell Bank of the cells that make up the Cell-in-a-Box encapsulated cell product for the treatment of pancreatic cancer. This step certainly clears the way to produce the MCB," stated Prof. Walter H. Günzburg, Chairman of the Board and Chief Development Officer of Austrianova and PharmaCyte’s Chief Scientific Officer.

On November 28, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported that VARUBI (rolapitant) IV, is now available in the United States (Press release, TESARO, NOV 28, 2017, View Source [SID1234522276]). The U.S. Food and Drug Administration (FDA) approved VARUBI injectable emulsion on October 25, 2017, for use in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.

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"The U.S. launch of VARUBI IV reinforces TESARO’s ongoing commitment to developing and commercializing therapies for people facing cancer," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "VARUBI IV offers healthcare providers an easy-to-use option for the prevention of delayed CINV. The ready-to-use, single-dose vial does not require saline and eliminates the need for reconstitution and mixing, and can be easily adopted into existing practice patterns. We are confident that we have the right team and strategy in place to ensure this product is made available in the clinic or hospital to all patients in need."

VARUBI is a highly selective and potent antagonist of human substance P/neurokinin 1 (NK-1) receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV). With a long plasma half-life of approximately seven days, a single dose of VARUBI, as part of an antiemetic regimen, significantly improved complete response (CR) rates in the delayed phase of CINV. Results from three Phase 3 trials of VARUBI oral tablets demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens. As a result, patients may be protected from nausea and vomiting during their most vulnerable time, in the days following chemotherapy. In addition, patients who received VARUBI reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. Results from a bioequivalence trial demonstrated comparability of the IV and oral formulations of VARUBI.

VARUBI IV is supplied in ready-to-use vials and does not require refrigerated storage or mixing. As a result, utilization in busy chemotherapy clinics is straightforward and easily adopted into existing practice patterns for administration of antiemetic regimens associated with emetogenic chemotherapy. VARUBI IV is to be administered up to two hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, and VARUBI is the first intravenously administered NK-1 receptor antagonist approved by the FDA that does not contain polysorbate 80.

"As an oncology nurse, I see the pressing need for a product like VARUBI IV for our patients," said Robin Wachsman, RN, BSN, CCRN, OCN, BCN, Director of Women’s Oncology Services, Baptist Medical Group, Memphis, TN. "With a polysorbate 80-free formulation and a long half-life, provided in a ready-to-use vial that does not require refrigeration, VARUBI IV will be a very welcomed addition to our anti-emetic regimen."

"Severe shortages of intravenous fluids continue to plague practices across the country," said Erin R. Fox, PharmD, BCPS, Senior Director, Drug Information at University of Utah Health. "Medications that are available in ready-to-use vials offer organizations a potential option to overcome this challenge and meet the needs of their patients."

The full prescribing information for VARUBI IV will be available at www.VarubiRx.com.

TOGETHER with TESARO
TOGETHER with TESARO is a patient resource program dedicated to supporting people living with cancer. The program assists with access issues, so that patients with cancer can be free to focus on treatment goals and simply living life. It provides a full suite of services to meet each patient’s needs and individual experience. A team of access and affordability experts is available to help oncology practices and patients gain access to the medication they require. TOGETHER with TESARO will continue to evolve and grow to meet provider and patient needs.

For more information, please visit www.togetherwithtesaro.com or call 1-844-2TESARO (1-844-283-7276).

About Chemotherapy-Induced Nausea and Vomiting (CINV)
Chemotherapy-induced nausea and vomiting is a debilitating, yet often preventable side effect of chemotherapy. Up to 50% of patients undergoing highly or moderately emetogenic chemotherapy experience delayed CINV (25 to 120 hours post chemotherapy) — even when prescribed a 5-HT3 receptor antagonist and corticosteroid. Blocking both 5-HT3 and NK-1 receptors has been shown to offer better control of nausea and vomiting than inhibiting 5-HT3 receptors alone. Adding a single dose of VARUBI to an antiemetic regimen, including a 5-HT3 receptor antagonist and corticosteroid, further improves prevention of CINV in the delayed phase following chemotherapy.

About the VARUBI (Rolapitant) Clinical Program
The superior efficacy of VARUBI was established in multiple global randomized, well-controlled, double-blinded clinical trials that enrolled more than 2,500 patients. VARUBI, when administered in combination with a 5-HT3 receptor antagonist and dexamethasone, was superior to a 5-HT3 receptor antagonist and dexamethasone alone in preventing delayed CINV in patients receiving either moderately or highly emetogenic chemotherapy.

The clinical profile of VARUBI in cisplatin-based highly emetogenic chemotherapy (HEC) was confirmed in two identical Phase 3 studies: HEC1 and HEC2. Both trials met their primary endpoint of complete response (CR), and demonstrated statistical superiority of rolapitant (180 mg oral) compared to active control (5-HT3 receptor antagonist plus dexamethasone) in the delayed phase (25–120 hours) of CINV. In HEC1, 264 patients received rolapitant and 262 received active control. The proportion of patients achieving a CR was 72.7% vs. 58.4% (p=<0.001). In HEC2, 271 patients received rolapitant and 273 received active control. The proportion of patients achieving a CR was 70.1% vs. 61.9% (p=0.043). The most common adverse reactions (≥3%) among patients receiving cisplatin-based chemotherapy were neutropenia (9% VARUBI vs. 8% control), hiccups (5% vs. 4%), and abdominal pain (3% vs. 2%).

A Phase 3 trial was also conducted to evaluate rolapitant (180 mg oral) compared to active control in 1,332 patients receiving moderately emetogenic chemotherapy regimens, including anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. This trial met its primary endpoint of CR, and demonstrated statistical superiority of rolapitant compared to active control (5-HT3 receptor antagonist plus dexamethasone) in the delayed phase of CINV. The proportion of patients achieving a CR was 71.3% vs 61.6% (p=<0.001). The most common adverse reactions (≥3%) among patients receiving these chemotherapies were decreased appetite (9% VARUBI vs. 7% control), neutropenia (7% vs. 6%), dizziness (6% vs. 4%), dyspepsia (4% vs. 2%), urinary tract infection (4% vs. 3%), stomatitis (4% vs. 2%), and anemia (3% vs. 2%).

Primary data from the three Phase 3 studies have been published in Lancet Oncology, the analysis of the non-AC MEC population was presented at the 2015 annual meeting of the Multinational Association for Supportive Care in Cancer, and commentary has been provided in Nature Reviews Clinical Oncology.

In addition to the Phase 3 program, a bioequivalence study was conducted in healthy volunteers to compare the exposure of the 166.5 milligram dose of IV rolapitant to the exposure of a 180 milligram dose of oral rolapitant. Study participants were randomized to receive a single dose of either 166.5 milligrams of intravenous rolapitant administered over 30 minutes (n=61) or 180 milligrams of oral rolapitant (n=62). The primary endpoint of this pivotal study was bioequivalence, defined by estimating whether the 90% confidence intervals (CI) for the ratio of the area under the curves (AUCs) of the two formulations are entirely included within the acceptance range of 80% to 125%. Safety and tolerability were also assessed for both formulations. The safety profile was consistent with previous clinical trials with oral rolapitant, except for infusion-site reactions observed with the IV formulation.

VARUBI Additional Safety Information
VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index, such as thioridazine and pimozide. VARUBI can significantly increase the plasma concentrations of thioridazine and pimozide, which may result in QT prolongation and Torsades de Pointes.

VARUBI is a moderate inhibitor of CYP2D6 and significantly increases the plasma concentrations of CYP2D6 substrates for at least 28 days, with inhibitory effects expected to persist for an unknown duration. Monitor for adverse reactions when VARUBI is coadministered with CYP2D6 substrates without a narrow therapeutic index (avoid coadministration with CYP2D6 substrates with a narrow therapeutic index, thioridazine and pimozide; see Contraindication).

In clinical trials, the most common adverse reactions reported were neutropenia, hiccups,
decreased appetite and dizziness. IV administration of VARUBI was also associated with infusion-related symptoms (e.g., sensation of warmth, abdominal pain, dizziness, and paresthesia).

Avoid use of VARUBI in patients who require chronic administration of strong CYP3A4 inducers (e.g., rifampin), as significantly reduced plasma concentrations of VARUBI can decrease the efficacy of VARUBI.

VARUBI, administered as an IV or oral medication, is not an inhibitor of CYP3A4 and no dose adjustment is required for co-administered CYP3A4 substrates, including dexamethasone.

VARUBI IV did not inhibit breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). VARUBI given as an oral dose is an inhibitor of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Increased plasma concentrations of BCRP substrates (e.g., methotrexate, topotecan, or irinotecan) and P-gp substrates (e.g., digoxin) with a narrow therapeutic index may result in potential adverse reactions. Monitor digoxin concentrations with concomitant use of VARUBI, and adjust the dosage as needed to maintain therapeutic concentrations.

Monitor INR and prothrombin time and adjust the dosage of warfarin, as needed, to maintain target INR.

VARUBI is available by prescription only. Please see full prescribing information, including additional important safety information, available at www.varubirx.com.