On November 16, 2015 Genmab A/S (OMX: GEN) reported that the U.S. Food and Drug Administration (FDA) has approved DARZALEX (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMiD (Press release, Genmab, NOV 16, 2015, View Source [SID:1234508262]).1 This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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DARZALEX is the first human CD38 monoclonal antibody (mAb) approved anywhere in the world and the first therapeutic antibody ever approved to treat multiple myeloma. The approval comes just two months after the Biologics License Application (BLA) was accepted for Priority Review by the FDA in September 2015. In May 2013, DARZALEX received Breakthrough Therapy Designation from the FDA for the indication approved today. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize DARZALEX.

Genmab will receive a milestone payment from Janssen of USD 45 million associated with the first commercial sale of the product in the United States. As this is expected to occur quickly after this approval, Genmab is improving its financial guidance for the year. See the Outlook section of this announcement for more information.

"This is an important day for patients in the United States with double refractory multiple myeloma, who will now have DARZALEX as a new treatment option for this incurable disease. The successful approval of DARZALEX is the culmination of many years of hard work, perseverance and collaboration on the part of clinical study investigators, Genmab employees and our colleagues at Janssen. Our work at Genmab is aimed at improving the lives of patients and we are both proud and humbled to have created this first-in-class therapeutic antibody and to have played a key part in the rapid and expansive development of DARZALEX," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The pivotal Phase II MMY2002 (SIRIUS) study showed treatment with single-agent DARZALEX resulted in an overall response rate (ORR) of 29.2 percent in patients who received a median of five prior lines of therapy, including a PI and an IMiD, and is expected to be published in a top medical journal soon. Stringent complete response (sCR) was reported in 2.8 percent of patients, very good partial response (VGPR) was reported in 9.4 percent of patients, and partial response (PR) was reported in 17 percent of patients. For responders, the median duration of response was 7.4 months. At baseline, 97 percent of patients were refractory to their last line of therapy, 95 percent were refractory to both a PI and an IMiD, and 77 percent were refractory to alkylating agents. Sixty-three percent were refractory to pomalidomide, and 50 percent were refractory to carfilzomib.1 Additional data from four other studies, including the Phase I/II GEN501 monotherapy study — published in The New England Journal of Medicine in August 2015 — also support this approval.

The warnings and precautions for DARZALEX include infusion-related reactions (IRRs) and interference with serological testing.2 The most commonly occurring adverse reactions (in 20 percent or more of patients in three pooled clinical studies) were IRRs, fatigue, nausea, back pain, anemia, neutropenia (abnormally low levels of neutrophils, a type of white blood cell) and thrombocytopenia (abnormally low levels of platelets in the blood).1

In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions, none of which were considered drug-related. IRRs were reported in approximately half of all patients treated with DARZALEX, the majority of which (91 percent) occurred during the first infusion. Seven percent of patients had an IRR at more than one infusion. Common (≥5 percent) symptoms of IRRs included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea, and nausea, and these were mild to moderate in severity.1 Severe IRRs (4 percent), including bronchospasm (1.3 percent), hypertension (1.3 percent), and hypoxia, or decreased oxygen supply to the tissues (0.6 percent), were also reported.1

The recommended dose of DARZALEX is 16 mg/kg body weight administered as an intravenous infusion.1 The dosing schedule begins with weekly administration (weeks 1 to 8), and reduces in frequency to every two weeks (weeks 9-24) and ultimately every four weeks (week 25 onwards until disease progression).1

Janssen is currently the global sponsor of all but one clinical study, the Phase I/II GEN501 monotherapy study which was conducted by Genmab. DARZALEX will be commercialized in the U.S. by Janssen Biotech, Inc.

OUTLOOK

Genmab is improving its 2015 financial guidance published on November 3, 2015, due to the inclusion of a daratumumab milestone of USD 45 million associated with the anticipated first commercial sale of the product in the United States, following the FDA approval of daratumumab.

Operating Result

We expect our 2015 revenue to be in the range of DKK 1,025 — 1,100 million, an increase of DKK 300 million compared to DKK 725 — 800 million in the previous guidance. We have increased our projected daratumumab milestones to DKK 540 — 600 million from the prior estimate of DKK 240 — 300 million due to inclusion of an additional milestone of USD 45 million associated with the first commercial sale of the product in the United States. Our projected revenue for 2015 consists primarily of non-cash amortization of deferred revenue totaling DKK 285 million, daratumumab & DuoBody milestones and royalties on sales of Arzerra of DKK 80 million.

We expect our 2015 operating expenses to remain in the range of DKK 550 — 600 million.

The transfer of the ofatumumab collaboration from GSK to Novartis became effective in March 2015. This results in Genmab having no ofatumumab development costs in 2015 and beyond, and no requirement to pay its deferred funding liability totaling DKK 176 million. During the first quarter of 2015, the deferred liability was reversed and the corresponding gain was recognized as other income in our income statement.

As a result of the increased revenue, we now expect the operating income for 2015 to be approximately DKK 625 – 700 million, compared to DKK 325 – 400 million in the previous guidance.

Cash Position

There is no change to the cash position at the end of 2015 of DKK 3,000 – 3,100 million as we expect to receive payment for the additional milestone shortly after year-end. The revised guidance includes proceeds from warrants exercised in 2015.
In addition to factors already mentioned, the estimates above are subject to change due to numerous reasons, including but not limited to achievement of certain milestones associated with our collaboration agreements; the timing and variation of development activities (including activities carried out by our collaboration partners) and related income and costs; Arzerra sales and corresponding royalties to Genmab; fluctuations in the value of our marketable securities; and currency exchange rates. The financial guidance does not include any additional potential proceeds from future warrant exercises and also assumes that no additional significant agreements are entered into during 2015 that could materially affect the results.

About multiple myeloma

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.3 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.4 Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.5 Globally, it is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015.6 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.7 Patients who relapse after treatment with standard therapies, including PIs or IMiDs, have poor prognoses and few treatment options.8

About DARZALEX (daratumumab)

DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMiD.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,9 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,9 antibody-dependent cellular phagocytosis10,11 and antibody-dependent cellular cytotoxicity.1,9

Five Phase III clinical studies with Daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

Access to DARZALEX

DARZALEX will be available for distribution in the U.S. within two weeks following FDA approval. Janssen Biotech offers comprehensive access and support information, resources and services to assist U.S. patients in gaining access to DARZALEX through the Janssen CarePath program. For more information, health care providers or patients can contact: 1-844-55DARZA (1-844-553-2792). Information will also be available at www.DARZALEX.com.
Important Safety Information

CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS

Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis. Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions. Patients with a history of obstructive pulmonary disorders may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and may result in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs may mask detection of antibodies to minor antigens in the patient’s serum1. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions, fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection.
DRUG INTERACTIONS – No drug interaction studies have been performed.

On November 16, 2015 Cellectis S.A. (Alternext: ALCLS; Nasdaq: CLLS), a biopharmaceutical company focused on developing immunotherapies based on gene edited CAR-T cells (UCART), reported its results for the three- and nine-month periods ended September 30, 2015 (Press release, Cellectis, NOV 16, 2015, View Source [SID:1234508258]).

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Recent Corporate Highlights

Cellectis

– Completed a series of three production runs of UCART19, its lead TALEN gene edited product candidate, confirming the implementation of Cellectis’ manufacturing process in GMP conditions.

– Announced that Great Ormond Street Hospital (GOSH) and University College London (UCL) will present, during the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper) in December, data from the first in man clinical use of Cellectis’ TALEN gene edited allogeneic UCART19 product candidate.

– Announced that a poster and an oral presentation on its engineered allogeneic CAR T-cell product candidates, UCARTCS1 and UCART123, will be presented in December during the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper).

Calyxt

– Completion of field trials of its non-regulated status cold storable potato product and high oleic soybean product.

Financial Results
Since Cellectis did not have consolidated financial statements for individual quarters during fiscal year 2014, no comparative quarterly 2014 figures will be presented during 2015. Cellectis will publish quarter-over-quarter comparative figures starting with the first quarter of 2016.

Cellectis’ consolidated financial statements have been prepared in accordance with International Financial Reporting Standards, or IFRS, as issued by the International Accounting Standards Board ("GAAP").

Third Quarter and First Nine Months 2015 Financial Results

Cash Position: As of September 30, 2015 Cellectis had €279.4 million in cash and cash equivalents compared to €112.3 million as of December 31, 2014. This increase is primarily attributable to the $228 million of proceeds from Cellectis’ U.S. initial public offering in March 2015, partly offset by €22 million of cash flows used in operating activity, €3.3 million of acquisitions of tangible assets, and the repurchase for €3.5 million of 25% of the minority shares of Cellectis Bioresearch S.A.S, in each case during the first nine months of 2015.

Revenues and Other Income: Total revenues and other income were €10.0 million for the third quarter of 2015 and primarily comprised €7.1 million of collaboration revenues, €0.5 million of license revenues, €1.0 million of grant revenues and €1.5 million of research tax credit revenues. Total revenues and other income were €27.2 million for the nine-month period ended September 30, 2015 and primarily comprised €21.7 million of collaboration revenues, €1.6 million of license revenues, €1.1 million of grant revenues and €2.8 million of research tax credit revenues.

Total Operating Expenses and Other Operating Income: Total operating expenses and other operating income for the third quarter of 2015 were €23.4 million, which includes non-cash stock-based compensation expenses of €9.5 million. Total operating expenses and other operating income for the nine-month period ended September 30, 2015 were €56.3 million, which includes non-cash stock-based compensation of €17.5 million.

R&D Expenses: Research and development expenses for the third quarter of 2015 were €13.5 million, including personnel expenses of €8.2 million and external purchases and other expenses of €5.3 million. Research and development expenses for the third quarter notably reflected the impacts of (i) non-cash stock-based compensation expense of €4.5 million and (ii) social charges related to stock-options granted during the third quarter of €1.8 million. Research and development expenses for the nine-months ended September 30, 2015 were €29.6 million, including personnel expenses of €19.2 million and external purchases and other expenses of €10.4 million. Research and development expenses for the nine-month period ended September 30, 2015 notably reflected the impacts of (i) non-cash stock-based compensation expense of €8.2 million and (ii) social charges related to free shares and stock-options granted during this period of €5.9 million.

SG&A Expenses: Selling, general and administrative expenses were €9.6 million for the third quarter of 2015, and included personnel expenses of €7.9 million and external purchases and other expenses of €1.7 million. SG&A expenses for the third quarter notably reflected the impacts of (i) non-cash stock-based compensation expense of €5.0 million and (ii) social charges related to stock-options granted during the third quarter of €1.8 million. Selling, general and administrative expenses were €25.9 million for the nine-month period ended September 30, 2015, and included personnel expenses of €19.1 million and external purchases and other expenses of €6.8 million. SG&A expenses for this nine-month period notably reflected the impacts of (i) non-cash stock-based compensation expense of €9.3 million and (ii) social charges related to free shares and stock-options granted during this period of €6.3 million.

Financial Gain: Financial gain was €0.7 million for the third quarter of 2015 and €0.5 million for the nine-month period ended September 30, 2015, which, in each case, is primarily attributable to an overall net favorable Euro-Dollar exchange rate applied to U.S. dollar-denominated cash and cash equivalents during the applicable periods.

Net Loss Attributable to Shareholders of Cellectis: Net loss attributable to shareholders of Cellectis was €12.8 million, or €0.36 per share, for the third quarter of 2015. This notably reflects the impact of (i) non-cash stock-based compensation of €9.5 million and (ii) social charges on stock-based compensation of €3.6 million. Adjusted net loss attributable to shareholders of Cellectis for the third quarter of 2015, which excludes the non-cash stock-based compensation expense of €9.5 million, was €3.3 million, or €0.09 per share. Net loss attributable to shareholders of Cellectis was €28.8 million or €0.85 per share, for the nine-month period ended September 30, 2015. This notably reflects the impact of (i) non-cash stock-based compensation of €17.5 million and (ii) social charges on stock-based compensation of €12.2 million. Adjusted net loss attributable to shareholders of Cellectis for the nine-month period ended September 30, 2015, which excludes the non-cash stock-based compensation expense of €17.5 million, was €11.3 million, or €0.33 per share.

Please see "Note Regarding Use of Non-GAAP Financial Measures" for a reconciliation of GAAP net income to adjusted net income.

On November 16, 2015 Bristol-Myers Squibb Company (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and priority review a supplemental Biologics License Application (sBLA) for Opdivo for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy (Press release, Bristol-Myers Squibb, NOV 16, 2015, View Source [SID:1234508257]). The FDA previously granted Opdivo Breakthrough Therapy Designation for this indication, underscoring the critical need for new treatment options for patients with advanced RCC who have received prior therapy. The projected FDA action date is March 16, 2016.

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Michael Giordano, M.D., senior vice president, head of Oncology Development, Bristol-Myers Squibb, commented, "There remains a significant unmet medical need for advanced renal cell carcinoma patients who have received prior therapy and are often repeatedly treated with agents that are similar in mechanism. We are pleased the FDA has accepted our sBLA for Opdivo in RCC, and we will continue to work with urgency to bring Opdivo to patients with this cancer."

This sBLA submission is based on CheckMate -025, a Phase 3 study that evaluated the overall survival of Opdivo in patients with previously treated advanced RCC versus everolimus, a current standard of care in this patient population. The trial was stopped early in July 2015 because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its primary endpoint of overall survival. Data from CheckMate -025 were recently presented at the 2015 European Cancer Congress and simultaneously published in The New England Journal of Medicine.

About Renal Cell Carcinoma

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

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide. Opdivo is the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in more than 37 countries including the United States, Japan, and in the European Union.

Indications and Important Safety Information for OPDIVO (nivolumab)

INDICATIONS

OPDIVO (nivolumab) is indicated for the treatment of unresectable or metastatic melanoma as a single agent in patients with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor and in combination with ipilimumab in patients with BRAF V600 wild-type melanoma.

These indications are approved under accelerated approval based on tumor response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred in 0.5% (5/978) of patients receiving OPDIVO as a single agent. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 037, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; Grade 3 (n=1) and Grade 2 (n=5).

In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients receiving OPDIVO as a single agent: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). Across the clinical trial experience in 188 patients with melanoma who received OPDIVO in combination with YERVOY, in Checkmate 069 (n=94) and an additional dose-finding study (n=94), fatal immune-mediated pneumonitis occurred in 0.5% (1/188) of patients. In Checkmate 069, there were six additional patients who died without resolution of abnormal respiratory findings. In Checkmate 069, pneumonitis, including interstitial lung disease, occurred in 10% (9/94) of patients receiving OPDIVO in combination with YERVOY and 2.2% (1/46) of patients receiving YERVOY. Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving OPDIVO in combination with YERVOY: Grade 5 (n=1), Grade 3 (n=2) and Grade 2 (n=3).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In combination with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO as a single agent. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 069, diarrhea or colitis occurred in 57% (54/94) of patients receiving OPDIVO in combination with YERVOY and 46% (21/46) of patients receiving YERVOY. Immune-mediated colitis occurred in 33% (31/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=1), Grade 3 (n=16), Grade 2 (n=9), and Grade 1 (n=5).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 037, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; Grade 3 (n=2) and Grade 2 (n=1). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 069, immune-mediated hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2 (n=2).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, and thyroid disorders can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, and thyroid function prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

In Checkmate 069, hypophysitis occurred in 13% (12/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=2) and Grade 2 (n=10). Adrenal insufficiency occurred in 1% (n=555) of patients receiving OPDIVO as a single agent. In Checkmate 069, adrenal insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 069, hypothyroidism occurred in 19% (18/94) of patients receiving OPDIVO in combination with YERVOY. All were Grade 1 or 2 in severity except for one patient who experienced Grade 3 autoimmune thyroiditis. Grade 1 hyperthyroidism occurred in 2.1% (2/94) of patients receiving OPDIVO in combination with YERVOY. In Checkmate 037, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated TSH occurred in 17% of patients receiving OPDIVO as a single agent. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 037, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO as a single agent. In Checkmate 069, Grade 2 or higher immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94) of patients. One patient died without resolution of renal dysfunction.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 037 (n=268), the incidence of rash was 21%; the incidence of Grade 3 or 4 rash was 0.4%. In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO as a single agent including four Grade 3 cases. In Checkmate 069, immune-mediated rash occurred in 37% (35/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=6), Grade 2 (n=10), and Grade 1 (n=19).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. Across clinical trials of 8490 patients receiving OPDIVO as a single agent or in combination with YERVOY, <1% of patients were identified as having encephalitis. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO as a single agent.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. The following clinically significant immune-mediated adverse reactions occurred in <2% (n=555) of single-agent OPDIVO-treated patients: uveitis, pancreatitis, abducens nerve paresis, demyelination, polymyalgia rheumatica, and autoimmune neuropathy. Across clinical trials of OPDIVO administered as a single agent at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: facial nerve paralysis, motor dysfunction, vasculitis, diabetic ketoacidosis, and myasthenic syndrome. In Checkmate 069, the following additional immune-mediated adverse reactions occurred in 1% of patients treated with OPDIVO in combination with YERVOY: Guillain-Barré syndrome and hypopituitarism. Across clinical trials of OPDIVO in combination with YERVOY, the following additional clinically significant, immune-mediated adverse reactions were identified: uveitis, sarcoidosis, duodenitis, pancreatitis, and gastritis.

Infusion Reactions

Severe infusion reactions have been reported in <1% of patients in clinical trials of OPDIVO as a single agent. In Checkmate 057, Grade 2 infusion reactions occurred in 1% (3/287) of patients receiving OPDIVO as a single agent. In Checkmate 069, Grade 2 infusion reactions occurred in 3% (3/94) of patients receiving OPDIVO in combination with YERVOY. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.

Embryofetal Toxicity

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

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO as a single agent. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 069, serious adverse reactions occurred in 62% of patients receiving OPDIVO; the most frequent serious adverse events with OPDIVO in combination with YERVOY, as compared to YERVOY alone, were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO as a single agent were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 069, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO in combination with YERVOY vs YERVOY alone were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

On November 16, 2015 Amgen (NASDAQ:AMGN) reported that the Company will present eight IMLYGICTM (talimogene laherparepvec) abstracts, including data from the Phase 3 trial and new data from its Phase 1b combination trial with Merck’s anti-PD-1 therapy, at the 12th International Congress of the Society for Melanoma Research (SMR), to be held on Nov. 18-21 in San Francisco (Press release, Amgen, NOV 16, 2015, View Source;p=RssLanding&cat=news&id=2112841 [SID:1234508254]).

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"The analyses from our Phase 3 monotherapy trial confirm the clinical significance of durable responses and the benefit IMLYGIC may bring to patients living with metastatic melanoma," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "As we advance understanding in the emerging science of oncolytic viral therapy, we are also excited to share early data on the use of IMLYGIC in combination with another immunotherapy."

The Phase 1b data on IMLYGIC in combination with an investigational use of Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in patients with unresectable metastatic melanoma (NCT02263508) has been accepted as a late-breaking abstract. The oral presentation is Saturday, Nov. 21, in Plenary Session 11 (Late Breaking Clinical Updates) between 1:30 to 3:40 p.m. PT in the San Francisco Marriott Marquis Salon 9-15:

Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma (G. Long)

Additionally, the Company will present analyses from OPTiM, the Phase 3 trial that served as the basis of the U.S. Food and Drug Administration’s (FDA) approval of IMLYGIC in October 2015. The following will be presented on Thursday, Nov. 19, from 6 to 8 p.m. PT at the Poster Reception in the San Francisco Marriott Marquis Salon 1-8:

Safety profile of talimogene laherparepvec (T-VEC) in OPTiM, a phase 3 trial for melanoma (F. Collichio)
Long-term follow up from the phase 2 study of talimogene laherparepvec (T-VEC) for metastatic melanoma (J. Nemunaitis)
Durable-response (DR)-associated benefits in patients (pts) with unresected stage IIIB-IV melanoma treated with talimogene laherparepvec (T-VEC) or GM-CSF in OPTiM (H. Kaufman)
Durable complete responses (CR) in patients (pts) with stage IIIB-IV melanoma treated with talimogene laherparepvec (T-VEC) in OPTiM (R. Andtbacka)
Reduced risk of developing visceral/bone metastasis (VM) in patients (pts) with stage IIIB/C/IVM1a melanoma treated with talimogene laherparepvec (T-VEC) vs GM-CSF (R. Andtbacka)
Did patients in OPTiM have truly unresectable disease? Results of an independent review (M. Faries)
Current treatment patterns in patients with metastatic melanoma: A retrospective claims database analysis in the United States (U.S.) (Y. Chen)
Abstracts are available on the SMR website at www.melanomacongress.com/abstracts.

About IMLYGIC (talimogene laherparepvec)
IMLYGIC is a genetically modified herpes simplex type 1 virus that is injected directly into tumors. IMLYGIC replicates inside tumor cells and produces GM-CSF, an immunostimulatory protein. IMLYGIC then causes the cell to rupture and die in a process called lysis. The rupture of the cancer cells causes the release of tumor-derived antigens, which together with virally derived GM-CSF may help to promote an anti-tumor immune response. However, the exact mechanism of action is unknown.

IMLYGIC is the first oncolytic viral therapy approved by the FDA based on therapeutic benefit demonstrated in a pivotal study. IMLYGIC is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. IMLYGIC has not been shown to improve overall survival or have an effect on visceral metastases.

Important Safety Information

Contraindications

Do not administer IMLYGIC to immunocompromised patients, including those with a history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, and those on immunosuppressive therapy, due to the risk of life-threatening disseminated herpetic infection.
Do not administer IMLYGIC to pregnant patients.
Warnings and Precautions

Accidental exposure to IMLYGIC may lead to transmission of IMLYGIC and herpetic infection, including during preparation and administration. Health care providers, close contacts, pregnant women, and newborns should avoid direct contact with injected lesions, dressings, or body fluids of treated patients. The affected area in exposed individuals should be cleaned thoroughly with soap and water and/or a disinfectant.

Caregivers should wear protective gloves when assisting patients in applying or changing occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and cleaning materials. Exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant.

To prevent possible inadvertent transfer of IMLYGIC to other areas of the body, patients should be advised to avoid touching or scratching injection sites or occlusive dressings.

Herpetic infections: Herpetic infections (including cold sores and herpetic keratitis) have been reported in IMLYGIC-treated patients. Disseminated herpetic infection may also occur in immunocompromised patients. Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to prevent viral transmission.

Patients or close contacts with suspected signs or symptoms of a herpetic infection should contact their health care provider to evaluate the lesions. Suspected herpetic lesions should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442). Patients or close contacts have the option of follow-up testing for further characterization of the infection.

IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of IMLYGIC. Consider the risks and benefits of IMLYGIC treatment before administering antiviral agents to manage herpetic infection.

Injection Site Complications: Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds.

Impaired healing at the injection site has been reported. IMLYGIC may increase the risk of impaired healing in patients with underlying risk factors (e.g., previous radiation at the injection site or lesions in poorly vascularized areas). If there is persistent infection or delayed healing of the injection site, consider the risks and benefits of continuing treatment.

Immune-Mediated events including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with IMLYGIC. Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events.

Plasmacytoma at Injection Site: Plasmacytoma in proximity to the injection site has been reported in a patient with smoldering multiple myeloma after IMLYGIC administration in a clinical study. Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or in whom plasmacytoma develops during treatment.

Adverse Reactions

The most commonly reported adverse drug reactions (> 25%) in IMLYGIC-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. Pyrexia, chills, and influenza-like illness can occur at any time during IMLYGIC treatment, but were more frequent during the first 3 months of treatment.
The most common Grade 3 or higher adverse reaction was cellulitis.

On November 16, 2015 Oncothyreon Inc. (Nasdaq:ONTY), a clinical-stage biopharmaceutical company dedicated to the development of oncology products that can improve the lives and outcomes of patients, reported that data from the company’s ongoing trials of ONT-380, an orally active, reversible and selective small-molecule HER2 inhibitor being developed for the treatment of metastatic breast cancer, will be presented at the upcoming San Antonio Breast Cancer Symposium (SABCS) being held December 8-12, 2015 in San Antonio, TX (Press release, Oncothyreon, NOV 16, 2015, View Source [SID:1234508251]).

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"We are looking forward to presenting additional and updated clinical trial data on ONT-380 for the treatment of patients with HER2-positive breast cancer, including an analysis of patients that suffer from central nervous system (CNS) metastases, at SABCS," said Robert L. Kirkman, M.D., President and CEO of Oncothyreon. "CNS metastases impact up to 50 percent of women with HER2-positive metastatic breast cancer and represent a major unmet medical need. ONT-380 is an exciting molecule that has the potential to provide a much needed treatment option for this patient population."

The SABCS presentation details are as follows:

A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC)

First Author: Cristiano Ferrario, Segal Cancer Centre, Jewish General Hospital, Montreal, QC
Date/Time: Friday, December 11, 2015 at 7:30-9:00 a.m. CT
Session: Poster Session 4: Treatment: HER2-Targeted Therapy
Abstract P4-14-20

ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets)

First Author: Rashmi Krishna Murthy, MD Anderson Cancer Center, Houston, TX
Date/Time: Friday, December 11, 2015 at 7:30-9:00 a.m. CT
Session: Poster Session 4: Treatment: HER2-Targeted Therapy
Abstract P4-14-19