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On October 28, 2015 Cellectis (Paris:ALCLS) (NASDAQ:CLLS) (Alternext: ALCLS – Nasdaq: CLLS) reported that a series of three production runs of UCART19, its lead TALEN gene edited product candidate, was performed, confirming the implementation of Cellectis’ manufacturing process in GMP conditions (Filing, 6-K, Cellectis, OCT 28, 2015, View Source [SID:1234507825]).

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The manufacturing process for Cellectis’ allogeneic CAR T-cell product line, Universal CARTs or UCARTs, yields frozen, off-the-shelf, allogeneic, engineered CAR T-cells. UCARTs are meant to be readily available CAR T-cells for a large patient population. The TALEN-based gene editing (knock-out of the TCR-alpha and CD52 genes) is designed to suppress T-cell alloreactivity and confer resistance to alemtuzumab to the T-cells. This important milestone shows that UCARTs can be manufactured in GMP conditions. It also demonstrates the industrial production of UCART19, as well as the capacity of Cellectis’ pipeline of UCART product candidates to be manufactured for clinical investigations.

"It is very exciting to lead a novel allogeneic gene therapy platform at the critical time when a R&D concept is translated into a GMP clinical grade industrial product to be investigated in clinical studies," said Arjan Roozen, Vice President, GMP Solutions and Manufacturing.

"Cellectis has reached a critical milestone both for the Company and our industry, creating new opportunities for patients. Historically, cell-based therapies have grown in the world of individual grafts. With TALEN-based gene editing they have now started moving toward that of industrial pharmaceutical products broadly available to patients, and Cellectis, as a leading company in the field of gene editing, is at the forefront of this evolution," added David J.D. Sourdive, Executive Vice President, Corporate Development.

About UCART19

UCART19 is a potential best-in-class allogeneic engineered T-cell product for treatment of CD19 expressing hematologic malignancies, initially developed in Chronic lymphocytic leukemia (CLL) and Acute lymphoblastic leukemia (ALL). Servier has an option under the collaboration agreement to acquire the exclusive rights to further develop and commercialize UCART19. Engineered allogeneic CD19 T-cells currently stand out as a real therapeutic innovation for treating various types of leukemia and lymphoma. Cellectis’ approach with UCART19 is based on the preliminary positive results from clinical trials using products based on the CAR technology and has the potential to overcome the limitation of the autologous current approach by providing an allogeneic frozen, "off-the-shelf" T-cell based medicinal product.

Arjan Roozen, Vice President GMP Solutions and Manufacturing

Arjan Roozen received a BSc degree in molecular microbiology from Larenstein, Velp in The Netherlands. Arjan joined Cellectis in March 2015. In his present position of VP GMP Solutions & Manufacturing, he is responsible for all GMP pharmaceutical manufacturing activities including the biological raw materials.

Before joining Cellectis, Arjan worked for over 20 years at different biotechnology departments at Centocor, Solvay Pharmaceuticals, Biogen Idec, Crucell, Proxy laboratories and Pharmacell and gained significant experience in QC, QA and manufacturing GMP aspects. The last 4 years within Pharmacell, Arjan Roozen was responsible for GMP operations involved in significant number of cell therapy technology transfer projects as well as responsible for cell therapy commercial products. He was also involved in regulatory audit and filings for EMA and FDA.

Varian Medical Systems Reports Results for Fourth Quarter of Fiscal Year 2015

On October 28, 2015 Varian Medical Systems (NYSE:VAR) reported non-GAAP net earnings of $1.04 per diluted share and GAAP earnings of $0.99 per diluted share for the fourth quarter of fiscal year 2015 (Press release, Varian Medical Systems, OCT 28, 2015, View Source [SID:1234507824]). For the full fiscal year 2015, non-GAAP earnings were $4.29 per diluted share, and GAAP earnings were $4.09 per diluted share. Varian’s revenues totaled $818 million for the fourth quarter of fiscal year 2015, up 1 percent from the year-ago quarter and up 6 percent in constant currency. Varian’s revenues for the full fiscal year were $3.1 billion, up 2 percent versus fiscal year 2014 and up 6 percent in constant currency. The company ended the fourth quarter with a $3.5 billion backlog, up 10 percent from the end of fiscal year 2014.

"During the quarter, our Oncology Systems business generated healthy constant currency order growth, the Particle Therapy business gathered momentum, and the Imaging Components business continued to experience declines in orders, revenues and margins," said Dow R. Wilson, CEO of Varian Medical Systems. "As we previously reported, we experienced a shortfall of high-margin revenues in our Oncology business when several TrueBeam systems and related software slipped out of the quarter."

The company finished the fiscal year with $845 million in cash and cash equivalents and $496 million of debt. Cash flow from operations was $153 million for the fourth quarter and $470 million for the fiscal year. During the quarter, the company spent $128 million to repurchase about 1.5 million shares of common stock.

Oncology Systems

Oncology Systems’ fourth quarter revenues totaled $633 million, up 2 percent from the same quarter of fiscal year 2014 and up 9 percent in constant currency. Annual revenues were $2.3 billion, even with the prior fiscal year, and up 6 percent in constant currency.

Fourth-quarter gross orders were $919 million, equal to the year-ago quarter and up 5 percent in constant currency. In the Americas, fourth quarter Oncology gross orders declined by 5 percent in dollars and constant currency. In EMEA, gross orders were up 13 percent in dollars and up 25 percent in constant currency. In APAC, gross orders declined by 3 percent in dollars but rose 6 percent in constant currency. Annual Oncology gross orders were $2.7 billion, even with fiscal year 2014 and up 6 percent in constant currency. In the Americas, annual gross orders were up 1 percent in dollars and constant currency. In EMEA gross orders were flat in dollars but up 12 percent in constant currency. In APAC, order growth was also flat in dollars but up 9 percent in constant currency.

"Oncology gross orders were strong in EMEA during the quarter when we booked orders for over 100 systems," said Wilson. "North American orders grew by 4 percent in the quarter driven by customers continuing to upgrade to newer technologies, replacements of competitors’ products, and increased software sales. We believe we gained share in constant currency in all regions."

Imaging Components

Imaging Components revenues were $155 million for the fourth quarter, down 8 percent from the year-ago period, and $611 million for the fiscal year, down 7 percent from fiscal year 2014. Gross orders were $165 million for the fourth quarter, down 30 percent from the year-ago period, and totaled $605 million for the fiscal year, down 16 percent from fiscal year 2014.

"Price erosion in response to aggressive euro- and yen-based competitors was the principal cause of the decline in orders and revenues for panels and tubes in our Imaging Components business," said Wilson. "Gross orders for security products were down $63 million or 57 percent for the fiscal year, and annual revenues fell by $34 million or 37 percent, due largely to instability in key international markets. The company has initiated a restructuring program to right-size the Imaging Components business and to get it back on a growth track."

During the fourth quarter of fiscal year 2015, the company paid approximately €52 million in cash to acquire Claymount Investments B.V., a privately-held, Netherlands-based supplier of components and subsystems for X-ray imaging equipment manufacturers.

Other

The company’s Other category, including the Varian Particle Therapy business and the Ginzton Technology Center, recorded revenues of $30 million for the fourth quarter and $144 million for fiscal year 2015. It generated gross orders of $141 million in the quarter and $317 million for the fiscal year. During the quarter, the Particle Therapy business booked orders for three proton therapy centers, comprising two in the UK and one in New York. "It is gratifying to see growing global market demand for Varian’s proton therapy systems," said Wilson. "We are gaining momentum in this important clinical space."

Outlook

"We believe that for fiscal year 2016 total company non-GAAP earnings will be in the range of $4.45 to $4.55 per diluted share and revenues will increase by about 4 to 5 percent on a reported basis," said Wilson. "For the first quarter of fiscal year 2016, we expect revenues to be roughly even with the year-ago quarter in dollars. With ongoing challenges experienced by Imaging Components in the second half of fiscal year 2015 as well as the effect of year-over-year changes in currency exchange rates, we expect non-GAAP earnings for the first quarter of fiscal year 2016 to be in the range of $0.88 to $0.92 per diluted share."

Non-GAAP Items

Beginning this quarter, the company is reporting non-GAAP operating earnings, non-GAAP net earnings and non-GAAP diluted earnings per share to provide comparisons against prior periods excluding certain items that may not be indicative of its core operating results and business outlook, allow better comparability among company peers, and provide additional transparency. Non-GAAP operating earnings and non-GAAP net earnings exclude the following items that are included under GAAP: amortization of intangible assets, acquisition-related expenses and or benefits, restructuring charges, impairment charges, significant litigation charges or benefits and associated legal costs. From time to time, the company may exclude other items if it is consistent with the goal of providing useful information to investors. Tax effects on non-GAAP items are calculated based on the company’s effective tax rate other than when the underlying item has a materially different tax treatment. Additional details and a table reconciling the GAAP to non-GAAP financial measures are included in this release.

KEYTRUDA® (pembrolizumab) from Merck Awarded Prix Galien USA 2015 Best Biotechnology Product Award

On October 28, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy for the treatment of advanced melanoma and metastatic non-small cell lung cancer in patients whose disease has progressed after other therapies, received the Prix Galien USA 2015 Award for Best Biotechnology Product (Press release, Merck & Co, OCT 28, 2015, View Source [SID:1234507818]).

"As a company built on a foundation of scientific excellence, Merck is honored to again have been chosen as a recipient of this prestigious award," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "This achievement is a testament to the remarkable contributions of everyone at Merck, as well as the many physicians and patients who participated in our clinical trials, in helping to bring KEYTRUDA to patients."

The Prix Galien Award recognizes the pharmaceutical industry’s outstanding achievement in the development of new medicines. An internationally recognized award, the Prix Galien was founded in France in 1969 by French pharmacist Roland Mehl and is considered the highest accolade for pharmaceutical research and development.

This latest award for KEYTRUDA is Merck’s seventh Prix Galien USA award in nine years. The company was previously recognized for ZOSTAVAX (2013), VICTRELIS (2012), ROTATEQ (2010), ISENTRESS (2008) and JANUVIA and GARDASIL (2007). In total, around the world, Merck has won the Prix Galien 40 times, making Merck the most-awarded company of all time.

CytRx to Present Additional Data from its Phase 1b/2 Clinical Trial Combining Aldoxorubicin with Ifosfamide/Mesna at the CTOS 2015 Annual Meeting

On October 28, 2015 CytRx Corporation (Nasdaq: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that a poster titled "A Phase 1b/2 Study of Aldoxorubicin plus Ifosfamide/Mesna in Untreated Sarcoma Patients" will be presented at the 20th Annual Connective Tissue Oncology Society (CTOS) Annual Meeting in Salt Lake City, Utah, November 4 – 7, 2015 (Press release, CytRx, OCT 28, 2015, View Source;p=RssLanding&cat=news&id=2103413 [SID:1234507814]). The poster will discuss the trial design and current results of CytRx’s on-going clinical trial in patients with metastatic soft and non-soft tissue sarcomas. In this study, 7 subjects received 170 mg/m2 aldoxorubicin, and 3 subjects received 250 mg/m2 aldoxorubicin (125 or 185 mg/m2 doxorubicin equivalents), administered intravenously every 4 weeks. All patients also received 1 gram/m2/day ifosfamide/mesna administered as a continuous 24 hour infusion for up to 14 days, every 4 weeks. As of September 30, 2015, 8 subjects demonstrated tumor shrinkage, with 3 subjects having documented partial responses. Six subjects are still receiving treatment. Grade 3 or 4 adverse events included neutropenia (90%), anemia (70%), nausea or vomiting (10%) and febrile neutropenia (10%). No subject exhibited cardiotoxicity by echocardiogram.

Dr. Sant Chawla M.D., F.R.A.C.P., Director of the Sarcoma Oncology Center and principal investigator for this trial stated, "The use of doxorubicin with ifosfamide and mesna remains a treatment option for many sarcoma patients. Replacing doxorubicin with aldoxorubicin may lead to improved clinical outcomes for these first-line sarcoma patients, since we already know that aldoxorubicin demonstrated superiority to doxorubicin in the previously completed Phase 2b trial in first-line tissue sarcomas."

"The presentation of the Phase 1b/2 clinical trial data at CTOS demonstrates to the sarcoma community the potential use of aldoxorubicin as part of a multi-drug regimen to treat sarcomas," said Steven A. Kriegsman, CytRx’s Chairman and Chief Executive Officer. "The on-going trial will generate important dosing, safety and efficacy data in treatment-naive patients. We remain excited about the prospects of aldoxorubicin in our pivotal global Phase 3 trial in sarcoma patients that have previously received chemotherapy, with top-line data expected in the second half of 2016."

Phase 1b/2 Trial Design

Aldoxorubicin is administered at escalating doses by intravenous infusion (IVI) on Day 1 every 28 days, and 1 gm/m2/day of ifosfamide and an equivalent dose of mesna is administered via continuous infusion with a portable at-home pump for up to 14 days every 28 days starting on Day 1 of each cycle, until disease progression, unacceptable toxicity or the patient withdraws consent. The primary objective of the trial is to determine the preliminary safety of administration of aldoxorubicin in combination with ifosfamide in patients with metastatic, locally advanced, or unresectable STS as measured by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiograms (ECHO) or multiple-gated acquisition (MUGA) scans, electrocardiogram (ECG) results, and weight. The secondary objective of the trial is to evaluate the activity of aldoxorubicin in combination with ifosfamide/mesna in this population, assessed by overall response rate (ORR), progression-free survival (PFS) and PFS at 4 and 6 months. This Phase 1b/2 trial is being conducted at the Sarcoma Oncology Center in Santa Monica, California.

About Soft Tissue Sarcoma

Soft tissue sarcoma is a cancer occurring in muscle, fat, blood vessels, tendons, fibrous tissues and connective tissue, and can arise anywhere in the body at any age. According to the American Cancer Society, there are approximately 50 types of soft tissue sarcomas. In 2015 more than 11,900 new cases were diagnosed in the U.S. and approximately 4,900 Americans died from this disease. In addition, approximately 40,000 new cases and 13,000 deaths in the U.S. and Europe are part of a growing underserved market.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

Bristol-Myers Squibb’s Opdivo (nivolumab) Recipient of Prix Galien USA 2015 Award for Best Biotechnology Product

On October 28, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that it received the Prix Galien USA 2015 Award for Best Biotechnology Product for Opdivo (nivolumab), the Company’s PD-1 immune checkpoint inhibitor (Press release, Bristol-Myers Squibb, OCT 28, 2015, View Source [SID:1234507813]). Bristol-Myers Squibb was recognized for its innovative discovery and development of Opdivo in approved indications for previously treated metastatic squamous non-small cell lung cancer (NSCLC), and in unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor, for which it received accelerated approval based on tumor response rate and durability of response. Since the submission for the Best Biotechnology Award, Opdivo has also been approved by the U.S. Food and Drug Administration (FDA) in the combination of Opdivo + Yervoy, the first FDA-approved regimen of two Immuno-Oncology agents, in BRAF V600 wild-type unresectable or metastatic melanoma, as well as for the treatment of patients with metastatic non-squamous NSCLC with progression on or after platinum-based chemotherapy.

The announcement was made during the ninth annual Prix Galien USA Awards Ceremony held on October 27, 2015 in New York City. The Prix Galien USA Award, which is selected by a preeminent scientific committee that includes several Nobel Laureates, honors outstanding achievements in improving the human condition through the development of innovative therapies. This is the second honor received by Bristol-Myers Squibb in the Best Biotechnology Product category, making it the only company to receive this award for two Immuno-Oncology agents. In 2012, Yervoy received the award, following its initial approval for unresectable or metastatic melanoma. Building on this pioneering science, the Company continues to research the potential of Immuno-Oncology to extend survival in some of the hardest-to-treat cancers.

"We are pleased to be acknowledged for our Company’s scientific contributions to this historic time in cancer research, when the science of Immuno-Oncology is helping to change expectations in cancer care," said Francis Cuss, MB BChir, FRCP, executive vice president and chief scientific officer, Bristol-Myers Squibb. "Receiving the Prix Galien USA 2015 Award for Best Biotechnology Product underscores our efforts with the Opdivo early- and late-stage clinical program in patients with some of the hardest-to-treat cancers, like advanced melanoma and squamous non-small cell lung cancer."

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 was 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.

In the U.S., Opdivo is indicated for patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. Opdivo is also approved for use in combination with Yervoy, for the treatment of patients with BRAF V600 wild-type unresectable or metastatic 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 confirmatory trials. Opdivo is also indicated in the U.S. 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 due to T-cell activation and proliferation. 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) 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. 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. 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 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 YERVOY Phase 3 study, 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 YERVOY Phase 3 study, 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 YERVOY Phase 3 study, 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 YERVOY Phase 3 study, 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 YERVOY Phase 3 study, 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 its mechanism of action, OPDIVO 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 OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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.

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 YERVOY Phase 3 study, 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%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING for YERVOY regarding immune-mediated adverse reactions.