On November 10, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection, for intravenous use, for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy (Press release, Bristol-Myers Squibb, NOV 10, 2016, View Source [SID1234516486]).1 Opdivo is the first and only Immuno-Oncology treatment proven in a Phase 3 trial to significantly extend overall survival (OS) for these patients.1 In oncology clinical trials, OS is considered the gold standard primary endpoint to evaluate the outcome of any therapy.3

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The approval was based on results from the Phase 3, CheckMate -141 trial in which Opdivo demonstrated statistically significant and clinically meaningful superior OS vs the comparator arm (investigator’s choice of methotrexate, docetaxel or cetuximab), with a 30% reduction in the risk of death (HR=0.70 [95% CI: 0.53-0.92; p=0.0101]).1 The median OS was 7.5 months (95% CI: 5.5-9.1) for Opdivo compared to 5.1 months (95% CI: 4.0-6.0) for investigator’s choice.1 Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity. Please see the Important Safety Information section below.

"With this approval in head and neck cancer, we continue to lead the field in bringing our Immuno-Oncology science and the potential for increasing survival to more people with cancer," said Chris Boerner, Head of U.S. Commercial, Bristol-Myers Squibb. "We take tremendous pride in the unprecedented speed and rigor with which we have brought Opdivo to market to address unmet needs across more tumor types than any other Immuno-Oncology treatment."

Squamous cell carcinoma of the head and neck (SCCHN) accounts for more than 90% of all head and neck cancers, and more than 50% of SCCHN patients present with Stage III or higher disease (locally advanced or metastatic), which has higher potential for progression and recurrence.4,5 The relative five-year survival rate for metastatic head and neck cancers is <38%, and can be as low as 4% for recurrent or metastatic Stage IV disease.6,7

"Squamous cell carcinoma of the head and neck that progresses on or after platinum-based therapy is a debilitating and hard-to-treat disease associated with a very poor prognosis," said Maura Gillison, M.D., Ph.D., lead investigator, Jeg Coughlin Chair of Cancer Research, The Ohio State University Wexner Medical Center. "This latest approval for Opdivo reinforces the potential to provide patients with improved overall survival, considered the gold standard in cancer care."

Based on a pre-planned interim analysis, CheckMate -141 was stopped early in January 2016 because an assessment conducted by the independent Data Monitoring Committee concluded the study met its primary endpoint of OS. In April 2016, the FDA granted Breakthrough Therapy Designation to Opdivo for recurrent or metastatic SCCHN after platinum-based therapy, underscoring the need for new treatment approaches for this disease. In October, the U.S. National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines to recommend treatment with Opdivo as the only category 1 single-agent therapy for patients with recurrent or metastatic head and neck cancer with disease progression on or after platinum-containing chemotherapy.2 Opdivo has now been approved in five tumor types in under two years.1

CheckMate -141 Confirms Superior OS in SCCHN

CheckMate -141 was a global Phase 3, open-label, randomized, trial evaluating Opdivo versus investigator’s choice of therapy in patients with recurrent or metastatic SCCHN who had tumor progression during or within six months of receiving platinum-based therapy administered in the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting.1,8 Patients were included regardless of their HPV or PD-L1 status.1 Patients were randomized 2:1 to receive Opdivo 3 mg/kg intravenously over 60 minutes every two weeks (n=240), or investigator’s choice (n=121) of: methotrextate 40 to 60 mg/m2 intravenously weekly, docetaxel 30 to 40 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly.1 Therapies chosen for investigator’s choice represent the most commonly used therapies in the platinum refractory setting.9,10 The primary endpoint was OS.1 The trial’s secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).11

In the trial, Opdivo demonstrated statistically significant superior OS with a 30% reduction in the risk of death (HR=0.70 [95% CI: 0.53-0.92; p=0.0101]), and a median OS of 7.5 months (95% CI: 5.5-9.1) for Opdivo compared to 5.1 months (95% CI: 4.0-6.0) for the investigator’s choice arm.1 There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs 5.8% [95% CI: 2.4, 11.6] for Opdivo and investigator’s choice, respectively.1 Data from CheckMate -141 were published in The New England Journal of Medicine in October.8

"We are excited to see the continued benefits of ongoing Immuno-Oncology research from a company with a long-standing commitment to head and neck cancer like Bristol-Myers Squibb," said Brian Hill, oral cancer survivor and founder, The Oral Cancer Foundation. "Today’s approval provides hope for the thousands of previously treated SCCHN patients and their loved ones by bringing a new treatment option that has the potential to extend lives."

The safety profile of Opdivo in CheckMate -141 was consistent with prior studies in patients with melanoma and non-small cell lung cancer.8 Opdivo was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction.1 Serious adverse reactions occurred in 49% of patients receiving Opdivo.1 The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were pneumonia, dyspnea, aspiration pneumonia, respiratory failure, respiratory tract infection, and sepsis.1 Please see the Important Safety Information section below.

About Head & Neck Cancer

Cancers that are known as head and neck cancers usually begin in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth and the throat.12 In 2016, approximately 64,000 new cases of head and neck cancer are estimated to be diagnosed in the U.S., resulting in more than 13,000 deaths.4,13,14 Head and neck cancers are more than twice as common among men as they are among women.4

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment modality alongside surgery, radiation and chemotherapy for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents and continue to study the role of combinations in cancer.

Our collaboration with academia as well as small and large biotech companies is responsible for researching the potential Immuno-Oncology and non-Immuno-Oncology combinations, with the goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing expectations in hard-to-treat cancers and the way patients live with cancer.

U.S. FDA APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

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

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

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

OPDIVO can cause immune-mediated hepatitis. 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 patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

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 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

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) 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

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

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 Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 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. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

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. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-Fetal 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 an 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 (n=268). 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 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice.

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%).

Checkmate Trials and Patient Populations

Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck.

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

On November 10, 2016 Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to ADCETRIS (brentuximab vedotin) for the treatment of patients with CD30-expressing mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) who require systemic therapy and have received one prior systemic therapy (Press release, Seattle Genetics, NOV 10, 2016, View Source [SID1234516472]). MF and pcALCL are the most common subtypes of cutaneous T-cell lymphoma (CTCL), accounting for more than 75 percent of the disease. ADCETRIS has been evaluated in CD30-expressing CTCL in investigator- and corporate-sponsored clinical trials, including the phase 3 ALCANZA study. The positive topline results of the ALCANZA trial were announced in August 2016 and an abstract was accepted for oral presentation at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting, December 3-6, 2016 in San Diego, California. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30 which is expressed on skin lesions in approximately 50 percent of patients with CTCL. ADCETRIS is currently not approved for the treatment of CTCL.

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Discover why more than 1,500 members use 1stOncology™ to excel in:

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

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The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies on one or more clinically significant endpoints.

"The decision by the FDA to grant ADCETRIS Breakthrough Therapy Designation further reinforces our belief that ADCETRIS represents a meaningful advance in the treatment of CD30-expressing CTCL," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "The Breakthrough Therapy Designation supports our goal to expedite the review and approval process to make ADCETRIS available to patients in this setting who may benefit. We look forward to presenting the data from our phase 3 ALCANZA trial in an oral session at the upcoming ASH (Free ASH Whitepaper) annual meeting and intend to submit a supplemental Biologics License Application to the FDA in the first half of 2017 for approval in this setting."

This Breakthrough Therapy Designation was based on data from the phase 3 ALCANZA clinical trial. The phase 3 ALCANZA trial evaluated ADCETRIS in CD30-expressing CTCL and met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). This randomized trial, which received a Special Protocol Assessment (SPA) agreement from the FDA and scientific advice from the European Medicines Agency (EMA), compared the use of single-agent ADCETRIS to a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in 131 patients with CD30-expressing CTCL who received prior systemic or radiation therapy.

The title of the phase 3 ALCANZA abstract accepted for oral presentation at the ASH (Free ASH Whitepaper) Annual Meeting is below and can be found at www.hematology.org:

Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician’s Choice (Methotrexate or Bexarotene): the Phase 3 ALCANZA Study (Abstract #182, oral presentation on Saturday, December 3, 2016 at 2:15 p.m. PT)
Phase 3 ALCANZA Clinical Trial Design

The ALCANZA trial is a randomized, open-label phase 3 study designed to evaluate single-agent ADCETRIS versus a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in patients with CD30-expressing CTCL, including those with pcALCL or MF. The primary endpoint is ORR4 as assessed by Global Response Score in the ADCETRIS arm compared to the control arm. Key secondary endpoints are complete response rate, progression-free survival and reduction in the burden of symptoms during treatment. The clinical trial enrolled 131 patients at 50 sites globally. Patients with pcALCL must have received at least one prior systemic or radiation therapy and patients with MF must have received at least one prior systemic therapy. Patients received ADCETRIS every three weeks versus investigator’s choice for up to approximately one year. This international multi-center trial has been conducted in North and South America, Europe and Australia under operational responsibility of Takeda Pharmaceuticals.

ADCETRIS received orphan drug designation from the FDA for the treatment of MF, which is the most common type of CTCL. ADCETRIS also received orphan drug designation from the European Commission for CTCL, including subtypes pcALCL and MF.

About CTCL

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. Progression from limited skin involvement may be accompanied by tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs. According to published literature, CD30 is expressed on skin lesions in approximately 50 percent of CTCL patients.

The standard treatment for systemically pretreated CTCL includes skin-directed therapies, radiation and systemic therapies. The systemic therapies currently approved for treatment have demonstrated 30 to 45 percent objective response rates, with low complete response rates.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including two phase 3 studies, ECHELON-1 in frontline classical Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in 65 countries.

In June 2016, the European Commission extended the current conditional approval of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On November 10, 2016 Pfizer Inc. (NYSE:PFE) reported that the European Commission (EC) has approved IBRANCE (palbociclib) for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer (Press release, Pfizer, NOV 10, 2016, View Source [SID1234516471]). The approval is for IBRANCE to be used in combination with an aromatase inhibitor. The approval also covers the use of IBRANCE in combination with fulvestrant in women who have received prior endocrine therapy.

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IBRANCE is the first medicine to be approved in Europe that works by inhibiting cyclin-dependent kinases 4 and 6 (CDK 4/6). It also is the first new medicine approved for the treatment of women with this type of metastatic breast cancer in the first-line setting in nearly 10 years. Women with HR+/HER2- metastatic breast cancer represent about 60 percent of all metastatic breast cancer cases.1

"Today’s approval of IBRANCE in the European Union (EU) brings an innovative and much-needed new treatment option to tens of thousands of women with HR+/HER2- metastatic breast cancer," said Andreas Penk, M.D., regional president, International Developed Markets, Pfizer Oncology. "With strong and consistent data in three pivotal clinical studies and rapid adoption as a standard of care in the U.S., IBRANCE represents a potential new benchmark for the treatment of HR+/HER2- metastatic breast cancer in Europe."

The EC approval is based on a robust submission package including results from the Phase 2 PALOMA-1 trial in postmenopausal women with estrogen receptor-positive (ER+)/HER2- metastatic breast cancer who had not received prior systemic therapy for their advanced disease, the Phase 3 PALOMA-2 trial in the same population and the Phase 3 PALOMA-3 trial in women with HR+/HER2- metastatic breast cancer who had progressed on prior endocrine therapy. All three randomized trials demonstrated that IBRANCE in combination with an endocrine therapy significantly prolonged progression-free survival (PFS) compared to endocrine therapy alone or endocrine therapy with placebo.

Breast cancer is the most common invasive cancer among women in Europe, with more than 464,200 new cases and 131,260 deaths per year.2 Up to 30 percent of women diagnosed with and treated for early breast cancer will go on to develop metastatic breast cancer,3,4 which occurs when the cancer spreads beyond the breast to other parts of the body.5 There is no cure for metastatic breast cancer,6 and patients are in need of new treatment options that help keep their cancer from worsening, manage symptoms and help them maintain quality of life for as long as possible.3,5

"Palbociclib is an exciting advance in the management of women with hormone receptor-positive breast cancer. Patients with this type of breast cancer are usually treated with hormone therapy but many will progress or relapse – and as a result require chemotherapy, which often comes with life-limiting side-effects," said Nicholas Turner, M.D., Ph.D., team leader at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, as well as principal investigator of the PALOMA-3 trial. "Palbociclib, when used in combination with standard hormone therapy, increases the duration of tumor control and is well tolerated by most women – and could delay the need for women with this type of advanced breast cancer to start chemotherapy."

"Metastatic breast cancer patients in Europe need new treatment options available to them," said Kathi Apostolidis, two-time breast cancer survivor and vice president of the European Cancer Patient Coalition. "Metastatic breast cancer places a heavy burden on cancer patients and their families, but patients hope that novel treatments may have the potential to provide better quality of life and outcomes."

About the IBRANCE Pivotal Trials

PALOMA-1

The Phase 2 PALOMA-1 trial evaluated IBRANCE in combination with letrozole compared with letrozole alone as a first-line, or initial, therapy in 165 postmenopausal women with ER+/HER2- advanced breast cancer who had not received previous systemic treatment for their advanced disease. The combination of IBRANCE plus letrozole significantly prolonged PFS compared to letrozole alone (HR=0.488 [95% CI: 0.319–0.748]), with the median PFS of 20.2 months (95% CI: 13.8–27.5) in the IBRANCE arm compared to 10.2 months (95% CI: 5.7–12.6) in women who received letrozole alone. The most common adverse events (≥20%) of any grade reported in patients treated with IBRANCE plus letrozole versus letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%) and diarrhea (21% vs 10%).7

PALOMA-2

The Phase 3 PALOMA-2 trial evaluated IBRANCE in combination with letrozole compared with letrozole plus placebo as a first-line treatment in 666 postmenopausal women with ER+/HER2- metastatic breast cancer, the same patient population as PALOMA-1. The combination of IBRANCE plus letrozole resulted in a statistically significant improvement in PFS (HR=0.58 [95% CI: 0.46–0.72], P<0.000001), with a median PFS of 24.8 months compared to 14.5 months for those who were treated with letrozole plus placebo. The most common adverse events (≥20%) of any grade reported in patients treated with IBRANCE plus letrozole versus letrozole plus placebo included neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia (33.3% vs 33.8%) and alopecia (32.9% vs 15.8%).8

PALOMA-3

The Phase 3 PALOMA-3 trial evaluated IBRANCE in combination with fulvestrant compared with placebo plus fulvestrant in 521 women with HR+/HER2- metastatic breast cancer, regardless of menopausal status, whose disease progressed on or after prior endocrine therapy. The combination of IBRANCE plus fulvestrant substantially improved PFS compared to fulvestrant plus placebo (HR=0.461 [95% CI: 0.360–0.591), P<0.0001), with a median PFS of 9.5 months (95% CI: 9.2–11.0) in the IBRANCE arm compared to 4.6 months (95% CI: 3.5–5.6) in women who received placebo plus fulvestrant. The most common adverse events (≥20%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant versus placebo plus fulvestrant included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%) and constipation (20% vs 16%).7

About IBRANCE (palbociclib)

IBRANCE is an oral inhibitor of cyclin-dependent kinases 4 and 6,7 which are key regulators of the cell cycle that trigger cellular progression.9,10 With this latest regulatory milestone, IBRANCE now is approved in more than 50 countries.

IBRANCE (palbociclib) INDICATIONS AND IMPORTANT SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

IBRANCE is indicated in the U.S. for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy. The indication in combination with letrozole is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

On November 10, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that daratumumab (DARZALEX) will be investigated in a Phase III clinical study in combination with carfilzomib (KYPROLIS) and dexamethasone in patients with relapsed/refractory multiple myeloma (Press release, Genmab, NOV 10, 2016, View Source [SID1234516464]). The study will be conducted under a master clinical trial collaboration and supply agreement between Genmab’s licensing partner for daratumumab, Janssen Biotech, Inc., and Onyx Pharmaceuticals, Inc., a wholly-owned subsidiary of Amgen, Inc. The agreement covers all potential opportunities for combining daratumumab and carfilzomib (a proteasome inhibitor) for the treatment of patients with cancer.

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The first study under this collaboration agreement will be a 450 patient Phase III, randomized, open-label, registration study that will seek to determine if daratumumab in combination with carfilzomib (56 mg/m2 twice weekly) and dexamethasone improves progression-free survival (PFS), compared to carfilzomib and dexamethasone alone in patients with multiple myeloma who have received one to three prior therapies. The study is anticipated to start dosing patients in 2017 and will be sponsored by Amgen.
"The new Phase III study combining daratumumab with carfilzomib and dexamethasone is an exciting addition to the broad and expansive development program for daratumumab and illustrates the strategy to explore as many clinical development opportunities for daratumumab as possible, and potentially establish daratumumab as the backbone treatment in multiple myeloma," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

As part of an earlier collaboration agreement between Janssen and Amgen, a separate, ongoing Phase I study (MMY1001 EQUULEUS) is evaluating the safety and pharmacokinetics of daratumumab in combination with a number of backbone multiple myeloma therapies including carfilzomib in newly diagnosed and relapsed/refractory patients with multiple myeloma.

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.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650 people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 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.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

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, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. 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,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.7,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. 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, non-Hodgkin’s lymphoma and solid tumors.