On June 29, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended expanded approval of the current indications for Opdivo (nivolumab) to include the adjuvant treatment of adult patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection (Press release, Bristol-Myers Squibb, JUN 29, 2018, View Source [SID1234527510]). This is the first time the CHMP has recommended a PD-1 inhibitor as an adjuvant treatment for any type of cancer. The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU).

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"This positive opinion supports the potential of Opdivo in the adjuvant setting to prevent relapse and progression to an advanced stage," said Arvin Yang, M.D., Ph.D., development lead, melanoma and genitourinary cancers, Bristol-Myers Squibb. "We look forward to the upcoming EC decision and the potential opportunity to bring Immuno-Oncology treatment options to more patients across the European Union."

The CHMP recommendation is based on data from the phase 3 CheckMate -238 trial, an ongoing, randomized double-blind study of Opdivo 3 mg/kg versus Yervoy (ipilimumab) 10 mg/kg in patients who have undergone complete resection of stage IIIB/C or stage IV melanoma according to the AJCC Cancer Staging Manual 7th edition. The U.S. Food and Drug Administration (FDA) expanded the approval of Opdivo to include the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection in December 2017.

About CheckMate -238

CheckMate -238 is an ongoing Phase 3, randomized double-blind study of Opdivo versus Yervoy in patients who have undergone complete resection of stage IIIB/C or stage IV melanoma. The trial randomized 906 patients 1:1 to receive either Opdivo 3 mg/kg every two weeks (n=453) or Yervoy 10 mg/kg (n=453) every three weeks for four doses and then every 12 weeks starting at week 24. Patients were treated until disease recurrence, unacceptable toxicity or withdrawal of consent for up to one year. The primary endpoint is Recurrence-free Survival (RFS), defined as the time between randomization and the date of first recurrence, new primary melanoma or death. After meeting the primary endpoint, the trial will continue to evaluate for overall survival, a secondary endpoint.

Adjuvant Therapy in Melanoma

Melanoma is separated into five staging categories (stages 0 to 4) based on the size or thickness of the tumor, whether or not it has spread to the lymph nodes or other organs, and certain other characteristics, such as growth rate.

Stage III melanoma has reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized), and requires surgical resection of the primary tumor as well as the involved lymph nodes. Some patients may also be treated with adjuvant therapy. Despite surgical intervention and possible adjuvant treatment, most patients experience disease recurrence and progress to metastatic disease. By five years, the majority of stage IIIB and IIIC patients (68% and 89%, respectively) experience disease recurrence.

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

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational medicines, including Immuno-Oncology (I-O) therapeutic approaches, for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the integrated scientific understanding of both tumor cell and immune system pathways, through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 24 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance the I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of transformational medicines like I-O therapies a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

INDICATIONS

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), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor-risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. 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 adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. 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 hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. 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 adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (10 mg/mL) is an injection for intravenous (IV) use.

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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients.

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. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) 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 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) 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 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, 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), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

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 as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) 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 breastfeeding 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 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

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 fatigue (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 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), and decreased appetite (21% vs 29%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain.

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 (ipilimumab); Checkmate 214–intermediate or poor risk advanced renal cell carcinoma in combination with YERVOY; Checkmate 142–MSI-H/dMMR metastatic colorectal cancer; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 040–hepatocellular carcinoma; Checkmate 037/066–advanced melanoma; Checkmate 017–squamous non-small cell lung cancer (NSCLC); Checkmate 057–non-squamous NSCLC; Checkmate 025–previously treated renal cell carcinoma; Checkmate 141–squamous cell carcinoma of the head and neck; Checkmate 275–urothelial carcinoma; Checkmate 238–adjuvant treatment of melanoma.

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

On June 28, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI) reported that on June 28, 2018 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending marketing authorisation for the medicinal product NERLYNX (neratinib) for the extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy (Press release, Puma Biotechnology, JUN 28, 2018, View Source [SID1234527509]). The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). Today’s decision is consistent with the CHMP’s positive trend vote, which was communicated to the Company on June 26, 2018.

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About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

On June 29, 2018 Novartis reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of Kymriah (tisagenlecleucel, formerly CTL019) – a novel one-time treatment that uses a patient’s own T cells to fight cancer (Press release, Novartis, JUN 29, 2018, View Source [SID1234527508]). The positive opinion includes two B-cell malignancies: B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse in patients up to 25 years of age; and diffuse large B-cell lymphoma (DLBCL) that is relapsed or refractory (r/r) after two or more lines of systemic therapy in adults.

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"The positive CHMP opinion for Kymriah is a watershed moment for pediatric and adult patients in Europe with aggressive blood cancers," said Liz Barrett, CEO, Novartis Oncology. "This truly transformative therapy helps address a profound unmet need, and Novartis is proud that our leadership in CAR-T innovation will make a meaningful difference to patients in the EU."

If approved by the European Commission, Kymriah will be the first CAR-T cell therapy available in the European Union (EU) for both DLBCL and B-cell ALL.

Both B-cell ALL and DLBCL are aggressive malignancies with significant treatment gaps for patients. In Europe, ALL accounts for approximately 80% of leukemia cases among children[1], and for those patients who relapse, the outlook is poor[2]. This low survival rate is in spite of patients having to undergo multiple treatments, including chemotherapy, radiation, targeted therapy or stem cell transplant, and further highlights the need for new treatment options. DLBCL is the most common form of non-Hodgkin lymphoma, accounting for up to 40% of all cases globally[3]. For patients who relapse or don’t respond to initial therapy, there are limited treatment options that provide durable responses, and survival rates are low for the majority of patients due to ineligibility for autologous stem cell transplant (ASCT) or because salvage chemotherapy or ASCT have failed[4].

The positive CHMP opinion is based on two pivotal Novartis-sponsored global, multi-center, Phase II trials, ELIANA and JULIET, which included patients from Europe, the US, Australia, Canada and Japan.

The collaboration of Novartis and the University of Pennsylvania has led to historic milestones in CAR-T cell therapy since 2012, including the initiation of the first global CAR-T trials, the PRIME designation granted by the EMA for Kymriah in pediatric patients with r/r B-cell ALL, and the approval of Kymriah in two distinct indications by the US Food and Drug Administration (FDA).

"Kymriah is already transforming the way we treat certain types of leukemia and lymphoma in the United States, and showing us that personalized cell therapies are an incredibly powerful tool in the fight against cancer," said Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center. "We are excited to see that through our collaboration with Novartis, physicians in more countries around the world may be able to use this novel and innovative CAR-T cell therapy to improve the treatment outcomes for their patients."

ELIANA is the first pediatric global CAR-T cell therapy registration trial, treating patients in 25 centers in the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain. JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL.

JULIET is also the largest global study evaluating a CAR-T cell therapy in patients with DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and the EU, including: Austria, France, Germany, Italy, Norway and the Netherlands.

The Novartis CAR-T cell manufacturing platform includes cryopreservation, the process of freezing patients’ harvested cells in order to preserve them, which provides physicians with the flexibility to decide when to initiate both the harvesting of patients’ cells and the infusion of Kymriah, based on each patient’s condition, and allows for this individualized treatment approach on a global scale.

"Today’s positive opinion from the CHMP marks a truly extraordinary moment for those who have been impacted by these types of advanced and aggressive B-cell malignancies," said Dr. Ulrich Jäger, Professor of Hematology at the Medical University of Vienna and Head of Hematology at the General Hospital of the City of Vienna. "European patients and doctors have been anxiously awaiting the introduction of Kymriah, which will bring a significant advancement in the treatment landscape for these patients who face a poor prognosis."

The European Commission will now review the CHMP recommendation to deliver its final decision, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway.

"This CHMP decision brings an innovative option closer to European patients who have exhausted most alternative treatments," said Zack Pemberton-Whiteley, Chair of the Global Acute Leukemia Advocates Network and Campaigns and Advocacy Director at Leukaemia Care. "It’s important to note that CAR-T therapy may be suitable for a limited group of patients. Working with healthcare professionals to ensure safe and timely access for those who need it will be of paramount importance."

Additional regulatory filings are under review for Kymriah in Canada, Switzerland, Australia and Japan.

About CAR-T
CAR-T is different from typical small molecule or biologic therapies because it is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient’s blood and reprogrammed in the laboratory to create T cells that are genetically coded to recognize and fight the patient’s cancer cells and other B cells expressing a particular antigen.

Novartis Leadership in Immuno-Oncology
Novartis is at the forefront of investigational immunocellular therapy as the first pharmaceutical company to initiate global CAR-T trials, and has significantly invested in CAR-T research and worked with pioneers in the field. Kymriah, the first approved CAR-T cell therapy, is the cornerstone of this strategy. Active research programs are underway targeting other hematologic malignancies and solid tumors, and include efforts focused on next generation CAR-Ts with evolved manufacturing schemes and gene edited cells.

Kymriah (tisagenlecleucel, formerly CTL019) Important Safety Information from the US Prescribing Information
Kymriah is currently only approved in the United States.

Kymriah is made from your own white blood cells and is a prescription cancer treatment used in patients up to 25 years old who have acute lymphoblastic leukemia (ALL) that is either relapsing (went into remission, then came back) or refractory (did not go into remission after receiving other leukemia treatments). It is also used in patients with certain forms of large B-cell lymphoma that have relapsed or are refractory after having at least two other kinds of treatment.

Kymriah may cause side effects that are severe or life threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4’F/38’C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion.
Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their healthcare provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all of the possible side effects of Kymriah. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their healthcare provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

Please see the full Prescribing Information for Kymriah, including Boxed WARNING, and Medication Guide at www.Kymriah.com

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," "under review," "strategy," "underway," "next-generation," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Kymriah and the other investigational or approved products described in this press release, regarding our ability to scale and sustain commercial manufacturing for Kymriah and such other products, or regarding potential future revenues from Kymriah and such other products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Kymriah or the other investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that Novartis will successfully scale and sustain commercial manufacturing for Kymriah or the other products described in this press release, or successfully sustain a network of treatment centers to offer Kymriah or such other products. Nor can there be any guarantee that Kymriah or such other products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, our ability to successfully scale and sustain commercial manufacturing and sustain a network of treatment centers; the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payer and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On June 28, 2018 Kymab reported its clinical trial agreement with F. Hoffmann-La Roche Ltd under which Roche will provide its PD-L1 blocking antibody atezolizumab for use in combination with Kymab’s lead investigational anti-ICOS antibody therapy KY1044 in Kymab’s upcoming Phase I/II clinical studies in patients with advanced solid cancers (Press release, Kymab, JUN 28, 2018, View Source [SID1234537005]).

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"We have presented preclinical data demonstrating strong synergies between an anti-PD-L1 treatment in combination with KY1044 against multiple tumour types," says Arndt Schottelius, MD, PhD, Executive Vice President, Research and Development of Kymab. "We look forward to the initiation of our first studies and exploration of the potential synergy of our programs for the benefit of patients with advanced solid cancers."

Kymab will be responsible for conducting the clinical trials, and both companies will share data from the trials. Kymab continues to retain all commercial rights to KY1044.

KY1044 is designed to both deplete intratumoral Regulatory T-cells and stimulate T Effector cells to enhance the immune response against tumors.

Kymab plans to conduct a Phase I/II study in a variety of solid tumours both as monotherapy and in combination with atezolizumab. Indications that have elevated levels of both ICOS and FOXP3 might be especially responsive to this combination of checkpoint inhibitors.

Kymab will lead studies to evaluate this hypothesis: atezolizumab, an anti-PD-L1 antibody that acts as a checkpoint inhibitor, and KY1044, an antibody targeting ICOS expression, will be tested for synergistic action to recalibrate the immune response. Kymab plans to initiate monotherapy studies of KY1044 in the first half of 2019 and studies in combination with TECENTRIQ in the second half.

Notes to Editors
Issued Cambridge, UK, 28 June 2018

Read the PDF version of the issued Press Release

TECENTRIQ (atezolizumab) is a registered trademark of Genentech, a member of the Roche Group.

About KY1044
KY1044 is a fully human monoclonal antibody discovered by Kymab’s unique suite of technologies. KY1044 has now been tested in number of highly illustrative syngeneic models, which demonstrate that KY1044 strongly inhibits tumor growth in cancers both as a monotherapy and in combination with other immunotherapies.

Inducible T Cell Co Stimulator (ICOS), is expressed upon activation on T cells and at high levels on the majority of FOXP3+ regulatory CD4+ T cells. Importantly, available data demonstrate that depletion of these immunosuppressive cells from the tumor microenvironment enhances the patient’s anti-tumor immune response.

Scientific Posters and Presentations can be located in the pipeline section on the Company’s website: View Source

On June 28, 2018 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN:ATNM) ("Actinium" or "the Company"), reported that Dr. Joseph Jurcic, Director of the Hematologic Malignancies Section and Professor of Medicine at Columbia University Medical Center, has initiated Actimab-A MRD, a new clinical trial for patients with AML who are in remission but have detectable minimal residual disease (MRD) (Press release, Actinium Pharmaceuticals, JUN 28, 2018, View Source [SID1234527514]). The trial will study the safety/tolerability of Actimab-A in the postremission consolidation setting and include dose finding analyses. The trial will also study the impact of Actimab-A on minimal residual disease (MRD) as well as progression-free (PFS) and overall survival (OS) rates. The investigational new drug (IND) application for this trial has been cleared by the FDA.

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Together with Dr. Jurcic, Actinium will host a webcast to discuss the planned trial, participation information is as follows:

Date: July 10, 2018
Time: 8:00 AM ET
Registration Link: View Source
Telephone participation: U.S./Canada Toll Free: (855) 427-0225 or (718) 865-8336
Conference ID: 2540

Dr. Joseph Jurcic said, "Although patients with AML can achieve complete remissions with induction therapy, the rate of relapse remains high resulting in high mortality rates. Strong evidence exists that minimal residual disease is a major driver of disease relapse and clearly demonstrates the need for improved consolidation therapies that can effectively target MRD. Based on the clinical profile of Actimab-A to date, I am excited to study this therapy for use as a consolidation therapy. It will be a significant advancement for AML patients if this trial shows the ability to target MRD and reduce relapse rates."

There are an estimated 21,000 patients diagnosed with AML annually in the United States and over 350,000 cases of AML worldwide. According to the National Cancer Institute, 5-year survival for AML patients under age 65 is 45% while 5-year survival for patients over 65 is 6% with the median age of diagnosis of AML patients being 68. With curative intent induction chemotherapy, 45% – 65% of patients can achieve complete remission but up to 80% of patients will relapse despite postremission consolidation treatment. Currently, non-transplant-based consolidation therapies consist mainly of chemotherapy such as high-dose Cytarabine. The presence of MRD has been shown to be associated with higher rates of relapse and earlier relapse in multiple studies. Recently, the FDA approved a therapy for patients with a certain type of B-cell leukemia who are in remission but have detectable MRD.

Dr. Mark Berger, Actinium’s Chief Medical Officer said, "Actimab-A has many points of differentiation that I feel make it well suited to address MRD treatment as consolidation therapy. Given that patients receive chemotherapy as induction therapy, I believe it is important to develop a non-chemotherapy based consolidation therapy that has fewer toxicities and side effects than chemotherapy. This is particularly important for older patients, who do not have the same ability to tolerate high dose therapies as young patients, and who are the majority of patients with AML. We believe our ARC or Antibody Radiation Conjugate approach enables precision targeting of residual AML cells and potentially provide a means by which MRD can be eliminated and relapse rates lowered. We look forward to working with Dr. Jurcic to execute this important trial for AML patients."

Sandesh Seth, Actinium’s Chairman and CEO said, "We are excited by the continued expansion of our CD33 program and intend to solidify our position as the best-in-class CD33 targeting therapy by demonstrating its potential in multiple diseases and multiple indications. Expansion into the consolidation setting is an important achievement towards this end. Further, the application of our therapy for MRD, strategically aligns us with the forefront of scientific exploration in a clinical setting. We believe the breadth of our CD33 program is unmatched given that we are now studying our ARC not only in multiple AML settings including induction, consolidation and in relapsed/refractory disease but also in multiple myeloma as a therapeutic, and in MDS as targeted conditioning to enable a bone marrow transplant. With this important trial poised to start and clinical data expected from our ongoing trials, we are confident in our ability to realize the intrinsic value of this program and advance these trials to benefit the greatest number of patients."

About Actimab-A
Actimab-A is an antibody radio-conjugate (ARC) comprised of the anti-CD33 monoclonal antibody lintuzumab labeled with the radioisotope actinium-225. CD33 is a marker expressed on AML cells of virtually all affected patients. Actimab-A has been studied in over 100 patients to date and is the only CD33 targeting agent being studied in a broad range of diseases in which the CD33 antigen is expressed, including AML, myelodysplastic syndrome (MDS) and multiple myeloma.

Actinium-225 is highly differentiated radioisotope that emits high amounts of energy through the release of four alpha-particles that can cause double-stranded breaks in DNA with known resistance mechanisms to Actinium-225. Given the limited distance of its energy in the body, it is potentially sparing of non-targeted cells leading to better tolerability and less toxicities.

Actimab-A has been granted Orphan Drug Designation from both the U.S. Food and Drug Administration and the European Medicines Agency for newly diagnosed AML in patients age 60 and above.