On April 6, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that the European Commission has approved Opdivo (nivolumab) monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults (Press release, Bristol-Myers Squibb, APR 6, 2016, View Source [SID:1234510484]). Opdivo is the only approved PD-1 inhibitor to demonstrate superior overall survival (OS) in two separate Phase 3 trials in previously treated metastatic NSCLC; one trial in squamous NSCLC (CheckMate -017) and the other in non-squamous NSCLC (CheckMate -057), the basis of this approval. Together, these trials confirm the benefit of Opdivo for patients with previously treated metastatic NSCLC, regardless of PD-L1 expression. The approval allows for the expanded marketing of Opdivo in previously treated metastatic NSCLC in all 28 Member States of the European Union.

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Emmanuel Blin, senior vice president, Head of Commercialization, Policy and Operations, Bristol-Myers Squibb, commented, "At Bristol-Myers Squibb, our goal is to help improve survival outcomes for patients with hard-to-treat cancers, such as advanced non-small cell lung cancer. Today’s approval is indicative of our commitment to bringing our Immuno-Oncology science and the potential for long-term survival to a broader range of lung cancer patients in Europe. Opdivo is the only PD-1 inhibitor approved in Europe to have demonstrated, in two separate Phase 3 trials, a significant survival advantage in this patient population, offering a much-needed new treatment option to patients fighting this disease."

The approval is based on the results of Phase 3 trial, CheckMate -057, which were published in The New England Journal of Medicine. In CheckMate -057, Opdivo was evaluated in patients with metastatic non-squamous NSCLC compared to docetaxel, and included patients regardless of PD-L1 expression. Opdivo demonstrated superior OS compared to docetaxel, with a 27% reduction in the risk of death (HR=0.73 [95% CI: 0.59-0.89; p=0.0015]) with a one-year survival rate of 51% for Opdivo (95% CI: 44.6-56.1) versus 39% for docetaxel (95% CI: 33.3-44.6). Biomarker testing for PD-L1 expression is not required with Opdivo. The Summary of Product Characteristics (SmPC) notes that physicians should consider the delayed onset of Opdivo effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher number of deaths within the first 3 months was observed with Opdivo compared to docetaxel. Factors associated with early deaths were poorer prognostic factors and/or more aggressive disease combined with low or no tumor PD-L1 expression.

Luis Paz-Ares, M.D., Hospital Universitario Doce de Octubre, Madrid, Spain, commented, "Today’s approval expands the availability of Opdivo as a treatment option for a broader range of lung cancer patients – previously treated metastatic squamous and now non-squamous non-small cell lung cancer – which represents the majority of diagnosed lung cancer cases. As the only approved PD-1 inhibitor proven to have demonstrated a survival benefit versus a standard of care, regardless of PD-L1 expression, healthcare providers can offer treatment with Opdivo to appropriate patients who have received prior chemotherapy without the need to first conduct biomarker testing to determine PD-L1 expression. This approval is meaningful news for patients and their families who are in need of new treatment options."

Proven Superior Overall Survival Versus Docetaxel in Previously Treated Metastatic NSCLC

CheckMate -057 is an open-label, randomized Phase 3 study, which evaluated Opdivo versus docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with overall survival (OS) as the primary endpoint. Objective response rate (ORR) and progression-free survival (PFS) were evaluated as secondary endpoints. This study included patients regardless of PD-L1 expression level. In the study, patients were randomized to receive Opdivo (3 mg/kg administered intravenously every two weeks) versus docetaxel (75 mg/m2 administered intravenously every three weeks). The prespecified interim analysis was conducted when 413 events were observed (93% of the planned number of events for final analysis).

Opdivo demonstrated superior OS in previously treated metastatic non-squamous NSCLC compared to docetaxel, with a 27% reduction in the risk of death (HR=0.73 [95% CI: 0.59-0.89; p=0.0015]) with a one-year survival rate of 51% for Opdivo (95% CI: 44.6-56.1) compared to 39% for docetaxel (95% CI: 33.3-44.6). The median OS was 12.2 months in patients receiving Opdivo (95% CI: 9.66-14.98) and 9.4 months with docetaxel (95% CI: 8.0-10.68). The ORR in the Opdivo arm was 19% (56/292; 4 complete responses, 52 partial responses; 95% CI: 15-24) and 12% with docetaxel (36/290; 1 complete response, 35 partial responses; 95% CI: 9-17, p=0.0246). For patients administered Opdivo, median duration of response was 17.2 months and 5.6 months for docetaxel. Median PFS was 2.3 months for Opdivo versus 4.2 months for docetaxel (HR=0.92 [95% CI: 0.77-1.11, p=0.3932]).

Results of a post-hoc, exploratory multivariate analysis conducted in support of the SmPC development, indicated that Opdivo-treated patients with poorer prognostic features and/or aggressive disease when combined with low or no tumor PD-L1 expression may be at higher risk of death within the first 3 months (Opdivo arm [59/292, 20.2%] as compared to the docetaxel arm [44/290, 15.2%]). There were no early deaths due to study drug toxicity in either arm.

The safety profile of Opdivo in CheckMate -057 was consistent with prior studies. Serious adverse reactions occurred in 47% of patients receiving Opdivo. In the overall patient population, the most frequent serious adverse reactions in at least 2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pleural effusions and respiratory failure. Opdivo was discontinued in 13% of patients and was delayed in 29% of patients for an adverse reaction. The most common adverse reactions in patients treated with Opdivo (reported in >20% of patients) were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%) and constipation (23%).

The PD-L1 IHC 28-8 PharmDx, a test which was used to assess PD-L1 expression in the CheckMate -057 trial, is now Conformité Européene (CE) marked in Europe, and can be used to provide additional information for physicians. PD-L1 testing is not required to initiate Opdivo treatment for locally advanced or metastatic NSCLC patients.

CheckMate -017 is a landmark, Phase 3, open-label, randomized clinical trial that evaluated Opdivo 3mg/kg intravenously over 60 minutes every two weeks versus standard of care, docetaxel 75 mg/m2 intravenously administered every three weeks in patients with advanced squamous NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The study’s primary endpoint was OS and secondary endpoints included PFS and ORR. The trial included patients regardless of their PD-L1 expression status.

Results from CheckMate -017 showed a 41% reduction in the risk of death with a one-year survival rate of 42% for Opdivo (42.1% [95% CI: 33.7, 50.3]) versus 24% (23.7% [95% CI: 16.9, 31.1]) for docetaxel (HR=0.59 [96.8% CI: 0.43, 0.81; p=0.0002]). Median OS was 9.2 months versus 6 months for Opdivo and docetaxel, respectively. Opdivo also demonstrated consistent, statistically significant and clinically meaningful improvements across secondary endpoints, ORR and PFS, versus docetaxel in patients with previously treated advanced squamous NSCLC. Survival benefit was observed regardless of PD-L1 expression across all pre-specified expression levels (1%, 5% and 10%). The safety profile of Opdivo in CheckMate -017 was consistent with prior studies. Findings from CheckMate -017 were published in The New England Journal of Medicine and presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85% of cases. About 25% to 30% of all lung cancers are squamous cell carcinomas, and non-squamous NSCLC accounts for approximately 50% to 65% of all lung cancer cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47% and 50%; for Stage IV NSCLC, the five-year survival rate drops to 2%.

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 choice alongside surgery, radiation, chemotherapy and targeted therapies 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. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for OS and other important measures like durability of response. 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.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice. At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard to treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating OS as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 48 countries including the United States, Japan, and in the European Union.

U.S. FDA APPROVED INDICATIONS

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

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2).

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases.

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.

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. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. 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 Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO.

Embryo-fetal Toxicity

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

Lactation

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

Serious Adverse Reactions

In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure.

Common Adverse Reactions

In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%).

On April 6, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that the European Commission has approved Opdivo (nivolumab) monotherapy for an additional indication in advanced renal cell carcinoma (RCC) after prior therapy in adults (Press release, Bristol-Myers Squibb, APR 6, 2016, View Source [SID:1234510483]). Opdivo is the first and only PD-1 immune checkpoint inhibitor approved in Europe to demonstrate an overall survival (OS) benefit versus a standard of care in this patient population. This approval allows for the expanded marketing of Opdivo in previously treated advanced RCC in all 28 Member States of the European Union.

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Emmanuel Blin, senior vice president, Head of Commercialization, Policy and Operations, Bristol-Myers Squibb, commented, "Today’s approval is reflective of our commitment to bring Opdivo and the potential for long-term survival to broad patient populations, including previously treated advanced renal cell carcinoma. Opdivo is the only PD-1 inhibitor approved in Europe to demonstrate a significant survival advantage in this patient population. At Bristol-Myers Squibb, we are driven to work with speed to deliver new treatment options to help more patients, and in less than a year, we have expanded the approval of Opdivo in Europe to include three distinct types of advanced cancer."

This approval is based on the results of the Phase 3 study CheckMate -025, which were published in The New England Journal of Medicine. In CheckMate -025, Opdivo was evaluated in patients with advanced clear-cell RCC who received prior anti-angiogenic therapy compared to everolimus. Patients treated with Opdivo achieved a median OS of 25 months versus 19.6 months for everolimus (HR=0.73 [98.5% CI: 0.57-0.93; p=0.0018]), representing a greater than five month improvement over a current standard of care. CheckMate -025 also evaluated patients’ quality of life (QoL) and found that patients treated with Opdivo had improved survival and QoL compared to everolimus throughout the duration of treatment.

Dr. Bernard Escudier, Chair of the Genitourinary Oncology Committee, Institut Gustave Roussy in Villejuif, France, commented, "For the first time, previously treated advanced renal cell carcinoma patients in Europe will now have access to an Immuno-Oncology agent that has demonstrated a significant overall survival benefit along with a favorable safety profile compared to everolimus. In addition to the clinical efficacy results, patients treated with Opdivo experienced an improvement in their health-related quality of life and had significantly lower symptom burden throughout treatment compared to patients receiving everolimus. Combined, these data support the use of Opdivo in clinical practice and represent important progress toward establishing a new standard of care in Europe."

First PD-1 Inhibitor to Demonstrate Significant Overall Survival Benefit In Previously Treated Advanced RCC

CheckMate -025 is an open-label, randomized Phase 3 study, which evaluated Opdivo versus everolimus in patients with advanced clear-cell renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy, with overall survival (OS) as the primary endpoint. Objective response rate (ORR) was evaluated as a secondary endpoint. In the study, patients were randomized to receive Opdivo (3 mg/kg administered intravenously every two weeks) compared to everolimus (10 mg administered orally daily). The prespecified interim analysis was conducted when 398 events were observed (70% of the planned number of events for final analysis).

Results from CheckMate -025 showed that patients treated with Opdivo achieved a more than five month improvement in OS, with median OS of 25 months for Opdivo and 19.6 months for everolimus (HR=0.73 [98.5% CI: 0.57-0.93; p=0.0018]). An OS benefit was seen regardless of PD-L1 expression. In addition to improving OS, Opdivo demonstrated a superior ORR compared to everolimus (25.1% [95% CI: 21-29.6] vs. 5.4% [95% CI: 3.4-8.0]). Forty-nine (47.6%) Opdivo responders had ongoing responses of up to 27.6 months.

In addition to the OS benefit observed with Opdivo, patients treated with the drug also experienced an improvement over time in disease related symptoms and non-disease specific quality of life compared to patients receiving everolimus. Patients were assessed using validated and reliable scales in the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and the EuroQoL EQ-5D. Results showed that as early as week 20, patients receiving Opdivo had a significant improvement in disease related symptoms, while patients receiving everolimus showed a significant deterioration by week 4.

The safety profile of Opdivo in CheckMate -025 was consistent with prior studies. Serious adverse events occurred in 47% of patients receiving Opdivo. The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In the study, the most common adverse reactions (≥20%) reported in patients receiving Opdivo versus everolimus 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%).

About Renal Cell Carcinoma

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

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 choice alongside surgery, radiation, chemotherapy and targeted therapies 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. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for OS and other important measures like durability of response. 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.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice. At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard to treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating OS as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 48 countries including the United States, Japan, and in the European Union.

U.S. FDA APPROVED INDICATIONS

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

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1).

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1).

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). Adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). Thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). Hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6).

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis.

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. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. 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 Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus.

Embryo-fetal Toxicity

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

Lactation

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

Serious Adverse Reactions

In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Common Adverse Reactions

In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus 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%).

On April 6, 2016 Arrowhead Research Corporation (NASDAQ:ARWR) reported that it has changed its corporate name to Arrowhead Pharmaceuticals, Inc (Press release, Arrowhead Research Corporation, APR 6, 2016, View Source [SID:1234510482]). The company’s common stock will continue to trade on the NASDAQ Global Select Market under the existing stock ticker symbol, ARWR. These shares have been assigned a new CUSIP number of 04280A100. Holders of stock certificates with the prior corporate name, need not take any action.

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As part of this name change, the company has also launched a new corporate website at www.arrowheadpharma.com and a new Twitter handle @ArrowheadPharma.

Chris Anzalone, Ph.D., president and CEO of Arrowhead Pharmaceuticals, said: "Now is the time to acknowledge that our key priorities are increasingly focused on advancing products through clinical development to bring innovative new medicines to patients. The name Arrowhead Pharmaceuticals is more consistent with our stage of development as a company and reflects the great progress we’re making on our broad pipeline of RNAi-based drugs."

On April 6, 2016 Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, reported it has entered a worldwide collaboration and license agreement with TESARO, Inc., for exclusive rights to the investigational compound niraparib in prostate cancer (Press release, Johnson & Johnson, APR 6, 2016, View Source [SID:1234510457]). Niraparib is an orally administered poly polymerase (PARP) inhibitor, currently in late-stage development for patients with metastatic breast cancer and ovarian cancer.

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According to terms of the license agreement and collaboration arrangement, Janssen will have global rights and be responsible for all development and commercialization activities for niraparib for use in prostate cancer, except in Japan. TESARO will maintain global development, manufacturing and commercial rights for all other indications.

In addition to an upfront payment, TESARO will be eligible to receive milestone payments, based upon the achievement of specified development, regulatory and commercial milestones, as well as royalties on future worldwide sales.

Separate to the exclusive license and collaboration arrangement, Johnson & Johnson Innovation – JJDC, Inc. will make an equity investment in TESARO.

"PARP inhibitors are an exciting, emerging class of medicines in prostate cancer, and we believe niraparib will perfectly complement our existing portfolio," said Peter F. Lebowitz, M.D., Ph.D., Oncology Therapeutic Area Head, Janssen Research & Development, LLC. "Our team is eager to apply its prostate cancer expertise to niraparib, and enthusiastic about its potential to expand our impact on the lives of men with this disease."

PARP proteins play a key survival role in DNA repair in cancer cells. By inhibiting PARP, certain defective cancer cells are not able to repair themselves, leading to cell death. A portion of men with prostate cancer have these defective cancer cells and may benefit from use of a PARP inhibitor, either alone, or in combination with other treatments.

On April 6, 2016 BIND Therapeutics, Inc. (NASDAQ: BIND), a biotechnology company developing targeted and programmable therapeutics called ACCURINS, reported preliminary top-line results from the BIND-014 (PSMA-targeted docetaxel nanoparticles) phase 2 iNSITE 1 trial in advanced non-small cell lung cancer (NSCLC) of squamous histology and the iNSITE 2 trial in cervical and head and neck cancers (Press release, BIND Therapeutics, APR 6, 2016, View Source [SID:1234510456]).

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In the iNSITE 1 trial, for the primary endpoint, BIND-014 demonstrated a 52.5 percent 6-week disease control rate (6wDCR) for the intent-to-treat population (n=40) and a 70.0 percent 6wDCR in the per protocol population (n=30), which exceeded the protocol defined criteria for success of 65 percent. BIND intends to seek licensing or collaboration opportunities for further development of BIND-014 in NSCLC. In the first stage of the iNSITE 2 trial, for the primary endpoint, BIND-014 demonstrated an objective response rate of 10 percent in the head and neck cancer cohort (n=20); there were no objective responses in the cervical cancer cohort (n=23). Based on these results, BIND has decided to halt further enrollment in the iNSITE 2 trial in advanced cervical and head and neck cancers. Additional details from the iNSITE 1 and iNSITE 2 trials are listed below and the Company expects to present further details at an upcoming medical meeting.

Data from these trials suggest that BIND-014 continues to provide meaningful improvements in safety and tolerability, and at least similar efficacy when administered at a 20 percent lower dose in comparison to historical studies with docetaxel. As a result, the Company believes that these new data further validate the potential of the ACCURINS platform.

"While the single-arm design of these trials precludes definitive conclusions, we remain especially intrigued by the iNSITE 1 data in squamous histology non-small cell lung cancer patients," said Hagop Youssoufian, M.D., chief medical officer, BIND Therapeutics. "We believe these data provide additional clinical validation that ACCURINS successfully widen the therapeutic window of conventional docetaxel. Taken together, we believe these data justify further development of BIND-014 in clinical settings where improved safety and tolerability may be valuable to patients."

Following these results and in connection with the previously announced shift in research and development strategy, BIND also announced a restructuring plan designed to streamline operations and reduce the Company’s operating expenses. The restructuring will include a workforce reduction of 38 percent, and is expected to be substantially complete by the end of April 2016, after which the Company will have 61 employees. In addition, BIND will evaluate options for the Company’s wholly owned subsidiary in Moscow. Collectively, these actions are expected to bring BIND’s quarterly cash burn rate to approximately $6 million per quarter by the third quarter of 2016.

"This workforce reduction is a necessary action to bring our operating costs to a more sustainable level, allowing the ongoing development of our pipeline of innovative therapeutic candidates that address challenges small molecule chemistry or antibody engineering have not been able to overcome," said Andrew Hirsch, president and chief executive officer, BIND Therapeutics. "We truly appreciate the efforts of all of the employees affected by this action and thank them for their dedicated service and contributions to the development of our ACCURINS technology. Furthermore, our decision to continue development of BIND-014 with a collaborator was based on the fact that recent advances in the treatment paradigm for second-line solid tumors have shifted the development, regulatory and reimbursement pathway for BIND-014 such that the capital and resources required to execute on this strategy are more appropriate in collaboration with a larger company."

In addition to the workforce reduction initiatives, the Company is actively working with an investment bank to initiate a review of financial and strategic alternatives with the goal of maximizing stockholder value. Potential alternatives to be explored and evaluated during the review process may include raising additional capital, a strategic collaboration with one or more parties, or the licensing, sale or divestiture of some of the Company’s proprietary technologies. Pending a decision to undertake any financial or strategic alternatives, BIND is continuing its development and collaboration activities in accordance with its current innovative medicines strategy while managing its cash position. There is no finite timetable for completion of the financial and strategic review process.

Shift in Research & Development Focus
In December 2015, BIND announced the appointment of Jonathan Yingling, Ph.D., to the role of chief scientific officer. BIND believes Dr. Yingling has provided the scientific expertise necessary to accelerate BIND’s transformation from a technology platform business focused on improving the therapeutic index of chemotherapeutics to an innovative medicines company focused on leveraging the unique advantages of ACCURINS to maximize clinical benefit for patients. As a result, BIND recently announced a shift in its research and development efforts to focus on developing innovative medicines that incorporate unique combinations of novel tumor-directed targeting ligands and new classes of payloads, including oligonucleotides and molecularly targeted therapies. BIND’s innovative medicines strategy aims to create nanoparticles with synergistic properties by leveraging three differentiating attributes of the ACCURINS technology platform:

ACCURINS can potentially be functionalized with ligands that elicit a biological response and enhance disease tissue accumulation;
ACCURINS are able to incorporate therapeutic payloads with diverse physical and chemical properties, including highly charged APIs; and
ACCURINS can be engineered to optimize the efficacy of the encapsulated drug by controlling its release rate.
"We’ve made significant advances in the ACCURINS technology since BIND-014 was developed in 2009 and we are leveraging those advances to accelerate our new innovative medicines pipeline," said Jonathan Yingling, Ph.D., chief scientific officer at BIND. "In addition to ongoing collaborations that have resulted in molecularly targeted kinase inhibitor ACCURINS, one of which is in phase 1 trials, several new product concepts are being pursued internally. We believe our ACCURINS technology has the potential to create a pipeline of products that elicit tumor cell death, modulate the tumor microenvironment, or both, as a means to maximize clinical benefit for patients."

The Company currently has one kinase inhibitor Accurin, AZD2811, in phase 1 clinical trials in collaboration with AstraZeneca. A second kinase inhibitor Accurin is currently in IND (investigational new drug) -enabling activities through a collaboration with Pfizer. Following optimization of lead product candidates and completion of preclinical studies, BIND anticipates initiation of clinical testing for one or more proprietary innovative product candidates as early as 2018.

iNSITE 1 in squamous histology NSCLC
The Company’s decision to pursue additional development of BIND-014 through a collaboration or licensing opportunity follows an analysis of 40 patients in the intent-to-treat (ITT) population and 30 patients in the per-protocol (PP) population with squamous histology NSCLC.


ITT [n=40] PP[n=30]
6-week Disease Control Rate
(6wDCR) 52.5%
[36.1-68.5]
70.0%
[50.6-85.3]
6wDCR ± 7 days* 70.0%
[53.5-83.4]
86.7%
[69.3-96.2]
Overall Response Rate (ORR) 10.0%
(1 confirmed, 3 unconfirmed)
13.3%
(1 confirmed, 3 unconfirmed)

*Per the study protocol, scans were performed every 6 weeks after Cycle 1 Day 1 and had a ± 7 day allowance. The primary endpoint was strictly defined as disease control rate of 6 weeks or greater which had the effect of excluding patients whose data was gathered within the 7 day allowance of the 6 week timepoint. As a result, patients whose first post-treatment scan occurred between week 5 and week 6 were excluded from the primary analysis. Including these patients in a sensitivity analysis results in an 86.7 percent response rate in the PP population. While the study protocol does not permit the inclusion of these patients in the primary endpoint, the Company believes these data are meaningful.

iNSITE 2 in advanced cervical and head and neck cancers
The primary endpoint of the two-stage iNSITE 2 trial was ORR with a target of at least one response in the first 20 patients for advancement from stage 1 to stage 2. In the head and neck cancer cohort (20 evaluable patients), the ORR was 10 percent; there were no responses in the cervical cancer cohort (23 evaluable patients). Based on these results, the Company has decided to halt further enrollment in the iNSITE 2 trial in advanced cervical and head and neck cancers.
Safety data in more than 300 patients treated with BIND-014 to date continue to demonstrate meaningful improvements in hematologic and non-hematologic toxicities when compared to historical docetaxel data.