November 24, 2015 – Presage Biosciences, an oncology company pioneering a radical new drug development approach that incorporates human efficacy data much earlier in development and clinical trials, reported that it has in–‐licensed voruciclib, its first clinical stage drug program (Press release, Presage Biosciences, NOV 24, 2015, View Source [SID1234520400]).

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Voruciclib is an oral CDK inhibitor that has been in clinical development for cancer indications and will be developed in combination with other standard of care agents. "Using our CIVO platform, we have been able to rapidly identify and understand the biology of voruciclib combinations that hold potential for further clinical development," said Nathan Caffo, President of Presage. "CIVO clearly distinguished voruciclib from other CDK inhibitors in ways that were unexpected." Voruciclib was previously being developed by Piramal Enterprises Limited, one of India’s large diversified companies, with a presence in Healthcare, Healthcare Information Management and Financial Services. "Presage is taking advantage of our unique capabilities to discover and validate effective cancer drug combinations as we develop voruciclib in the clinic," said Richard Klinghoffer, PhD., Chief Scientific Officer of Presage. "Combating drug resistance in cancer requires that clinicians identify the right combinations of drugs for patients at the outset of treatment. We expect that the CIVO platform can play a key role in informing this new approach to cancer drug development." Presage has developed CIVO, a predictive in vivo assessment technology for drug development that enables the first side–‐by–‐side comparison of multiple drugs and combinations within a single living tumor while still in a patient’s body, without exposing the patient to the toxicity of systemic dosing. Presage is actively in–‐licensing promising compounds and using CIVO to develop a portfolio of proprietary oncology therapies. CIVO was shown to accurately predict systemic response to oncology drugs in multiple experiments in human xenografted mouse models. Additional results in canine patients and a first–‐in–‐human study in lymphoma patients are summarized in a study published in the May 2015 issue of Science Translational Medicine by researchers at Fred Hutchinson Cancer Research Center and Presage Biosciences.

On November 24, 2015 Eli Lilly and Company (NYSE: LLY) reported that the U.S. Food and Drug Administration (FDA) has approved Portrazza (necitumumab injection for intravenous use, 800 mg/50 mL), in combination with gemcitabine and cisplatin, as the first biologic for the first-line treatment of people with metastatic squamous non-small cell lung cancer (NSCLC) (Press release, Eli Lilly, NOV 24, 2015, View Source [SID:1234508347]). Portrazza is not indicated for treatment of nonsquamous NSCLC.

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Metastatic squamous NSCLC is a difficult-to-treat form of lung cancer with few treatment options.[1],[2],[3],[4] The five-year survival rate for patients with metastatic disease is less than five percent.[5]

"We have seen advances in lung cancer in the last 20 years, but not for the initial treatment of patients battling metastatic squamous non-small cell lung cancer. This is a complex disease and there is an urgent need for effective, first-line treatments," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "The approval of Portrazza is an important step forward that reaffirms Lilly’s commitment to discovering new treatments that respond to the needs of individual patients."

Portrazza has been granted Orphan Drug Designation by the FDA. Orphan drug status is given in the U.S. by the FDA’s Office of Orphan Products Development (OOPD) to medicines that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.

The Portrazza approval is based on the results of SQUIRE, an open-label, randomized, multi-center Phase III trial that compared first-line treatment with Portrazza in combination with gemcitabine and cisplatin to treatment with gemcitabine and cisplatin alone in patients with metastatic squamous NSCLC. The main outcome measure, or primary endpoint, was overall survival. Portrazza is not indicated for treatment of nonsquamous NSCLC. The labeling for Portrazza contains Boxed Warnings regarding cardiopulmonary arrest and hypomagnesemia. See the full Important Safety Information, including Boxed Warnings, at the end of this press release and the Prescribing Information.

"Lung cancer is an extremely complicated disease that requires a variety of therapy options so doctors can choose an appropriate treatment for each patient’s unique circumstances," said Bonnie J. Addario, founder and chair of the Bonnie J. Addario Lung Cancer Foundation, and a lung cancer survivor. "Today’s approval represents progress for patients diagnosed with metastatic squamous non-small cell lung cancer, as each new therapy advances cancer care and gives patients hope for improved outcomes."

Lilly is committed to offering assistance programs for eligible patients receiving Portrazza, including a co-pay program that allows qualified patients to pay no more than $25 per dose. Patients, physicians, pharmacists or other healthcare professionals with questions about Portrazza should contact The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or visit www.lilly.com.

About Portrazza (necitumumab)

Portrazza (necitumumab), in combination with gemcitabine and cisplatin, is approved for the first-line treatment of people with metastatic squamous non-small cell lung cancer (NSCLC). Portrazza is not indicated for treatment of nonsquamous NSCLC. Portrazza is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human epidermal growth factor receptor 1 (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and inhibition of apoptosis, or cell death. As demonstrated in preclinical studies, EGFR plays a role in the formation (tumorigenesis) and spread (metastasis) of tumors.[6]

About the SQUIRE Trial

SQUIRE was an open-label, randomized, multi-center Phase III trial that compared first-line treatment with Portrazza in combination with gemcitabine and cisplatin to treatment with gemcitabine and cisplatin alone in patients with metastatic squamous NSCLC. Patients on both arms of the study were allowed to receive a maximum of six cycles of chemotherapy. Patients on the Portrazza arm demonstrating at least stable disease continued to receive additional cycles of Portrazza until disease progression or unacceptable toxicity. The trial enrolled 1,093 people with stage IV squamous NSCLC, of which 91 percent had a baseline performance status (PS) 0-1, and nine percent had PS 2. Of patients enrolled, 91 percent had metastatic disease at two or more sites. The SQUIRE study was conducted across 184 investigative sites in 26 countries.[7]

SQUIRE was the first and only randomized Phase III study conducted specifically in patients with metastatic squamous NSCLC to demonstrate a statistically significant improvement in overall survival over gemcitabine and cisplatin alone, specifically in the first-line setting. Portrazza combination therapy showed a statistically significant improvement in overall survival, the main outcome measure (HR 0.84; 95% CI: 0.74-0.96; p=0.01), with a median overall survival of 11.5 months (95% CI: 10.4-12.6) for the Portrazza arm, as compared to 9.9 months (95% CI: 8.9-11.1) for those treated with gemcitabine and cisplatin alone. This translated to a 16 percent reduction in risk of death. The percentage of deaths at the time of analysis was 77 percent (418 patients) on the Portrazza arm and 81 percent (442 patients) on the control arm. The significant survival improvement observed in SQUIRE was supported by a statistically significant improvement in progression-free survival (HR 0.85; 95% CI: 0.74-0.98; p=0.02), with a median progression-free survival (PFS) of 5.7 months (95% CI: 5.6-6.0) on the Portrazza arm, as compared to 5.5 months (95% CI: 4.8-5.6) for those treated with gemcitabine and cisplatin alone. The percentage of events at the time of analysis was 79 percent (431 patients) on the Portrazza arm and 76 percent (417 patients) on the control arm. Overall response rate (ORR) was also assessed and there was no difference between arms, with an ORR of 31 percent (95% CI: 27-35) for the Portrazza plus gemcitabine and cisplatin arm and an ORR of 29 percent (95% CI: 25-33) for the gemcitabine and cisplatin arm (p=0.40).

Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with Portrazza plus gemcitabine and cisplatin as compared to three (0.6%) of 541 patients treated with gemcitabine and cisplatin alone in SQUIRE. Twelve of the 15 patients died within 30 days of the last dose of Portrazza and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within six months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in SQUIRE. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known. Hypomagnesemia occurred in 83 percent of patients receiving Portrazza in combination with gemcitabine and cisplatin, as compared to 70 percent of patients treated with gemcitabine and cisplatin alone. Hypomagnesemia was severe (grade 3 or 4) in 20 percent of patients on the Portrazza plus gemcitabine and cisplatin arm, compared to seven percent of patients on the gemcitabine and cisplatin alone arm. Because of these risks, the Portrazza Prescribing Information contains instructions about monitoring for electrolyte imbalances and treating as necessary. Portrazza labeling contains additional Warnings and Precautions for venous and arterial thromboembolic events (some fatal), dermatologic toxicities, infusion-related reactions, increased toxicity and increased mortality in patients with nonsquamous NSCLC, and embryofetal toxicity. See the full Important Safety Information, including Boxed Warnings, at the end of this press release and the Prescribing Information.

The most common adverse reactions (all grades) observed in Portrazza-treated patients at a rate of > 15 percent and > 2 percent higher than gemcitabine and cisplatin alone were rash (44% vs 6%), vomiting (29% vs 25%), diarrhea (16% vs 11%), and dermatitis acneiform (15% vs 0.6%). The most common severe (grade 3 or higher) adverse events that occurred at a > 2 percent higher rate in Portrazza-treated patients compared to patients treated with gemcitabine and cisplatin alone were venous thromboembolic events (5%; including pulmonary embolism), rash (4%), and vomiting (3%). See the full Important Safety Information, including Boxed Warnings, at the end of this press release and the Prescribing Information.

About Squamous Non-Small Cell Lung Cancer (NSCLC)

NSCLC is the most common type of lung cancer, and accounts for about 85 percent of all lung cancer cases.[8] Squamous NSCLC, which represents about 30 percent of all lung cancer cases, is a devastating, difficult-to-treat form of the disease.[1],[2],[3],[8] Patients face an imposing disease and symptom burden with very poor prognosis; the five-year survival rate for patients with metastatic disease is less than five percent.[5] Until now, little progress has been made over the last two decades, particularly in the first-line setting, leaving a significant unmet medical need.[4]

Lilly PatientOne

The Lilly PatientOne program addresses financial and coverage issues for qualified uninsured, underinsured, and insured patients who are prescribed a Lilly Oncology product. Lilly PatientOne provides reimbursement assistance for eligible patients who are prescribed a Lilly Oncology product, such as information about coding and billing, prior authorization, benefits investigation, and denied claim appeals, as well as operating a patient assistance program. Lilly also offers a co-pay program that allows qualified Portrazza patients to pay no more than $25 per dose. To learn more, visit www.LillyPatientOne.com or call 1-866-4PatOne (1-866-472-8663).

INDICATION

Portrazza is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer. Portrazza is not indicated for treatment of nonsquamous non-small cell lung cancer.

IMPORTANT SAFETY INFORMATION FOR PORTRAZZA

WARNING: CARDIOPULMONARY ARREST and HYPOMAGNESEMIA
Cardiopulmonary arrest and/or sudden death occurred in 3% of patients treated with Portrazza in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after Portrazza administration.

Hypomagnesemia occurred in 83% of patients receiving Portrazza in combination with gemcitabine and cisplatin, and was severe in 20% of patients. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of Portrazza during treatment and for at least 8 weeks following completion of Portrazza. Withhold Portrazza for grade 3 or 4 electrolyte abnormalities. Replete electrolytes as medically appropriate.
Warnings and Precautions

Cardiopulmonary Arrest

Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with Portrazza plus gemcitabine and cisplatin as compared to 3 (0.6%) of 541 patients treated with gemcitabine and cisplatin alone in study 1. Twelve of the 15 patients died within 30 days of the last dose of Portrazza and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in study 1. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium prior to each infusion of Portrazza during treatment and after Portrazza administration for at least 8 weeks after the last dose. Withhold Portrazza for grade 3 or 4 electrolyte abnormalities; subsequent cycles of Portrazza may be administered in these patients once electrolyte abnormalities have improved to grade < 2. Replete electrolytes as medically appropriate.

Hypomagnesemia

Hypomagnesemia occurred in 83% of 461/538 patients with available laboratory results treated with Portrazza as compared to 70% of 457/541 patients with available laboratory results treated with gemcitabine and cisplatin alone in study 1. Hypomagnesemia was severe (grade 3 or 4) in 20% of the patients treated with Portrazza compared to 7% of the patients treated with gemcitabine and cisplatin alone. The median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks) after initiation of Portrazza. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each infusion of Portrazza during treatment, and for at least 8 weeks following the completion of Portrazza. Withhold Portrazza for grade 3 or 4 electrolyte abnormalities; subsequent cycles of Portrazza may be administered in these patients once hypomagnesemia and related electrolyte abnormalities have improved to grade < 2. Replete electrolytes as medically appropriate.

Venous and Arterial Thromboembolic Events (VTE and ATE)

VTE and ATE, some fatal, were observed with Portrazza in combination with gemcitabine and cisplatin. In study 1, the incidence of VTE was 9% in patients receiving Portrazza plus gemcitabine and cisplatin versus 5% in patients receiving gemcitabine and cisplatin alone, and the incidence of grade 3 or higher VTEs was 5% versus 3%, respectively. The incidence of fatal VTEs was similar between arms (0.2% vs 0.2%). The most common VTEs were pulmonary embolism (5%) and deep-vein thrombosis (2%).
The incidence of ATEs of any grade was 5% versus 4%, and the incidence of grade 3 or higher ATE was 4% versus 2% in the Portrazza-containing and gemcitabine and cisplatin arms, respectively, in study 1. The most common ATEs were cerebral stroke and ischemia (2%) and myocardial infarction (1%). In an exploratory analysis of study 1, the relative risk of VTE or ATE was approximately 3-fold higher in patients with a reported history of VTE or ATE than in patients with no reported history of VTE or ATE. Discontinue Portrazza for patients with serious or life-threatening VTE or ATE.

Dermatologic Toxicities

Dermatologic toxicities, including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized rash, skin fissures, maculo-papular rash, and erythema, occurred in 79% of patients receiving Portrazza in study 1. Skin toxicity was severe in 8% of patients. Skin toxicity usually developed within the first 2 weeks of therapy and resolved within 17 weeks after onset. For grade 3 skin reactions, modify the dose of Portrazza. Limit sun exposure. Discontinue Portrazza for severe (grade 4) skin reactions or grade 3 skin induration/fibrosis.

Infusion-Related Reactions (IRRs)

In study 1, 1.5% of Portrazza-treated patients experienced IRRs of any severity with 0.4% grade 3 IRRs. No patients received premedication for IRR for the first dose of Portrazza in study 1. Most IRRs occurred after the first or second administration of Portrazza. Monitor patients during and following Portrazza infusion for signs and symptoms of IRR. Discontinue Portrazza for serious or life-threatening IRR.

Nonsquamous NSCLC—Increased Toxicity and Increased Mortality

Portrazza is not indicated for the treatment of patients with nonsquamous NSCLC. In a study of Portrazza plus pemetrexed and cisplatin (PC) versus PC alone (study 2), patients treated with Portrazza and PC experienced more serious (51% vs 41%) and fatal toxicities (16% vs 10%) and cardiopulmonary arrest/sudden death within 30 days of the last study drug (3.3% vs 1.3%) compared to patients who received PC alone.

Embryofetal Toxicity

Based on animal data and its mechanism of action, Portrazza can cause fetal harm when administered to a pregnant woman. Disruption or depletion of epidermal growth factor receptor (EGFR) in animal models results in impairment of embryofetal development, including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR signaling has resulted in embryolethality as well as postnatal death in animals. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Portrazza and for 3 months following the final dose.

Most Common Adverse Reactions

Adverse reactions (all grades; grade 3/4) that occurred at an incidence rate of > 5% (all grades) or a > 2% (grade 3/4) difference between patients receiving Portrazza plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in study 1 were rash (44% vs 6%; 4% vs 0.2%), dermatitis acneiform (15% vs 0.6%; 1% vs 0%), acne (9% vs 0.6%; 0.4% vs 0%), pruritus (7% vs 0.9%; 0.2% vs 0.2%), dry skin (7% vs 1%; 0% vs 0%), skin fissures (5% vs 0%; 0.4% vs 0%), vomiting (29% vs 25%; 3% vs 0.9%), diarrhea (16% vs 11%; 2% vs 1%), stomatitis (11% vs 6%; 1% vs 0.6%), weight decreased (13% vs 6%; 0.7% vs 0.6%), hemoptysis (10% vs 5%; 1% vs 0.9%), pulmonary embolism (5% vs 2%; 4% vs 2%), headache (11% vs 6%; 0% vs 0.4%), VTE (9% vs 5%; 5% vs 3%), paronychia (7% vs 0.2%; 0.4% vs 0%), and conjunctivitis (7% vs 2%; 0.4% vs 0%).
The most common adverse reactions (all grades) observed in Portrazza-treated patients at a rate of > 15% and > 2% higher than gemcitabine and cisplatin alone were rash (44% vs 6%), vomiting (29% vs 25%), diarrhea (16% vs 11%), and dermatitis acneiform (15% vs 0.6%).

The most common severe (grade 3 or higher) adverse events that occurred at a > 2% higher rate in Portrazza-treated patients compared to patients treated with gemcitabine and cisplatin alone were VTE (5%; including pulmonary embolism), rash (4%), and vomiting (3%).

Clinically relevant adverse reactions (all grades) reported in > 1% and < 5% of patients treated with Portrazza were dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%), phlebitis (2%), and hypersensitivity/IRRs (1.5%).
In study 1, 12% of the patients in the Portrazza arm discontinued study treatment due to an adverse reaction. The most common Portrazza-related toxicity leading to Portrazza discontinuation was skin rash (1%).

Electrolyte abnormalities (all grades; grade 3 or 4) according to laboratory assessment at an incidence rate of > 10% and a > 2% difference between arms in patients receiving Portrazza plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in study 1 included hypomagnesemia (83% vs 70%; 20% vs 7%), hypokalemia (28% vs 18%; 5% vs 3%), hypocalcemia (45% vs 30%; 6% vs 2%), albumin corrected hypocalcemia (36% vs 23%; 4% vs 2%), and hypophosphatemia (31% vs 23%; 8% vs 6%).
The median time to onset of hypomagnesemia was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received Portrazza. In study 1, 32% of the patients in the Portrazza arm and 16% of the patients who received gemcitabine and cisplatin alone received magnesium replacement.

Use in Specific Populations

Pregnancy: Based on animal data and its mechanism of action, Portrazza can cause fetal harm when administered to a pregnant woman. Disruption or depletion of EGFR in animal models results in impairment of embryofetal development, including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR signaling has resulted in embryolethality as well as postnatal death in animals. No animal reproduction studies have been conducted with necitumumab. There are no available data for Portrazza exposure in pregnant women. Advise pregnant women of the potential risk to a fetus and the risk to postnatal development.

Lactation: There is no information regarding the presence of necitumumab in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Portrazza, advise a nursing woman not to breastfeed during treatment with Portrazza and for 3 months following the final dose.
Females of Reproductive Potential: Based on its mechanism of action, Portrazza can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Portrazza and for 3 months following the final dose.

Geriatric Use: Of the 545 patients in the Portrazza plus gemcitabine and cisplatin arm in Study 1, 213 (39%) were 65 years and over, while 108 (20%) were 70 years and over. In an exploratory subgroup analysis of study 1, the hazard ratio for overall survival in patients 70 years or older was 1.03 (95% CI: 0.75, 1.42). Of the adverse reactions that occurred at an incidence rate of > 5% (all grades) or a > 2% (grade 3/4) difference between patients receiving Portrazza plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone, there was a higher incidence ( > 3%) of venous thromboembolic events including pulmonary embolism in patients age 70 and over compared to those who were younger than age 70.
Please click to access full Prescribing Information for Portrazza, including Boxed Warnings for cardiopulmonary arrest and hypomagnesemia at View Source

On November 24, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection, for intravenous use, as a single agent for the treatment of patients with BRAF V600 wild-type (WT) unresectable or metastatic melanoma (Press release, Bristol-Myers Squibb, NOV 24, 2015, View Source [SID:1234508344]). The approval is based on data from the Phase 3 trial, CheckMate -066, which evaluated overall survival as the primary endpoint in treatment-naïve patients with BRAF WT unresectable or metastatic melanoma compared to chemotherapy (dacarbazine).

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"Our focused approach to Immuno-Oncology research is to deliver treatment options that have the potential to improve long-term survival outcomes for patients," said Michael Giordano, M.D., senior vice president, head of Oncology Development, Bristol-Myers Squibb. "Opdivo has become a critical part of the treatment landscape for advanced melanoma patients and their physicians, both as a monotherapy and in combination, and we are committed to exploring opportunities for this treatment across stages of disease and lines of therapy."

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity. Please see additional Important Safety Information section below.

"Advanced melanoma continues to be one of the deadliest and most challenging cancers to treat, and ongoing research in Immuno-Oncology from clinical trials like CheckMate -066 shows the potential to provide improved overall survival for newly diagnosed patients with BRAF wild-type metastatic melanoma," said Jeffrey S. Weber, M.D., PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center. "This important news means that we now have another new option to offer patients with BRAF wild-type metastatic melanoma."

A supplemental Biologics License Application for Opdivo in BRAF V600 mutation positive unresectable or metastatic melanoma, which was filed subsequent to data from CheckMate -066, is still under review with the FDA.

Opdivo Demonstrated Efficacy in Newly Diagnosed BRAF Wild-Type Advanced Melanoma

CheckMate -066 is a Phase 3, randomized, double-blind study of treatment-naïve patients with unresectable or metastatic BRAF WT melanoma. Patients were randomized to receive Opdivo (intravenously 3 mg/kg q2w; n=210) or dacarbazine (intravenously 1000 mg/m2 q3w; n=208). The primary efficacy endpoint of the trial was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR).

In the trial, Opdivo demonstrated superior OS versus chemotherapy in the first-line setting. Results were based on the interim analysis conducted on 47% of the total planned events for OS (50 for the Opdivo arm; 96 for the dacarbazine arm). The median OS was not reached for Opdivo and was 10.8 months (95% CI: 9.3-12.1) in the dacarbazine arm (HR=0.42; 95% CI: 0.30-0.60; p<0.0001). Median PFS more than doubled with Opdivo (5.1 months [95% CI: 3.5-10.8] vs. 2.2 months [95% CI: 2.1-2.4] for patients treated with dacarbazine [HR=0.43; 95% CI: 0.34-0.56; p<0.0001]). ORR with Opdivo was 34% (4% complete response rate, 30% partial response rate [95% CI: 28-41]) compared to 9% with dacarbazine (1% complete response rate, 8% partial response rate [95% CI: 5-13]). At the time of analysis, 88% (63/72) of Opdivo-treated patients had ongoing responses, which included 43 patients with ongoing responses of six months or longer.

Last year, the CheckMate -066 trial was stopped early following a recommendation by the independent Data Monitoring Committee based on their analysis which showed evidence of superior OS in patients receiving Opdivo compared to the control arm. As a result, patients in the trial were unblinded and patients who had received dacarbazine were allowed to receive Opdivo. Dacarbazine was selected as the comparator in this study because, at the time the study protocol was designed, it represented the standard of care in many regions outside of the U.S. where Yervoy had not yet been approved for first-line use.

In the trial, serious adverse reactions occurred in 36% of patients receiving Opdivo. 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%). Adverse reactions led to permanent discontinuation of Opdivo in 7% of patients and dose interruption in 26% of patients. The most common adverse reactions in CheckMate -066 (>20%) reported with Opdivo versus dacarbazine were fatigue (49% vs. 39%), musculoskeletal pain (32% vs. 25%), rash (28% vs. 12%), and pruritus (23% vs. 12%).

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In the U.S., more than 73,000 cases of melanoma will be diagnosed this year and nearly 10,000 people are expected to die from the disease. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year survival rate of 25.5%, making it one of the most aggressive forms of cancer.

Leading Immuno-Oncology Development in Melanoma

Bristol-Myers Squibb is a pioneer in the field of cancer research and treatment known as Immuno-Oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer.

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor, and works by targeting the immune system through the PD-1 immune checkpoint pathway.

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as a monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

About Bristol-Myers Squibb’s Patient Support Programs for Opdivo

Bristol-Myers Squibb remains committed to helping patients through treatment with Opdivo. For support and assistance, patients and physicians may call 1-855-OPDIVO-1. This number offers one-stop access to a range of support services for patients and healthcare professionals alike.

About Bristol-Myers Squibb’s Access Support

Bristol-Myers Squibb is committed to helping patients access Opdivo and offers BMS Access Support to support patients and providers in gaining access. BMS Access Support, the Bristol-Myers Squibb Reimbursement Services program, is designed to support access to BMS medicines and expedite time to therapy through reimbursement support including Benefit Investigations, Prior Authorization Facilitation, Appeals Assistance, and assistance for patient out-of-pocket costs. BMS Access Support assists patients and providers throughout the treatment journey – whether it is at initial diagnosis or in support of transition from a clinical trial. More information about our reimbursement support services can be obtained by calling 1-800-861-0048 or by visiting www.bmsaccesssupport.com. For healthcare providers seeking Opdivo specific reimbursement information, please visit the BMS Access Support Product section by visiting www.bmsaccesssupportopdivo.com.

INDICATIONS and IMPORTANT SAFETY INFORMATION for OPDIVO (nivolumab)

INDICATIONS

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

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with unresectable or metastatic, BRAF V600 mutation-positive melanoma and disease progression following ipilimumab and a BRAF inhibitor. 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), in combination with (ipilimumab), is indicated for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma. 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 treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

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

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

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 037, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=5). In Checkmate 066, immune-mediated pneumonitis occurred in 1.4% (3/206) of patients receiving OPDIVO and in none of the 205 patients receiving dacarbazine: Grade 2 (n=3). 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). In Checkmate 069, pneumonitis, including interstitial lung disease, occurred in 10% (9/94) of patients receiving OPDIVO in combination with YERVOY and 2.2% (1/46) of patients receiving YERVOY. Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving OPDIVO in combination with YERVOY: Grade 5 (n=1), Grade 3 (n=2) and Grade 2 (n=3).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In combination with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 066, diarrhea or colitis occurred in 28% (58/206) of patients receiving OPDIVO and 25% (52/205) of patients receiving dacarbazine. Immune-mediated colitis occurred in 4.9% (10/206) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=5). 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). In Checkmate 069, diarrhea or colitis occurred in 57% (54/94) of patients receiving OPDIVO in combination with YERVOY and 46% (21/46) of patients receiving YERVOY. Immune-mediated colitis occurred in 33% (31/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=1), Grade 3 (n=16), Grade 2 (n=9), and Grade 1 (n=5).

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

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 037, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; Grade 3 (n=2) and Grade 2 (n=1). In Checkmate 066, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the dacarbazine-treated group, with increases in ALT (25% vs. 19%), AST (24% vs. 19%), alkaline phosphatase (21% vs. 14%), and total bilirubin (13% vs. 6%). Immune-mediated hepatitis occurred in 0.9% (2/206) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=1). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 069, immune-mediated hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2 (n=2).

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

Immune-Mediated Dermatitis

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

Immune-Mediated Neuropathies

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

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type I 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 I diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 069, hypophysitis occurred in 13% (12/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=2) and Grade 2 (n=10). In Checkmate 037, 066, 057, <1% of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 069, adrenal insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 037, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Checkmate 066, hypothyroidism occurred in 7% (14/206) of patients receiving OPDIVO (Grade 3 (n=1)) and 0.9% (2/205) of patients receiving dacarbazine. Hyperthyroidism occurred in 4.4% (9/206) of patients receiving OPDIVO (Grade 3 (n=1)) and 0.9% (2/205) of patients receiving dacarbazine. In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated TSH occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 069, hypothyroidism occurred in 19% (18/94) of patients receiving OPDIVO in combination with YERVOY. All were Grade 1 or 2 in severity except for one patient who experienced Grade 3 autoimmune thyroiditis. Grade 1 hyperthyroidism occurred in 2.1% (2/94) of patients receiving OPDIVO in combination with YERVOY. In Checkmate 066, diabetes mellitus or diabetic ketoacidosis occurred in 1.0% (2/206) of patients receiving OPDIVO and none of the 205 receiving dacarbazine; Grade 3 diabetic ketoacidosis (n=1) and Grade 2 diabetes mellitus (n=1).

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

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 037, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Checkmate 066, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the dacarbazine-treated group (11% vs. 10%). Grade 3 immune-mediated renal dysfunction occurred in 0.5% (1/206) of patients. In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 069, Grade 2 or higher immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94) of patients. One patient died without resolution of renal dysfunction.

Immune-Mediated Rash

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

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. Across clinical trials of 8490 patients receiving OPDIVO as a single agent or in combination with YERVOY, <1.0% of patients were identified as having 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. The following clinically significant immune-mediated adverse reactions occurred in <1.0% of OPDIVO-treated patients: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, systemic inflammatory response syndrome, Guillain-Barre syndrome and hypopituitarism. Across clinical trials of OPDIVO administered as a single agent at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome. Across clinical trials of OPDIVO in combination with YERVOY, the following additional clinically significant, immune-mediated adverse reactions were identified: sarcoidosis, duodenitis, and gastritis.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO as a single agent. 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 and 066, Grade 2 infusion reactions occurred in 1.0% (5/493) of patients receiving OPDIVO. In Checkmate 069, Grade 2 infusion reactions occurred in 3.2% (3/94) of patients receiving OPDIVO in combination with YERVOY.

Embryofetal Toxicity

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

Lactation

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

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. 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 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. In Checkmate 069, serious adverse reactions occurred in 62% of patients receiving OPDIVO; the most frequent serious adverse events with OPDIVO in combination with YERVOY, as compared to YERVOY alone, were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). 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%). In Checkmate 069, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO in combination with YERVOY vs YERVOY alone were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).

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

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

Please see U.S. Full Prescribing Information for OPDIVO.

Indication

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

Important Safety Information

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) 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.

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

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.

Recommended Dose Modifications

Endocrine: Withhold YERVOY for systemic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-mediated Enterocolitis

Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3-5 days or recurring after symptom improvement. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Immune-mediated Hepatitis

Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).

Immune-mediated Dermatitis

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., 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 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis.

Immune-mediated Neuropathies

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barre-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.

Immune-mediated Endocrinopathies

Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in Trial 1, 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 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY.

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.

Embryo-fetal Toxicity

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY.

Lactation

It is not known whether YERVOY is secreted in human milk. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Common Adverse Reactions

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

On November 24, 2015 Adaptimmune Therapeutics plc (Nasdaq: ADAP) reported that it has initiated a study of its affinity enhanced T-cell therapy targeting the NY-ESO-1 cancer antigen in patients with Stage IIIb or Stage IV non-small cell lung cancer (NSCLC), the most common type of lung cancer, representing approximately 85 percent of lung cancers (Press release, Adaptimmune, NOV 24, 2015, View Source [SID:1234508343]). Adaptimmune is developing the affinity enhanced T-cell therapy targeting NY-ESO-1 under a collaboration agreement with GlaxoSmithKline (GSK).

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"Lung cancer is the most common cancer worldwide and it is the leading cause of all cancer-related deaths, responsible for approximately 1 in 5 cancer deaths. NSCLC accounts for the vast majority of these cancer deaths and thus represents a great unmet medical need," commented Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "Our NY-ESO TCR therapeutic candidate is being studied in a number of solid tumors and hematological malignancies including synovial sarcoma, multiple myeloma, melanoma, ovarian cancer and gastric and esophageal cancer, and we are excited to initiate this study in patients with NSCLC. This new study marks an important step toward further elucidating the tolerability profile and anti-cancer activity of our promising therapeutic candidate in another cancer, and towards potentially reaching our goal of offering cancer patients an efficacious alternative therapy to current treatments."

This is an open label clinical study in up to 10 patients with locally advanced or metastatic NSCLC and whose disease has progressed or not responded to prior therapies. The company expects to begin dosing of patients shortly.

Patients with the HLA-A*0201, HLA-A*0205, and/or HLA-A*0206 allele, whose tumor expresses the NYESO-1 tumor antigen, and who meet study entry criteria will be eligible to receive a single dose of autologous genetically modified T-cells expressing affinity optimized TCRs specific for NY-ESO-1. Though the prevalence of HLA sub-types varies from population to population, the most common in the western world is HLA-A2. Among the HLA-A2 variants, the most prevalent are HLA-A*0201 and HLA-A*0206. The
primary objective of this study is to evaluate the safety and tolerability of Adaptimmune’s affinity enhanced T-cell therapy targeting NY-ESO in HLA-A*0201, HLA-A*0205 and/or HLA-A*0206 positive patients with NY-ESO-1 positive advanced NSCLC. Secondary objectives include evaluation of efficacy in these patients, measurement of persistence of genetically modified cells in the body, and evaluations of the phenotype and functionality of genetically modified cells isolated from peripheral blood or tumor post infusion.

For more information on this clinical trial, please visit ClinicalTrials.gov at: View Source (Identifier: NCT02588612).

About NSCLC
Lung cancer is the most common cancer worldwide, and is the leading cause of cancer deaths in both men and women in the United States. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. Non-small cell lung cancer, or NSCLC, is the most common type of lung cancer, representing approximately 85 percent of lung cancers. There are 3 main subtypes of NSCLC. Approximately 40 percent of lung cancers are adenocarcinomas, which start in early versions of the cells
that would normally secrete substances such as mucus. This type of lung cancer occurs mainly in current or former smokers, but it is also the most common type of lung cancer seen in non-smokers. Approximately 25 to 30 percent of all lung cancers are squamous cell carcinomas, which start in early versions of squamous cells which line the inside of the airways in the lungs and are generally linked to a history of smoking. Large cell (undifferentiated) carcinoma account for 10 to 15 percent of lung cancers
and can appear in any part of the lung.