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New Findings Show Durable Anti-Tumor Activity with KEYTRUDA® (pembrolizumab), Merck’s Anti-PD-1 Therapy, in Patients with Advanced Head and Neck Cancer, Regardless of PD-L1 Expression Status

On May 29, 2015 Merck reported new investigational data evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy from the KEYNOTE-012 Phase 1b study in 132 pre-treated patients with recurrent or metastatic head and neck cancer, regardless of PD-L1 expression status (Press release, Merck & Co, MAY 29, 2015, View Source [SID:1234504899]). In the evaluable patients, the overall response rate (ORR) (confirmed and unconfirmed) was 24.8 percent for KEYTRUDA (200 mg fixed dose every three weeks) (n=29/117) (95% CI, 17.3-33.6). When looking at HPV status, the ORR was similar among HPV-positive and HPV-negative disease (20.6 percent [n=7/34] and 27.2 percent [n=22/81], respectively) (95% CI, 8.7-37.9 and 17.9-38.2). These data, featured in the ASCO (Free ASCO Whitepaper) Press Program today, will be presented in an oral session by Dr. Tanguy Seiwert, The University of Chicago, on Monday, June 1 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #LBA6008).

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Merck has initiated a comprehensive clinical development program for KEYTRUDA evaluating a fixed dosing regimen (200 mg every three weeks) in head and neck cancer across multiple lines of therapy as monotherapy and in combination with chemotherapy and other agents. Results from KEYNOTE-012 were first presented at the 2014 ASCO (Free ASCO Whitepaper) Annual Meeting and showed 19.6 percent ORR for KEYTRUDA (10 mg/kg every two weeks) in heavily pre-treated patients with advanced head and neck cancer with tumor cells positive for PD-L1 expression.

"Advanced head and neck cancer is a severe and life-altering condition. Unfortunately we have few effective treatment options, particularly for patients whose disease is not responding to current therapies," said Dr. Seiwert. "As a practicing oncologist, I am very encouraged by the durable responses demonstrated with pembrolizumab in this study, and look forward to data being shared in the future from the additional confirmatory studies now being conducted in advanced head and neck cancer."

"The totality of the data presented at ASCO (Free ASCO Whitepaper) furthers our understanding of the clinical potential of KEYTRUDA in head and neck cancer, regardless of PD-L1 expression or HPV status," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Based on the results observed to date, we are advancing multiple registrational studies in head and neck cancer including randomized evaluations of overall survival and progression-free survival with KEYTRUDA, as monotherapy and in combination with chemotherapy, compared to standard of care."

Additional Results from KEYNOTE-012 in Advanced Head and Neck Cancer

Additional findings from KEYNOTE-012, the first and largest Phase 1b study of an anti-PD-1 therapy in advanced head and neck cancer, showed tumor shrinkage was achieved in 56 percent of total evaluable patients who had measurable disease with one post baseline scan (n=59/106). The median duration of response was not reached (7.3+ – 25.1+ weeks among patients with a confirmed response), with a median follow up duration of 5.7 months (0.2 – 8.7 months). At the time of the analysis, 86 percent of patients who responded continued to respond to treatment (n=25/29). The data are based on an analysis conducted with a cut-off of March 23, 2015.

Adverse events in the study were consistent with previously reported safety data for KEYTRUDA (n=132). The most common treatment-related adverse events (occurring in greater than or equal to 5% of patients) included: fatigue (15.2%), hypothyroidism (9.1%), decreased appetite (7.6%), rash (7.6%), dry skin (6.8%), and pyrexia (6.8%). Some patients experienced adverse events of special interest, including hypothyroidism (10.6%), pneumonitis (3.0%), thyroiditis (2.3%), colitis (0.8%), interstitial lung disease (0.8%), acquired epidermolysis bullosa (0.8%), drug induced liver injury (0.8%), epidermolysis (0.8%), and diabetic ketoacidosis (0.8%). Four patients experienced adverse events of special interest that resulted in treatment discontinuation. There were no treatment-related deaths.

About the KEYNOTE-012 Study

KEYNOTE-012 is an ongoing multi-center, non-randomized Phase 1b trial evaluating the safety, tolerability and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg every two weeks or 200 mg IV every three weeks) in patients with advanced triple negative breast cancer (TNBC), advanced head and neck cancer, advanced urothelial cancer, or advanced gastric cancer. The primary endpoints of the study include overall safety, tolerability, and anti-tumor activity (as measured by RECIST v1.1); secondary endpoints include progression-free survival (PFS), overall survival (OS), and duration of response.

About Head and Neck Cancer

Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. The leading modifiable risk factors for head and neck cancer include tobacco and heavy alcohol use. Other non-modifiable risk factors include infection with certain types of HPV, also called human papillomaviruses. Each year there are approximately 400,000 cases of cancer of the oral cavity and pharynx, in addition to approximately 160,000 cancers of the larynx, resulting in approximately 300,000 deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Lilly and AstraZeneca to Collaborate on Immuno-Oncology Combination Clinical Trial in Solid Tumors

On May 29, 2015 Eli Lilly and AstraZeneca reported that they have entered into a clinical trial collaboration to evaluate the safety and preliminary efficacy of AstraZeneca’s investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, in combination with CYRAMZA (ramucirumab), Lilly’s VEGF Receptor 2 antiangiogenic cancer medicine (Press release, Eli Lilly, MAY 29, 2015, View Source [SID:1234504896]). The planned study will assess the combination as a treatment for patients with advanced solid tumors.

The Phase I study is expected to establish the safety and a recommended dosing regimen – with the potential to open expansion cohorts in various tumors of interest – for the combination of MEDI4736 and ramucirumab. Under the terms of the agreement, the trial will be sponsored by Lilly. Additional details of the collaboration, including tumors to be studied and financial terms, were not disclosed.

MEDI4736 is a monoclonal antibody, developed by MedImmune, AstraZeneca’s global biologics research and development arm, directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Ramucirumab is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C and VEGF-D. Preclinical data indicate that combining VEGFR inhibitors with immune checkpoint blockades has the potential to enhance anti-tumor activity.

"The development of immune checkpoint inhibitors has been one of the more exciting research advancements in recent oncology history, but it is going to be even more interesting to see how these inhibitors can be combined with other proven targeted therapies," said Richard Gaynor, M.D., senior vice president, product development and medical affairs, Lilly Oncology. "This collaboration represents the next wave of immuno-oncology research by bringing together two innovative medicines – Lilly’s CYRAMZA and AstraZeneca’s MEDI4736 – as a novel combination that we hope will one day provide new cancer treatment solutions."

Robert Iannone, head of immuno-oncology, global medicines development at AstraZeneca, said, "We believe that combination therapy in immuno-oncology has the potential to transform the way cancer is treated. MEDI4736 is supported by a comprehensive development program and is emerging as a cornerstone of our combination-focused immuno-oncology pipeline targeting multiple tumor types. Our collaboration with Lilly is a great addition to our program and provides the opportunity to explore another exciting, novel combination that could deliver important clinical benefit to cancer patients."

Opdivo (nivolumab) First PD-1 Inhibitor to Demonstrate Superior Overall Survival Versus Standard of Care (docetaxel) in Previously-Treated Non-Squamous Non-Small Cell Lung Cancer in Pivotal Phase III Trial

On May 29, 2015 Bristol-Myers Squibb reported that Opdivo (nivolumab) is the first PD-1 inhibitor to demonstrate superior overall survival versus standard of care (docetaxel) in an open-label, randomized Phase III study (CheckMate -057) evaluating previously-treated patients with advanced, non-squamous non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, MAY 29, 2015, View Source [SID:1234504895]).

A 27% reduction in the risk of progression or death – the primary study endpoint – was reported for Opdivo (n=292) versus docetaxel (n=290) based upon a hazard ratio of 0.73 (96% CI, 0.59-0.89; P = 0.0015). Opdivo was associated with a doubling of overall median survival across the continuum of PD-L1 expression, starting at 1% level of expression, in the trial. The safety profile of Opdivo in CheckMate -057 was favorable versus docetaxel with grade 3–5 treatment-related adverse events reported in 10% of patients who were treated with Opdivo versus 54% in the docetaxel arm.

These data will be featured today, May 29, during the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) press briefing at 1:00 – 2:00 PM CDT and presented during a clinical science symposium on Saturday, May 30 from 8:51 – 9:03 AM CDT (Late Breaking Abstract #109).

"CheckMate -057 results reported today mark a milestone in the development of new treatment options for lung cancer, as Opdivo is the first PD-1 inhibitor to show a significant improvement in overall survival in a Phase III trial in non-squamous non-small cell lung cancer compared with the current standard of care, docetaxel," said Luis Paz-Ares, MD, Hospital Universitario Doce de Octubre, Madrid, Spain. "Our goal with clinical cancer research is to always look for new options that may improve upon, or in some cases replace, current standard of care. The CheckMate -057 results represent progress toward establishing a new standard of care that may replace docetaxel in PD-L1 expressers."

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. Lung cancer results in more deaths worldwide than colorectal, breast and prostate cancers combined. Non-small cell lung cancer is one of the most common types of the disease and accounts for approximately 85% of cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed.

"The survival results from this Phase III trial, as well as from CheckMate -017 in squamous NSCLC, validate the Bristol-Myers Squibb development strategy for Opdivo to improve survival expectations for patients with lung cancer," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "The CheckMate -057 results defined the role for PD-L1 expression, based upon an overall survival endpoint and showed that patients whose tumor expressed PD-L1 at 1% or greater levels achieved a doubling of overall survival. This represents a significant scientific advance in non-small cell lung cancer."

About CheckMate -057

CheckMate -057 is a landmark Phase III, open-label, randomized clinical trial that evaluated patients with advanced non-squamous NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The trial included patients regardless of their PD-L1 status. Secondary endpoints included objective response rate, progression-free survival and efficacy by tumor PD-L1 expression. Patients enrolled in the trial were administered Opdivo 3 mg/kg every two weeks versus standard of care, docetaxel, at 75 mg/m2 every three weeks.

In addition to improving overall survival, Opdivo demonstrated a superior objective response rate of 19% versus 12% for docetaxel (P = 0.0246). The median duration of response for Opdivo was 17.2 months versus 5.6 months for docetaxel, and median time to response of 2.1 months vs. 2.6 months, respectively.

CheckMate -057 also evaluated the efficacy of Opdivo by tumor PD-L1 expression. Of randomized patients, 78% (455/582) had tumor samples allowing the assessment of PD-L1 expression. Rates of PD-L1 expressing tumors were balanced between groups. Across pre-specified 1%, 5%, and 10% expression levels, PD-L1 status was predictive for benefit from Opdivo. In patients with PD-L1 expressing tumors, Opdivo demonstrated improved efficacy across all endpoints at all expression levels.

The safety profile of Opdivo in CheckMate -057 was consistent with prior studies and favorable versus docetaxel. Safety profile also was similar across expressers and non-expressers. Treatment-related adverse events were low in severity with Opdivo and occurred less frequently (any grade: 69%; grade 3–4: 10%) than docetaxel (any grade: 88%; grade 3–4: 54%), including both hematologic and non-hematologic toxicities. Treatment-related serious adverse events were reported less frequently with Opdivo (any grade: 7.3%; grade 3–4: 5.2%) than docetaxel (any grade: 20%; grade 3–4: 18%). Discontinuation due to treatment–related adverse events was less frequent with Opdivo (5%) than docetaxel (15%).

Proven Efficacy Across Histologies in Lung Cancer

CheckMate -057 is the second positive Phase III trial to demonstrate superior overall survival for Opdivo in non-small cell lung cancer. Earlier this year, the Phase III CheckMate -017 trial was stopped early due to superior overall survival versus docetaxel in previously-treated advanced squamous non-small cell lung cancer and formed the basis of the company’s first indication in lung cancer from the U.S. Food & Drug Administration’s (FDA) approval for Opdivo. Trial results from CheckMate -017 will be presented at ASCO (Free ASCO Whitepaper) during an oral abstract session on Sunday, May 31 from 4:30 – 4:42 PM CDT (Abstract #8009).

Phase I/II Opdivo (nivolumab) Trial Shows Bristol-Myers Squibb’s PD-1 Immune Checkpoint Inhibitor is First to Demonstrate Anti-Tumor Activity In Patients With Hepatocellular Carcinoma

On May 29, 2015 Bristol-Myers Squibb reported results from an interim analysis of CA209-040, a Phase I/II dose-ranging trial evaluating the safety and anti-tumor activity of Opdivo (nivolumab) in previously-treated patients with hepatocellular carcinoma (HCC) or advanced liver cancer (Press release, Bristol-Myers Squibb, MAY 29, 2015, View Source [SID:1234504892]).

Initial findings demonstrated that the estimated survival rate in evaluable patients (n=47) was 62% at 12 months. Results also show the safety profile of Opdivo is generally consistent with that previously-reported for Opdivo in other tumor types. These data will be featured today, May 29, during the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) press briefing at 1:00 – 2:00 p.m. CDT and presented on Saturday, May 30 from 8:27 a.m. – 8:39 a.m. CDT (Late Breaking Abstract #101).

"Hepatocellular carcinoma is an aggressive and fatal cancer, comprising 90 percent of all liver cancer in adults worldwide with limited therapeutic options for patients with advanced stage disease; no treatment advances have been made for patients who fail to respond or progress on the current standard of care," said Anthony B. El-Khoueiry, MD, lead study author and associate professor of clinical medicine and phase I program director at the University of Southern California Norris Comprehensive Cancer Center. "These preliminary data are encouraging and support the ongoing evaluation of nivolumab in this patient population, as they show promising preliminary survival data, and durable partial or complete response in one out of five nivolumab-treated patients, with many others experiencing stable disease."

More than 700,000 people around the world are diagnosed with HCC each year with a majority of all HCC cases caused by infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV), making HBV/HCV the most common risk factor for liver cancer worldwide. Patients with advanced HCC receiving the current standard of care have a median overall survival of less than 1 year. For patients who have relapsed or have disease progression, median survival with best supportive care is approximately 7 to 8 months.

"Bristol-Myers Squibb’s experience in hepatitis and Immuno-Oncology make us poised as leaders to advance Opdivo into additional studies of hepatocellular carcinoma," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Opdivo has demonstrated improvements in survival in a number of different tumor types. We are excited that this trial has shown the potential that this may extend to advanced liver cancer and hope to confirm these findings in future trials."

About the CA209-040

CA209-040 is a Phase I/II dose-ranging trial that evaluated the safety and anti-tumor activity of Opdivo in patients with HCC, the majority of whom had received prior treatment. The trial included 47 HCC patients who were enrolled into one of three treatment arms depending on whether or not they were infected with HCV or HBV. Patients enrolled in the trial received Opdivo doses ranging from 0.1 – 10 mg/kg intravenously every 2 weeks for up to 2 years. The primary objective was safety, tolerability, dose limiting toxicities, and maximum tolerated dose. Anti-tumor activity was a secondary objective (using RECIST 1.1 criteria), and overall survival was an exploratory objective.

As of this interim analysis, 62% of patients in the study were still alive after 12 months. Eight (19%) patients (of 42 evaluable patients) achieved a complete or partial response, meaning that the size of their tumors measured at baseline decreased by 30–100% with Opdivo treatment. In patients with response, duration of response ranged from more than 1.4 – 12.5 months. Seventeen patients remained on study treatment and 30 discontinued treatment due to progressive disease (n=26), complete response (n=2), or adverse events (n=2).

CA209-040 is the first trial to characterize the safety profile of Opdivo monotherapy in patients with HCC, including those with HCV and HBV infections. In the trial, safety and tolerability were well-characterized, with the frequency and intensity of treatment-related adverse events (AEs) being consistent across Opdivo dose levels. The majority of side effects were mild to moderate in nature with abnormal liver enzymes (19% AST and 15% ALT), rash (17%) and elevation of amylase (15%) and lipase (17%) being the most common; the abnormal liver enzymes and elevated amylase and lipase were not accompanied by any significant clinical symptoms. Grade 3–4 treatment-related AEs were infrequent (19%). There were no treatment-related deaths reported.

About Opdivo

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

Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, 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; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, 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; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, 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; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, 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 Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, 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 Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

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

Lactation

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

Serious Adverse Reactions

In Trial 1, 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 Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Pfizer’s RAPAMUNE® (sirolimus) Becomes First FDA-Approved Treatment for Lymphangioleiomyomatosis (LAM), A Rare Progressive Lung Disease

On May 29, 2015 Pfizer reported that the U.S. Food and Drug Administration (FDA) has approved RAPAMUNE (sirolimus) for the treatment of lymphangioleiomyomatosis (LAM), a rare, progressive disease that affects the lungs, kidneys and the lymphatic system (Press release, Pfizer, MAY 29, 2015, View Source [SID:1234504888]). This is the first approved treatment that helps stabilize lung function in patients with LAM.

"Pfizer is proud to gain approval for RAPAMUNE as the first treatment for patients with LAM, through our work with the FDA, the clinical investigation team and the LAM Foundation," said Rory O’Connor, MD, senior vice president and head of Global Medical Affairs, Global Innovative Pharmaceuticals Business, Pfizer Inc. "This type of cooperative effort creates opportunities for innovation in developing therapies for patients with rare diseases."

LAM is a rare progressive lung disease that usually affects women during their childbearing years and can result in abnormal growth of smooth muscle cells in the lung. Over time, the muscle growth can cause airway obstructions and limit the delivery of oxygen to the body. Approximately 800 patients in the U.S. are currently diagnosed with LAM, which is a rare disease and is often fatal. RAPAMUNE is also approved in the U.S. as an immunosuppressive agent for the prophylaxis of organ rejection in kidney transplant patients aged 13 years and older.

The FDA approval is based on the results from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus or MILES Trial. The MILES Trial included 89 LAM patients with moderate lung impairment and showed that those treated with RAPAMUNE for one year experienced stabilization of lung function measured by forced expiratory volume in one second (FEV1). The adverse drug reactions observed in this trial were consistent with the known safety profile for renal transplant patients receiving RAPAMUNE, with the addition of weight decreased, which was reported at a greater incidence with RAPAMUNE versus placebo. Serious adverse events were reported more frequently during the treatment period in patients receiving RAPAMUNE compared to the placebo group.

"I am thrilled for families living with LAM," said Dr. Francis X. McCormack, director of Pulmonary, Critical Care and Sleep Medicine at the University of Cincinnati College of Medicine and lead investigator of the MILES Trial. "The courage of the women who enrolled in the MILES trial made this possible. I am proud of the 200 investigators, coordinators and nurses who participated in the MILES trial that enabled FDA approval, and I sincerely thank all who supported the study."

Pfizer worked with the FDA, Dr. McCormack and the LAM Foundation to evaluate RAPAMUNE as a treatment option for LAM in the United States. The MILES trial was conducted by Dr. McCormack and conducted within the National Institutes of Health Rare Lung Diseases Consortium. Pfizer provided study drug and a portion of the funding but had no involvement in the design or conduct of the study. The LAM Foundation assisted with the recruitment of patients and logistics for the study.

"This approval is a landmark breakthrough for LAM patients to have access to this important treatment option," said Susan E. Sherman, executive director of the LAM Foundation. "It is the result of decades of work by researchers and women of the LAM community who volunteered for this pivotal clinical trial."

About RAPAMUNE

RAPAMUNE is an immunosuppressive agent indicated in the United States for the prophylaxis of organ rejection in patients aged 13 years and older receiving kidney transplants. It is prescribed to kidney transplant patients to help prevent their natural immune system from rejecting the transplanted kidney. RAPAMUNE is also indicated for the treatment of patients with LAM. Therapeutic drug monitoring is recommended for all patients receiving RAPAMUNE. RAPAMUNE has a boxed warning for infections and certain cancers. Please see the full prescribing information, including boxed warning and full indications at www.pfizer.com/products/product-detail/rapamune.

Important Safety Information

There is an increased risk of developing infections or certain cancers, especially lymphoma and skin cancers.RAPAMUNE (sirolimus) has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take RAPAMUNE after a liver or lung transplant. You should not take RAPAMUNE if you have had a liver or lung transplant without talking with your doctor.

Do not take RAPAMUNE if you know you are allergic to sirolimus or any of the other ingredients in RAPAMUNE. Symptoms of an allergic reaction include swelling of your face, eyes, or mouth; trouble breathing or wheezing; throat tightness; chest pain or tightness; feeling dizzy or faint; and rash or peeling of your skin.

Before taking RAPAMUNE, tell your doctor if you have liver problems, skin cancer or it runs in your family, high cholesterol or triglycerides, are breastfeeding or plan to breastfeed, and are pregnant or plan to become pregnant. Women of childbearing potential should use effective birth control before therapy, during therapy, and for 12 weeks after RAPAMUNE therapy has been stopped. RAPAMUNE may interact with other medicines. Make sure that your doctor is aware of all prescription and over-the-counter drugs that you are taking, including vitamins, herbs, and nutritional supplements.

RAPAMUNE may cause swelling in your hands, feet, and in various tissues of your body. Call your doctor if you have trouble breathing.

RAPAMUNE may cause your wounds to heal slowly or not heal well resulting in redness, drainage, or opening of the wound.

RAPAMUNE may increase the levels of cholesterol and triglycerides (lipids or fat) in your blood. Your doctor should do blood tests to check your lipids during treatment with RAPAMUNE. Your doctor may recommend treatment if your lipid levels become too high. Your lipid levels may remain high even if you follow your prescribed treatment plan.

In patients taking RAPAMUNE with cyclosporine, decreased kidney function has been observed. Your doctor will regularly check your kidney function.

RAPAMUNE may increase protein in your urine. Your doctor may monitor you for abnormal protein in your urine from time to time.

RAPAMUNE may increase your risk for viral infections. Certain viruses can live in your body and cause active infections when your immune system is weak. One of these viruses, BK virus, can affect how your kidney works and cause your transplanted kidney to fail. A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy causing death or severe disability.

RAPAMUNE may cause potentially life-threatening lung or breathing problems. Symptoms may include coughing, shortness of breath, or difficulty breathing.

When RAPAMUNE is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem resulting in unexplained bleeding or bruising.

The most common side effects of RAPAMUNE in people with renal transplant include high blood pressure, pain (including stomach and joint pain), diarrhea, headache, fever, urinary tract infection, low red blood cell count (anemia), nausea, and low platelet count (cells that help blood to clot), and high blood sugar (diabetes).

The most common side effects of RAPAMUNE in people with LAM include mouth sores, diarrhea, stomach pain, nausea, sore throat, acne, chest pain, upper respiratory tract infection, headache, dizziness, and sore muscles.

Tell your doctor if you have any side effect that bothers you or that does not go away.