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]).

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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%).

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.

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"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.

On May 29, 2015 Peregrine Pharmaceuticals reported that the company has entered into a sponsored research agreement with Memorial Sloan Kettering Cancer Center (MSK) to explore the potential of Peregrine’s proprietary phosphatidylserine (PS)-targeting antibody platform (Press release, Peregrine Pharmaceuticals, MAY 29, 2015, View Source [SID:1234504887]). The goal of the research is to identify effective treatment combinations based on Peregrine’s PS-targeting agents, including Peregrine’s lead clinical agent bavituximab, with other checkpoint inhibitors or immune stimulating agents that will further guide the bavituximab clinical development program.

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The studies at MSK will be performed under the direction of Taha Merghoub, Ph.D., Associate Attending Biologist, Melanoma and Immunotherapeutics Service, Ludwig Collaborative and the Swim Across America Laboratory, a part of the laboratory of Jedd D. Wolchok, M.D., Ph.D., a leader in the field of cancer immunotherapy. Dr. Wolchok serves as the Chief, Melanoma and Immunotherapeutics Service, Lloyd J. Old Chair for Clinical Investigation as well as an Associate Director of the Ludwig Center for Cancer Immunotherapy at MSK.

"The phosphatidylserine (PS) signaling pathway is a very interesting target for modulating the immune system’s response to cancer. We look forward to exploring the potential of PS-targeting agents alone and with other immune modulators that may lead to novel advances in cancer therapy," said Dr. Wolchok.

As part of the collaboration, researchers at MSK will conduct research to further explore the combination of PS-targeting agents, including bavituximab, that block a primary immunosuppressive pathway thereby allowing anti-tumor immune responses with other immuno-stimulatory agents that enhance immune responses. Specifically, MSK researchers will examine the combination of bavituximab alongside models of checkpoint blockade that are unresponsive to inhibition or co-stimulation given the ability of bavituximab to reprogram myeloid derived suppressor cells (MDSC) and increase tumoricidal T-cells in tumors, a mechanism of action that is complementary to checkpoint blockade and T-cell activation.

"A key focus of the Wolchok Lab’s research is studying novel immunotherapy combinations that work together to enable the immune system to recognize and destroy cancer. This collaboration will allow us to focus on the role and contribution of PS blockade therapy in determining which combination of the current and next generation of immune modulators is likely to increase the extent and amplitude of anti-tumor response. This important pre-clinical and translational work will potentially guide the design of the next generation of clinical studies with bavituximab," said Dr. Merghoub.

"We are delighted to be working with a world-renowned pioneer and leader in the immuno-oncology space, recognizing that there remains significant research in order for more cancer patients to realize the benefits of combination immune therapy," said Jeff T. Hutchins, Ph.D., VP of Preclinical Research at Peregrine. "Our internal and collaborative research presented over the last year has established a robust foundation of PS-targeting activity on which to initiate this next chapter in PS research and development."

"This collaboration is an important extension of our established research efforts to further explore and understand the potential of our PS-targeting platform including bavituximab our lead clinical candidate. This research will focus on better understanding how treatment with PS-targeting agents can assist other anti-tumor immunotherapies in order to work better," said Steven King, chief executive officer of Peregrine. "Our goal is to change the way cancer patients are treated by allowing their immune system to recognize and fight their disease. This collaboration will undoubtedly assist us in identifying potential new opportunities to better treat patients with cancer."

Peregrine’s antibodies target and bind to phosphatidylserine (PS), a highly immunosuppressive molecule normally located on the interior of cellular membranes, but, following stresses in the tumor environment, becomes exposed on tumor cells and cells that line tumor blood vessels, helping tumors to evade immune detection. PS-targeting antibodies block this immunosuppressive signal, thereby enabling the immune system to better recognize and fight the tumor. Preclinical data show that the combination of bavituximab and inhibitors of immune checkpoints reduce tumor-suppressive factors including myeloid-derived suppressor cells and confer increased tumor-specific immunity when compared to either treatment alone.

On May 29, 2015 and Merck reported an expanded collaboration to evaluate the efficacy and safety of talimogene laherparepvec, Amgen’s investigational oncolytic immunotherapy, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in a Phase 1, open-label trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) (Press release, Amgen, MAY 29, 2015, View Source [SID:1234504883]).

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In addition, the companies announced that a global, randomized Phase 3 trial evaluating the combination in patients with regionally or distantly metastatic melanoma is being initiated. As previously announced, the compounds are being studied in a Phase 1, open-label trial in this patient population.

Both immunotherapies are designed to modulate the immune system. Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumors (but not normal tissue) and to initiate an immune response against cancer cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2.

"We believe that talimogene laherparepvec has potential in several cancer types based on its proposed mechanism of action to initiate tumor antigen release and presentation, important steps in activating a systemic anti-tumor immune response," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Talimogene laherparepvec and KEYTRUDA are designed to result in anti-tumor immune responses through different and potentially complementary mechanisms of action. We hope these trials will provide us with insights on the combination of these therapies for patients with this form of cancer for whom treatment options are currently limited. We will discuss the design of the Phase 3 melanoma trial with global regulators and look forward to collaborating with Merck on this study."

"Expanding our collaboration with Amgen is a testament to our belief in the potential for immuno-oncology therapies to change the way we approach the treatment of many cancers, including advanced head and neck cancer where the options are limited," said Dr. Eric Rubin, vice president and therapeutic head, oncology early stage development, Merck Research Laboratories. "We look forward to studying the combination of talimogene laherparepvec and KEYTRUDA in head and neck cancer, and to advancing our collaboration in metastatic melanoma into a Phase 3 clinical trial."

About Squamous Cell Carcinoma of the Head and Neck
Squamous cell carcinomas of the head and neck (SCCHN) are cancers that begin in the squamous cells that line the mucosal surfaces inside the head and neck.1 This includes cancers of the nasal cavity, sinuses, lips, mouth, salivary glands, throat, and larynx.2 SCCHN is the sixth most common type of cancer, representing approximately 6 percent of all new cases.3 It is thought to account for an estimated 650,000 new cancer cases and 350,000 cancer deaths worldwide per year.3-5

About Talimogene Laherparepvec
Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumors (but not normal tissue) and to initiate an immune response to target cancer cells that have metastasized. Talimogene laherparepvec was designed to work in two important and complementary ways. First, it is injected directly into tumors where it replicates inside the tumor’s cells causing the cell to rupture and die in a process called lysis. Then, the rupture of the cancer cells can release tumor-derived antigens, along with GM-CSF, that can stimulate a system-wide immune response where white blood cells are able to seek out and target cancer that has spread throughout the body.

Amgen has initiated a comprehensive clinical development program for talimogene laherparepvec in metastatic melanoma, which includes combination studies with checkpoint inhibitors in patients with late-stage disease and monotherapy prior to surgery (neoadjuvant) in patients with resectable disease. Additionally, based on its clinical profile, talimogene laherparepvec has the potential to be studied in a variety of solid tumor types.

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.