On October 23, 2015 Janssen Biotech reported that the U.S. Food and Drug Administration (FDA) has approved YONDELIS (trabectedin) for the treatment of patients with unresectable (unable to be removed with surgery) or metastatic liposarcoma (LPS) or leiomyosarcoma (LMS) who received a prior anthracycline-containing regimen (Press release, Johnson & Johnson, OCT 23, 2015, View Source [SID:1234507776]). The approval was based on recently published clinical efficacy and safety data from the Phase 3, randomized, open-label, controlled study (ET743-SAR-3007), which evaluated YONDELIS versus the chemotherapy agent dacarbazine, in patients with unresectable or metastatic LPS or LMS previously treated with an anthracycline and at least one additional chemotherapy regimen.

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While approved for both LPS and LMS, YONDELIS is the first treatment to be specifically approved for LPS in the U.S.

"Our academic teams are dedicated to finding new treatments with scientific merit and the promise to improve outcomes for patients with sarcomas. Today’s announcement marks a meaningful event built upon years of research, offering new hope for people living with two of the most prevalent subtypes of this serious disease – liposarcoma and leiomyosarcoma – where there are limited available alternatives," said George D. Demetri, M.D.,† Director of the Ludwig Center at Harvard and Director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, and principal investigator of the Phase 3 registration trial. "In the clinical trial, YONDELIS significantly increased progression free survival compared to dacarbazine; this is an important endpoint for these patients, in whom rapid worsening of the disease can lead to worse symptoms and life-threatening situations."

The pivotal Phase 3 study enrolled over 500 patients and demonstrated an improvement in progression free survival (PFS) for patients treated with YONDELIS. The median PFS among the YONDELIS treatment group was 4.2 months (n=345; 95% confidence interval (CI): 3.0 – 4.8 months), while the median PFS in the dacarbazine treatment group was 1.5 months (n=173; 95% CI: 1.5 – 2.6 months), representing a 45% reduction in the risk of disease progression or death with YONDELIS (HR=0.55; 95% CI: 0.44 – 0.70; p<0.001). The final analysis of overall survival (OS) demonstrated a median OS of 13.7 months for the YONDELIS arm and 13.1 months in dacarbazine arm, which was not significant (HR=0.93; 95% CI: 0.75, 1.15; p=0.49).

LPS and LMS are subtypes of soft tissue sarcoma (STS) and represent more than 35% of all STS cases.2 LMS is an aggressive type of STS where smooth muscle cells become cancerous. LMS typically occurs in the uterus, abdominal cavity or blood vessels but can also arise in any part of the body.3, 4 LPS is comprised of several subtypes and develops in fat cells that become cancerous in any part of the body.5, 6

Since YONDELIS was first approved in Europe in 2007, approximately 50,000 patients in close to 80 countries have benefited from this therapy across all indications. "The U.S. approval for YONDELIS exemplifies our commitment to improving the health of people living with cancer and addressing unmet needs," said Roland Knoblauch, M.D., Ph.D., Clinical Leader, YONDELIS, Janssen Research & Development, LLC. "We are proud that our Phase 3 study is the largest ever conducted in this patient population and we’re delighted that patients in the U.S. can now benefit from the treatment."

The safety profile of YONDELIS in the Phase 3 study was consistent with previous clinical studies. The most serious risks associated with YONDELIS are neutropenic sepsis (severe infections due to decreased white blood cells), rhabdomyolysis (severe muscle problems), cardiomyopathy (heart muscle problems, including heart failure), hepatotoxicity (liver problems, including liver failure), anaphylaxis, and extravasation (leakage of YONDELIS out of the vein during infusion) leading to tissue necrosis (tissue cell damage or death) and embryofetal toxicity. Among the 378 patients who received at least one dose of YONDELIS in the randomized trial, the most common (≥20%) adverse reactions were nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%) and headache (25%). The most common (≥5%) Grade 3-4 laboratory abnormalities were neutropenia (43%), increased alanine transaminase (ALT) (31%), thrombocytopenia (21%), anemia (19%), increased aspartate aminotransferase (AST) (17%) and increased creatine phosphokinase (6.4%).

The recommended dose of YONDELIS is 1.5 mg/m2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks) until disease progression or unacceptable toxicity in patients with normal bilirubin and AST or ALT, less than or equal to 2.5 times the upper limit of normal.

On October 23, 2015 Amgen (NASDAQ:AMGN) reported that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion recommending that IMLYGIC (talimogene laherparepvec) be granted approval for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease (Press release, Amgen, OCT 23, 2015, View Source [SID:1234507773]). If approved by the European Commission, IMLYGIC would be the first in a class of novel agents known as oncolytic immunotherapies.

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IMLYGIC, administered via intralesional injection, is designed to cause the death of tumor cells and to initiate an anti-tumor immune response.

"We are pleased that IMLYGIC has received a positive opinion from the CHMP, and if approved by the European Commission, we look forward to continuing to work with European regulatory authorities to bring this innovative therapy to patients," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Metastatic melanoma continues to be one of the most difficult-to-treat cancers, often requiring the use of multiple treatment modalities. Despite recent advances, the five-year survival rate for patients who cannot be cured with surgery remains unacceptably low, demonstrating the critical need for additional approaches to control this disease."

The positive CHMP opinion was based on a global, randomized, open-label Phase 3 trial evaluating the safety and efficacy of IMLYGIC in patients with Stage IIIB, IIIC or IV melanoma when resection was not recommended compared to granulocyte-macrophage colony-stimulating factor (GM-CSF). In the 436-patient study, IMLYGIC significantly improved durable response rate (DRR), the primary endpoint of the trial, in the intent-to-treat population. DRR is defined as the percent of patients with complete response (CR) or partial response (PR) maintained continuously for a minimum of six months. A key secondary endpoint was overall survival (OS). The positive CHMP opinion reflects subgroup analyses where the effect on OS was largest in patients with unresectable melanoma that has not spread beyond the skin or lymph nodes.

The most commonly reported treatment-related adverse events were fatigue, chills, pyrexia, nausea, influenza-like illness and injection-site pain. Overall, 98 percent of these adverse reactions reported were mild or moderate in severity. The most common grade 3 or higher adverse reaction was cellulitis.

Melanoma is a type of skin cancer that is characterized by the uncontrolled growth of melanocytes, which are the cells responsible for providing the pigment to skin.1 Melanoma is the most aggressive and serious form of skin cancer, and remains a significant public health concern in the European Union (EU).2,3 In 2012, it was estimated that there were 56,000 new cases of melanoma in France, Italy, Spain, Germany and the U.K. causing nearly 9,500 deaths.4,5

Following this CHMP opinion, Amgen expects a decision on the Marketing Authorization from the European Commission in the coming months. IMLYGIC is also under review by the U.S. Food and Drug Administration.

About IMLYGIC (talimogene laherparepvec) in the EU

IMLYGIC is an oncolytic immunotherapy that is derived from HSV-1, which is commonly called the cold sore virus. IMLYGIC has been modified to replicate within tumors and to produce the immune stimulatory protein human GM-CSF. IMLYGIC causes the death of tumor cells and the release of tumor-derived antigens. It is thought that, together with GM-CSF, it will promote a systemic anti-tumor immune response and an effector T cell response.

About IMLYGIC (talimogene laherparepvec) in the U.S.

IMLYGIC is a genetically modified herpes simplex type 1 virus that is injected directly into tumors. IMLYGIC replicates inside tumor cells and produces GM-CSF, an immunostimulatory protein. IMLYGIC then causes the cell to rupture and die in a process called lysis. The rupture of the cancer cells causes the release of tumor-derived antigens, which together with virally derived GM-CSF may help to promote an anti-tumor immune response. However, the exact mechanism of action is unknown.