A Joint Meeting of the U.S. Food and Drug Administration’s (FDA) Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) and Oncologic Drugs Advisory Committee (ODAC) on Wednesday, April 29, 2015 discussed licensing of Thousand Oaks, California based Amgen, Inc.’s talimogene laherparepvec — Biologics License Application (BLA) 125518. Talimogene laherparepvec is an oncolytic immunotherapy for treatment of patients with injectable regionally or distantly metastatic melanoma. The drug was initially developed by BioVex, Inc. under the name OncoVEXGM-CSF until the company was acquired by Amgen in 2011.
Amgen presented and explained data supporting the BLA for talimogene laherparepvec monotherapy for treatment of patients with injectable regionally or distantly metastatic melanoma, including results of the pivotal study 005/05, referred to as OPTiM — a Phase 3, multicenter, open-label, randomized clinical trial comparing talimogene laherparepvec to GM-CSF in patients with advanced melanoma (stage IIIB, IIIC, or IV) that was not surgically resectable. The primary endpoint of the study was durable response rate (DRR), which showed that talimogene laherparepvec monotherapy is the first oncolytic immunotherapy to demonstrate therapeutic benefit in a Phase 3 pivotal trial for patients with metastatic melanoma.
Melanoma is the aggressive and serious type of skin cancer, and is characterized by uncontrolled growth of melanocytes — the cells responsible for providing pigment to the skin. The best treatment approach for Melanoma is early detection, but because it is not always possible to detect the cancer in its earlier stage, it can sometimes metastasize, to other parts of the body before being diagnosed. The number of new cases of melanoma in the U.S. has been increasing for the last 30 years, and metastatic melanoma continues to be one of the most difficult to treat cancers because it is highly aggressive and complex. Prevalence of metastatic melanoma patients experiencing recurrence from an earlier stage of disease is predicted to increase substantially by 2020.
Currently, an estimated 132,000 melanoma cases occur globally each year, and while in the U.S., Melanoma accounts for fewer than five percent of skin cancer cases, it causes the most skin cancer deaths. The annual incidence rate of melanoma having increased (in the Caucasian population) by more than 70 percent over the past 20 years. According to the American Cancer Society, with an estimated 74,000 new melanoma diagnoses and nearly 10,000 deaths this year, melanoma remains a significant public health concern in the U.S. Despite recent treatment advances, the five-year survival rate for melanoma is only 20 percent, so metastatic Melanoma remains a devastating and difficult-to-treat disease with a high unmet need, and additional safe and effective treatment options are needed.
“The incidence of melanoma, the most serious form of skin cancer, has continued to rise over the last 30 years, even as many other cancers are in decline,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “Despite recent advances, there is still an unmet need in this disease. For this reason, today’s discussion about talimogene laherparepvec for the treatment of patients with metastatic melanoma is important. If approved, this novel agent could provide physicians and patients with an additional treatment option for this disease.”
Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumors (but not normal tissue), to initiate an immune response to target cancer cells that have metastasized, and to fight cancer through two different and complementary mechanisms. First, it is injected directly into tumors and is designed to replicate until the membrane of the cancer cells rupture and release a possible array of tumor specific antigens and GM-CSF, a white blood cell growth factor that the virus is engineered to express. This is hypothesized to stimulate a system-wide immune response where white blood cells are able to seek out and target cancer that has spread throughout the body.
Ordinarily, herpes simplex 1 virus causes the common cold sore. Talimogene laherparepvec has been made safer by deleting two viral genes and has been further modified to encode the human gene for a molecule called granulocyte-macrophage colony stimulating factor (also known as GM-CSF).
Amgen has announced that it in place a comprehensive clinical development program for talimogene laherparepvec in treating metastatic melanoma. The program 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, the company says talimogene laherparepvec has potential to be investigated in a variety of solid tumor types.
Just over two years ago, on March 19, 2013, Amgen announced top-line results from the Phase 3 trial in melanoma, which evaluated the efficacy and safety of talimogene laherparepvec for treatment of unresected stage IIIB, IIIC or IV melanoma compared to treatment with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF).
The global, randomized, open-label, Phase 3 trial evaluated the safety and efficacy of talimogene laherparepvec compared to a control therapy with GM-CSF in over 400 patients with unresected stage IIIB, IIIC or IV melanoma.
Patients were randomized 2:1 to receive either talimogene laherparepvec intralesionally every two weeks or GM-CSF subcutaneously for the first 14 days of each 28 day cycle. Treatment could last for up to 18 months. Where appropriate, stable or responding patients could receive additional treatment on an extension protocol.
Angen says the study met its primary endpoint of durable response rate (DRR), defined as the rate of complete or partial response lasting continuously for at least six months. A statistically significant difference was observed in DRR: 16 percent in the talimogene laherparepvec arm versus two percent in the GM-CSF arm. The analysis of overall survival (OS), a key secondary endpoint of the study, is event driven. A pre-planned interim analysis conducted with the analysis of DRR showed an OS trend in favor of talimogene laherparepvec as compared to GM-CSF.
“These are the first Phase 3 results of this novel approach to cancer therapy,” said Dr. Harper at the time. “A high unmet need exists in melanoma and we believe the innovative mechanism of action of talimogene laherparepvec may offer a promising approach for these patients.”
The most frequent adverse events observed in the trial were fatigue, chills and pyrexia. The most common serious adverse events include disease progression, cellulitis and pyrexia.
On Sept. 30, 2013, Amgen released presented additional results from the Phase 3 trial at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress in Amsterdam (Abstract No. 3733 / P479).
New data presented at the meeting included investigator assessments of response: the durable response rate (DRR) was 19 percent with talimogene laherparepvec as compared with one percent for the GM-CSF arm, and the objective response rate was 31 percent versus six percent in the GM-CSF arm. Overall there was a high degree of correlation between the independent and investigator assessments. Key secondary endpoints include time to response and duration of response by independent assessment. The median time to response was 4.1 months (range 1.2 months – 16.7 months). The duration of response was longer in the talimogene laherparepvec arm, with an estimated 68 percent of talimogene laherparepvec responders achieving responses lasting at least nine months compared to 47 percent among the GM-CSF responders.
“These results further support the primary analysis reported at ASCO which demonstrated a statistically significant durable response rate,” commented Dr. Harper. “We look forward to the mature overall survival data expected next year.”
“This is the first successful Phase 3 study of a novel oncolytic immunotherapy,” observed Howard Kaufman, M.D., then a professor and director of the section of surgical oncology in the Department of General Surgery, Rush University Medical Center in Chicago. “The fact that this study met the primary endpoint shows the value of continuing to explore the potential of talimogene laherparepvec in regional and distant metastatic melanoma.” Dr. Kaufman is now Chief Surgical Officer, Associate Director for Clinical Science, and a Surgical Oncologist at the Rutgers Cancer Institute of New Jersey.
Dr. Kaufman notes that the Phase 3 trial enrolled 436 patients with advanced melanoma. The primary goal of the study was to determine if the oncolytic virus immunotherapy could improve durable response rates compared to patients treated with GM-CSF alone. This trial was a global, randomized, open-label, Phase 3 trial to evaluate the safety and efficacy of talimogene laherparepvec compared to a control therapy with GM-CSF in over 400 patients with unresected stage IIIB, IIIC or IV melanoma.
Patients were randomized 2:1 to receive either talimogene laherparepvec intralesionally every two weeks or GM-CSF subcutaneously for the first 14 days of each 28 day cycle. Treatment could last for up to 18 months. Where appropriate, stable or responding patients could receive additional treatment on an extension protocol. The researchers reported that talimogene laherparepvec improved durable responses in patients with advanced melanoma — defined as an objective response (at least 50 percent decrease in the size of both injected and un-injected tumors) lasting at least six months or greater. Further, Dr. Kaufman says in patients who had an objective response, nearly 40 percent were complete responses.
“An important secondary endpoint was an evaluation of overall survival, and this data shows a trend towards improved survival in patients treated with talimogene laherparepvec with a 21 percent reduction in the risk of dying when treated with talimogene laherparepvec,” says Dr. Kaufman. “In an exploratory subset analysis we also found that patients with Stage IIIB/C and IVM1a melanoma as well as patients receiving talimogene laherparepvec as first-line treatment had an especially prominent improvement in overall survival. Another important finding was a very tolerable safety profile with the most common side effects being mild fatigue, fever, chills, nausea and injection site reactions. These data are significant because this is the first randomized trial of an oncolytic virus in patients with cancer and suggests that talimogene laherparepvec treatment is safe and can result in durable clinical responses with a trend toward improved survival.”
The OPTiM study also provided additional secondary and exploratory data that demonstrated the effects of talimogene laherparepvec in patients with Stage III/IV metastatic melanoma, including:
• Improved overall (CR + PR) response rate compared with GM-CSF, 26.4 percent vs. 5.7 percent, respectively. In particular, the CR rate was higher in the talimogene laherparepvec arm than in the GM-CSF arm (10.8 percent vs. 0.7 percent, respectively).
• A strong trend in overall survival (OS). The median OS was 4.4 months longer in the talimogene laherparepvec arm than in the GM-CSF arm (hazard ratio: 0.79; p=0.051).
• Evidence of a systemic effect. Eight of 71 patients (11.3 percent) with visceral lesions that could not be injected (predominately in the lung and liver) had an overall decrease in those lesions of more than 50 percent.
The most frequently observed adverse events reported by study participants were fatigue, chills and pyrexia. The most common serious adverse events included disease progression, cellulitis and pyrexia. Serious adverse events occurred in 26 percent of talimogene laherparepvec patients and 13 percent of GM-CSF patients.
Rutgers Cancer Institute of New Jersey
American Cancer Society
U.S. Food and Drug Administration
Rush University Medical Center
Rutgers Cancer Institute of New Jersey