Investigational Immunotherapy Treatment Shows Durable Response in Patients with Metastatic Melanoma

Newswise — Research led by Howard L. Kaufman, MD, FACS, associate director for clinical science and chief surgical officer at Rutgers Cancer Institute of New Jersey and colleagues, shows advanced-stage melanoma patients have significant improvement in durable response rate and a trend toward improved survival when treated with a genetically-modified form of a herpes virus, whose native form causes the common cold sore.

Results from a phase III clinical trial examining the oncolytic virus talimogene laherparepvec and its ability to reduce the size of melanoma tumors injected with the treatment, was published today in the ‘Journal of Clinical Oncology’ (DOI: 10.1200/JCO.2014.58.3377). Dr. Kaufman, who is also a professor of surgery and medicine at Rutgers Robert Wood Johnson Medical School, shares more about the work:

Q: What is talimogene laherparepvec and how does it work?A: Talimogene laherparepvec is an investigational cancer treatment based on the herpes simplex 1 virus. 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). Talimogene laherparepvec is designed to fight cancer through two different mechanisms. First, the virus selectively replicates in tumor tissue – not normal tissue - after local injection into cancers. Secondly, the GM-CSF in the virus helps provide a boost to the body’s natural immune system, which helps fight cancer throughout the body.

Q: What did this study find and why are these findings significant?A: The global, randomized, phase III trial enrolled 436 patients with stages IIIB, IIIC and IV melanoma, a potentially fatal form of skin cancer. The primary goal of the study was to evaluate the safety and efficacy of the oncolytic virus immunotherapy, called T-VEC, compared to patients treated with GM-CSF alone. In 2013, we reported that indeed talimogene laherparepvec did improve durable responses in patients with advanced melanoma. This was defined as an objective response (at least 50 percent decrease in the size of both injected and un-injected tumors) within the first 12 months of treatment lasting at least six months or more. Further, 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. 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 response and overall survival. Another important finding was a very tolerable safety profile with the most common side effects being fatigue, 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.

Q: Is immunotherapy a new concept in cancer treatment?A: No, the potential promise of immunotherapy has been suggested for over a century but only recently have we better understood the molecular and cellular basis of how the immune system works to fight cancer. Melanoma has been a model for immunotherapy since the tumor seems to be highly susceptible to immune attack. Interleukin-2 was the first immunotherapy approved by the FDA for the treatment of melanoma in 1998. A major advance in melanoma immunotherapy came with the T cell checkpoint inhibitor, ipilimumab, which demonstrated a significant improvement in overall survival for patients with metastatic melanoma and achieved FDA approval in 2011. Since then, a variety of immunotherapy approaches have been tested which are demonstrating promise against melanoma, including PD-1 inhibitors, another T cell checkpoint. The results with T-VEC provide a new class of immunotherapy agent, with an acceptable safety profile, which may benefit patients who do not respond to other treatments and T-VEC may be especially useful in combination with other agents. This is actively being tested in clinical trials, many of which are available to patients at Rutgers Cancer Institute of New Jersey, as well as at other centers around the country.

Q: The U.S. Food and Drug Administration is scheduled this fall to review an application for approval of this treatment in patients with melanoma. Why is this important?A: Melanoma is the deadliest of skin cancers and can be difficult to treat when in advanced stages or has spread to other parts of the body. With the annual incidence rate of melanoma having increased (in the Caucasian population) by more than 70 percent over the past 20 years, we need to continue to find new ways to help improve patient outcomes. The new drugs in development are offering major hope for patients with melanoma. In addition, now that oncolytic viruses have demonstrated an acceptable risk/benefit profile in melanoma, this treatment may be tested against other types of cancer where options are more limited.

Dr. Kaufman collaborated on this work with Robert Hans Ingemar Andtbacka, Huntsman Cancer Institute/University of Utah; Frances A. Collichio, University of North Carolina at Chapel Hill; Thomas Amatruda, Minnesota Oncology; Neil N. Senzer, Mary Crowley Cancer Research Centers, Texas; Jason Chesney, University of Louisville, Kentucky; Keith A. Delman, Emory University, Georgia; Lynn E. Spitler, Northern California Melanoma Center, California; Igor Puzanov, Vanderbilt University Medical Center, Tennessee; Sanjiv S. Agarwala, Temple University School of Medicine, Philadelphia; Mohammed Milhem, University of Iowa Hospitals and Clinics; Lee Crammer, Universit of Iowa; Brendan Curti, Earle A. Chiles Research Institute, Oregon; Karl Lewis, University of Colorado Cancer Center; Merrick Ross, MD Anderson Cancer Center; Troy Guthrie, Baptist Cancer Institute, Florida; Gerald P. Linette, Washington University School of Medicine, Missouri; Gregory A. Daniels, University of California San Diego Medical Center; Kevin Harrington, Institute of Cancer Research, London; Mark R. Middleton, National Institute for Health Research Biomedical Research Centre, United Kingdom; Wilson H. Miller, Jr., McGill University, Canada; Jonathan S. Zager, Moffitt Cancer Center, Florida; Yining Ye, Bin Yao, Ai Li, all Amgen Inc., California; Susan Doleman, Amgen, Inc., Massachusetts; Ari VanderWalde and Jennifer Gansert, both Amgen Inc., California; Robert Coffin, Amgen Inc., California.Dr. Kaufman has served as a paid consultant to Amgen, Inc.