SILVER SPRING, MD—In a joint meeting here on Monday, two advisory committees to the Food and Drug Administration recommended approval of the biologic agent talimogene laherparepvec (T-VEC) for injectable regionally or distantly metastatic melanoma.
If approved, the product would be the first oncolytic immunotherapy approved by the agency, and this biologic drug would become a first-in-class therapy. While the FDA does not have to take the advice of its advisory committees, it frequently does.
Talimogene, a biologically engineered attenuated herpes simplex virus type 1, is designed to replicate selectively in cancerous tumors (but not in normal tissue) and to initiate an immune response in target cells that have metastasized. The drug is injected every two weeks directly into melanoma lesions, where it causes lysis of cancerous cells.
The combined vote was 22 in favor of approval and one against (with no abstentions) among members of the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) and the Oncologic Drugs Advisory Committee (ODAC).
Favorable Risk-Benefit Profile
Advisory committee members who cast “yes” votes generally agreed that the risk-benefit profile for talimogene is favorable and they wanted oncologists to have more options available to treat patients with advanced melanoma. “I think the risks are really minimal,” said CTGTAC Acting Chair Tabassum Ahsan, PhD, the Burk-Kleinpeter Professor at the Center for Aging and the Center for Stem Cell Research and Regenerative Medicine at Tulane University's Department of Biomedical Engineering.
“I'm more inclined to make this therapy available than to restrict it,” added Ahsan, who voted “yes.”
Very Careful Labeling and Guidance
“I voted ‘yes’ based on the overall benefit,” said CTGTAC member Barry J. Byrne, MD, PhD, Professor of Pediatrics and Molecular Genetics and Microbiology at the Powell Gene Therapy Center at the University of Florida College of Medicine. Byrne, like other committee members, said that if approved, the new therapy would need to be marketed with very careful labeling and instructions on how best to use the drug safely.
“There needs to be very careful guidance for dosing and administration,” agreed ODAC Chair Deborah K. Armstrong, MD, Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Armstrong, who voted “yes,” suggested that educational videos might be helpful if the drug reaches the market. Viral shedding could potentially expose health care providers and close patient contacts to talimogene, so safety precautions must be stringent.
“There are clearly patients in my clinic who need this [therapy]” said temporary ODAC voting member Patrick Hwu, MD, Professor in the Department of Melanoma Medical Oncology in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center. Hwu, who voted “yes,” noted that melanoma patients who come into the clinic are very heterogeneous, and “I need as many arrows in my quiver as possible.”
He said that although he has not used talimogene, based on the data he has seen, “This will be among the least toxic agents that we give in the clinic.”
The One ODAC ‘No’ Vote
The one “no” vote on talimogene was cast by temporary ODAC voting member Richard Sherry, MD, Staff Clinician in the Surgery Branch at the National Cancer Institute. During the extensive discussion at the day-long meeting, Sherry repeatedly expressed his unhappiness with the approval question on which the combined committees voted, stating that it did not and should have specified the patient population in which the drug would have the most benefit. The voting question before the combined committees should have made clear that the new therapy has a benefit for surgically unresectable metastatic melanoma (stage IIIB, IIIC, or IV) patients who do not have visceral disease, he said.
“The data are clear, and the question is muddy,” Sherry said. “This is a chance to make a statement. This drug is not appropriate for patients with visceral disease. I wish it [the vote] was 23-zip.”
Fill a Need for Subset of Patients with Advanced Disease
Although there are more options today for patients with metastatic melanoma, speakers generally agreed that talimogene would fill a need for a subset of patients with advanced disease who are not helped by currently approved drugs.
Because of recent drug approvals, “the landscape for patients with melanoma has changed considerably,” said Celia Witten, PhD, MD, Director of FDA's Office of Cellular, Tissue and Gene Therapies in the Center for Biologics Evaluation and Research (CBER). But, she noted, “melanoma remains a devastating disease,” and there are still many patients with advanced melanoma who need new treatment options.
The American Cancer Society estimates that this year 74,000 new melanoma cases will be diagnosed, and nearly 10,000 patients will die of their disease.
If Approved, Will Likely Be a Traditional vs. Accelerated Approval
The voting question asked committee members to base their vote on traditional FDA approval. Witten said that if the FDA approves talimogene, it will likely be a traditional approval, not an accelerated approval. The accelerated approval paradigm must “provide a meaningful advantage over available therapies,” and, based on the day-long discussion she had heard, “I'm not sure what that case would be,” she said.
The Biologics License Application for talimogene is based on a pivotal Phase III, multicenter, open-label, randomized 436-patient clinical trial called Study 005/05, referred to as OPTIM. Patients with advanced unresectable melanoma (stage IIIB, IIIC, or IV) were randomized to receive either talimogene or GM-CSF; the primary endpoint was durable response rate (DRR). In this study, 16.3 percent of talimogene patients achieved a complete or partial response within the first 12 months of treatment and maintained it continuously for at least six months, compared with 2.1 percent of patients treated with GM-CSF.
Although overall survival was not the endpoint, this study showed a strong trend in overall survival in the talimogene arm; the median overall survival was 4.4 months longer in the talimogene arm than in the GM-CSF arm. There was a suggestion of a systemic effect in the talimogene arm; eight of 71 patients (11.3%) with visceral lesions that could not be injected (located mostly in the lung and liver) had an overall decrease in those lesions of more than 50 percent.
The most common side effects were flu-like symptoms, fatigue, chills, pyrexia, nausea, and injection-site pain, most of which resolved within 72 hours. The most common serious adverse reaction was cellulitis.
“Certainly as a clinician taking care of these patients, I don't think we can have too many agents,” said Howard Kaufman, MD, Chief Surgical Director, Associate Director for Clinical Science, and Co-Leader of the Clinical Investigations and Precision Therapeutics Program at Rutgers Cancer Institute of New Jersey. Kaufman, a talimogene investigator who spoke on behalf of the drug for Amgen, its manufacturer, noted: “The incidence of melanoma has been rising for at least 30 years,” and added, “It's a bad disease; it's very unpredictable.”
Kaufman said that although there have been six drugs approved for melanoma since 2011, there are currently no approved therapies for the patient population represented in the OPTIM study, those with locoregionally advanced melanoma. “These are not simple little things to take care of,” he said of the melanoma lesions in this patient subgroup.
‘Existing Unmet Need’
There are toxicities associated with approved targeted therapies and immunotherapies for melanoma and they are not for all patients, said Kaufman, noting that talimogene meets an existing unmet need. “Melanoma is a complex cancer that requires the use of multiple treatment modalities over the course of the disease,” he said.
“Despite meaningful recent advancements, not all patients currently benefit; some patients are not candidates for or cannot tolerate existing therapies. Durable response and survival rates for metastatic melanoma are still unacceptably low; additional safe and effective treatment options like talimogene laherparepvec are required.”
He said he was impressed by the durable responses to talimogene that he has observed.
Powerful Statements from Patients
In casting their “yes” votes, several members of the two advisory committees said they found the testimony of melanoma patients who spoke during the public part of the meeting powerful: “Really the patients who spoke helped me focus,” said ODAC member Louis F. Diehl, MD, Professor of Medicine at Duke University Medical Center. “I would not like to take this drug out of the hands of oncologists.”
Randy Russell, who was diagnosed with melanoma five years ago, said he remembers his oncologist telling him, “I'm sorry, there's just nothing more I can do for you.” Russell, who owns Russell Home Improvements in Chattanooga, Tennessee, said, “I began to believe I would die.” He enrolled in a clinical trial of talimogene at Vanderbilt University after an oncologist told him that the new biologic therapy “had promise.”
He was a responder; “We could see improvement almost immediately,” he said. “My cancer was gone as if I had never had it.”
Bob Ribbans of East Amwell Township, New Jersey, was diagnosed in 2008 with two small melanoma lesions on his head; subsequently he developed more such lesions. He had six lesions injected with talimogene, and since November 2010 has been cancer free. Without the drug, he said, “I wouldn't be here.”
Donna Hyatt Brown of Huntsville, Alabama, herself a basal cell carcinoma patient, spoke on behalf of her father Lawrence Hyatt, an active man and farmer who at age 80 was still driving the school bus in his community. Diagnosed with melanoma shortly after his 80th birthday, Hyatt was treated with surgery, but was told in December 2009 to put his affairs in order because he might have only six months to live.
He was subsequently treated with the drug Aldara (imiquimod), but “along with the treatment came the ulcers,” Brown said. “Having been a user of Aldara myself, I knew how painful it must be for Dad.”
Like Randy Russell, Lawrence Hyatt enrolled in a clinical trial of talimogene at Vanderbilt University. “I believe by this time there were 70-plus spots on Dad's head that would have to be injected,” Donna Brown said. But by November 2010, “We had the all-clear. No cancer could be found on Dad's head. It was going to be a great time to plan Christmas instead of a funeral. Since then Dad has been completely free of melanoma.”
In an interview, Donna Hyatt Brown told OT that she was especially grateful to the physicians and nurses who cared for her father, and she came to testify before the FDA committees because she wanted other melanoma patients to be able to take talimogene if they qualified. She said she lost her mother to encephalitis in January 1969, and she wasn't about to lose her father without doing all she could to help him win his battle against melanoma.
At the FDA meeting, Amgen expressed its commitment to discussing potential labeling of talimogene, the appropriate use of the drug in patients who could receive the greatest benefit and future study options. In a statement issued after the all-day FDA meeting on talimogene, Amgen officials said: “It is clear from today's discussion that the committee recognized the importance of the need for new therapeutic options for patients with metastatic melanoma. We look forward to talking with the FDA about how to best make talimogene laherparepvec monotherapy available to patients as they complete their review of the Biologics License Application.”