ORLANDO, FL—For the first time, a synthetic peptide vaccine designed to boost immunogenicity has been shown to improve outcomes in patients with metastatic melanoma in a Phase III clinical trial.
Used in conjunction with standard interlekin-2 (IL-2) therapy, the vaccine improved the clinical response rate and prolonged the time to disease progression, compared with IL-2 alone, Patrick Hwu, MD, Professor and Chairman of the Department of Melanoma Medical Oncology at the University of Texas M. D. Anderson Cancer Center, reported here at the ASCO Annual Meeting.
There was also a trend toward improved survival rates among patients given the vaccine, “but the patients have to be followed longer before we can see statistical significance,” he said.
‘A Nice Milestone’
The so-called gp100:209–217(210M) peptide vaccine is a synthetic peptide cancer vaccine consisting of amino acid residues 209 through 217 of the glycoprotein 100 (gp100) melanoma antigen, with a methionine substitution at position 210 designed to improve immunogenicity. It's given along with IL-2, a powerful immune-system stimulant.
Vaccination with gp100:209–217 (210M) peptide stimulates the patient's immune system to mount a cytotoxic T-lymphocyte response against tumor cells expressing gp100, Dr. Hwu explained. The IL-2 multiplies the T cells into a “large army that can then attack the tumors to kill them.”
In a Phase II trial led by Steven Rosenberg, MD, PhD, 42% of 31 patients with metastatic melanoma receiving high-dose IL-2 plus the vaccine had objective responses, but this is the first Phase III study of the vaccine that is positive, Dr. Hwu said. “It's a nice milestone.”
The 21-center, Phase III trial involved 185 patients with Stage IV or locally advanced Stage III cutaneous metastatic melanoma, randomized to receive either the peptide vaccine followed by four days of high-dose IL-2 at 720,000 IU/kg/dose or high-dose IL-2 alone. The cycle was repeated every three weeks until the patients responded or progressed.
The overall clinical response rate was almost double in the vaccine arm—22.1%, compared with 9.7% for the patients who got interleukin-2 alone, Dr. Hwu said.
The median progression-free survival time was 2.9 months in the vaccine arm vs 1.6 months for IL-2 alone, again a significant difference.
The median overall survival time was 17.6 months in the vaccine arm compared with 12.8 in the IL-2 alone arm, but the difference did not reach statistical significance, Dr. Hwu said.
The vaccine was well tolerated. Side effects were swelling and redness at the injection site.
‘Rare, Positive Study in Metastatic Melanoma’
This is “a rare positive study” in metastatic melanoma, said the Discussant, Antoni Ribas, MD, Associate Professor of Medicine (Hematology/Oncology) and Surgery (Surgical Oncology) at UCLA.
Dr. Ribas said he would like to see further study to determine if the vaccine prolongs overall survival times. But since accruement for the current study took seven years, it's “uncertain that anyone will want to undertake a confirmatory Phase III trial for overall survival,” he said.
Louis M. Weiner, MD, Director of the Lombardi Comprehensive Cancer Center, said he “views this as a conceptual advance, teaching us that focusing the attention of the immune system on a specific cancer-related target increases the ability of the immune system to attack tumors, at least for a while.
“Many of us believe that a combined approach that includes an immune system attack on cancer cells will ultimately prove to be most useful in controlling cancers such as melanoma,” he said.
Dr. Weiner said one reason this vaccine may have worked while others have failed is because it was combined with high-dose IL-2.
“We have known for a while that IL-2 therapy is effective in a small percentage of melanoma patients. But when it is effective, it is highly effective,” he said.
But IL-2 “can be toxic and is not simple to use,” Dr. Weiner said.
The moderator of a news conference at the meeting that featured the study, Sonali M. Smith, MD, Associate Professor of Medicine at the University of Chicago Medical Center, called the findings very promising for a very poor-prognosis group of patients, and said that the approach might act as a “platform” for more potent vaccines.
Dr. Hwu agreed, noting that 80% of patients did not respond. He said he hopes to improve response rates in future trials by combining the vaccine with other immune-stimulating agents such as anti-CTLA-4.
Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. By using an anti-CTLA-4 agent, he said, “we can take the brakes off the immune system, which should allow the vaccine and IL-2 to work even better.”