An injectable immunotherapy that harnesses the immune system in killing tumor cells achieves a durable response in melanoma patients, with many experiencing a complete response (CR), say US scientists.
The product, talimogene laherparepvec (T-VEC), manufactured by Amgen, is a herpes simplex virus type 1–derived oncolytic immunotherapy that is injected directly into melanoma lesions.
It is currently awaiting approval in both Europe and the United States, where it was recently recommended for approval by the Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC), as previously reported by Medscape Medical News. The FDA decision is due by Oct. 27, 2015.
At its meeting, ODAC considered efficacy results from the first randomized controlled phase 3 study of an oncolytic immunotherapy in melanoma, known as OPTiM, which were published online May 26 in the Journal of Clinical Oncology.
The data show that 11% of patients achieved a CR; 65% had a durable response of ≥1 year. The greatest responses were seen in those with more advanced and treatment-naive disease.
"Durable responses to T-VEC were seen across all disease stages tested, including in patients within each subset of stage IV disease," say the researchers, led by Howard L. Kaufman, MD, FACS, Rutgers Cancer Institute of New Jersey, in New Brunswick.
Noting that T-VEC could potentially delay or prevent relapses or preclude progression to later disease stages, they add that it "represents a novel potential new treatment option for patients with injectable metastatic melanoma and limited visceral disease."
T-VEC eliminates cancer cells via two mechanisms. First, the herpes simplex virus has been genetically modified to selectively replicate in the tumor and cause cancer cell destruction while leaving normal cells alone. "So if you can inject it directly into the tumor cells, it will kill them," Dr Kaufman explained to Medscape Medical News.
The second mechanism is that T-VEC contains a gene for granulocyte-macrophage colony stimulating factor (GM-CSF), which is expressed locally in the tumor. This enhances the systemic antitumor immune response.
"Because the tumors are dying from a virus, the immune system gets engaged, and once that happens, the immune system can eradicate tumor cells anywhere in the body," Dr Kaufman added.
The study ― Oncovex (GM-CSF) Pivotal Trial in Melanoma (OPTiM) ― involved 436 patients with injectable melanoma that could not be resected surgically. They were randomly assigned in a 2:1 ratio to receive intralesional T-VEC or subcutaneous GM-CSF.
The primary endpoint was the durable response rate (DRR), defined as the rate of CR plus partial response continuously lasting ≥6 months and beginning within the first 12 months. Secondary endpoints included overall survival (OS) and the overall response rate.
The DRR was significantly higher among patients receiving T-VEC than among those given GM-CSF (16.3% vs 2.1%; odds ratio [OR], 8.9; P < .001). The overall response rate was also higher with T-VEC (26.4% vs 5.7%; P < .001). In all, 32 (10.8%) of patients receiving T-VEC experienced a CR, compared with just one (<1%) patient receiving GM-CSF.
The median time to response was 4.1 months among the 78 T-VEC patients who responded. This compares with a median response time of 3.7 months among the eight patients receiving GM-CSF who experienced a response.
The estimated probability of having a response at 12 months was 65% among T-VEC patients, with 56 of 78 responders showing an ongoing response at the final tumor assessment.
The median time to treatment failure was 8.2 months with T-VEC and 2.9 months with GM-CSF (hazard ratio [HR], 0.42). Median OS was 23.3 months and 18.9 months, respectively (HR, 0.79; P = .051), which just missed being statistically significant.
Further analysis revealed that the efficacy of T-VEC was greater in patients with stage IIIB, IIIC, or IVM1a disease than in those with stage IVM1b disease. It was also greater in patients with treatment-naive disease.
The most frequent adverse events (AEs) were chills, pyrexia, injection-site pain, nausea, flulike symptoms, and fatigue. The most common serious AEs included disease progression, cellulitis, and pyrexia, none of which occurred in more than 2% of patients. There were no treatment-related deaths.
"Very Important" Findings
Dr Kaufman emphasized that the findings are "very important." He said: "Despite all the advances in the field of melanoma, many patients do not respond to treatment."
"Some patients are not able to tolerate some of the drugs for a variety of reasons, and so any agent that has some activity is important."
He added: "Interestingly, I think one of the more important things in the data is that nearly 11% of the patients had a complete response.... We don't often see that in melanoma studies. I think that's very significant."
This finding may, indeed, underestimate the potential efficacy of V-TEC. "One of the problems with this study is that we only injected things that we could actually clinically palpate or feel, or get to by ultrasound guidance," Dr Kaufman said.
"[We could not inject] patients who may have had disease in the liver or the lungs...so those patients weren't really evaluated in this trial. We do plan to pursue studies where we now can inject the virus into those areas, and maybe then we will see stronger responses."
Perhaps even more important to Dr Kaufman is that the study opens the door for studying this particular type of approach in other types of cancer, particularly because T-VEC has few adverse effects.
Dr Kaufman said: "It's an easy agent to combine with other things, and we are in process of doing a phase Ib/II trial combining this with the T-cell checkpoint inhibitor ipilimumab [Yervoy, Bristol-Meyers Squibb Company]."
"We're already seeing dramatic responses; we're seeing closer to a 50% response rate, and with very little added toxicity. So I think that is going to be a very important future for this sort of agent."
The study was supported by Amgen, which also funded medical writing assistance. A number of conflicts of interest are listed in the article.
J Clin Oncol. Published online May 26, 2015. Abstract
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Cite this: Injectable T-VEC Offers Hope to Melanoma Patients - Medscape - May 28, 2015.