The American Cancer Society estimates that about 74,000 Americans will be diagnosed with melanoma this year and almost 10,000 will die from this deadliest form of skin cancer. Over the past several years, treatment of advanced cases of melanoma has been transformed as new FDA-approved therapies developed by several different companies have come onto the market. An FDA advisory committee recently approved a therapy that takes a totally novel approach that involves injecting a live attenuated virus directly into regionally or distant metastatic melanoma tumors.
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Amgen’s investigational product, talimogene laherparepvec, is an attenuated, replication-competent type 1 herpes simplex virus (HSV-1) that can express a biologically active form of human granulocyte–macrophage colony-stimulating factor (GM-CSF).
HSV-1 infections cause cold sores and sometimes genital herpes, although infection with human simplex virus 2 is more often the cause of genital herpes. Researchers have characterized the virulence genes of the virus. Talimogene laherparepvec, sometimes shortened to T-VEC, is made by depleting those virulence genes and inserting sequences that generate GM-CSF. It’s believed that removal of the virulence genes decreases the chances that the virus will infect nerve cells and will instead home in on tumor cells. By delivering GM-CSF, the genetically engineered virus enhances tumor antigen presentation to the immune system and induction of immune system attack on the malignancy.
Encouraging durable response results
Talimogene laherparepvec was studied in a randomized, open label phase 3 study to compare the new therapy with GM-CSF injections in subjects with unresectable stage IIIB, IIIC, and IV melanoma. A total of 437 subjects were randomized into the study at 64 study sites. The study was designed to demonstrate an improvement in durable response rate, which was defined as a complete response or partial response maintained for at least six months. Subjects were to receive therapy until Week 24, even if their melanoma was progressing. GM-CSF was used for comparison purposes because at the time that this study was designed, it was also in clinical studies as a treatment for melanoma. It is unclear, though, if GM-CSF by itself has any therapeutic value.
To be enrolled in the study, people had to be age 18 or older, have a histologically confirmed malignant melanoma of the stages listed in the previous paragraph, measurable disease of at least 1 cm, injectable disease (either on the surface of the skin or through the use of ultrasound guidance), ECOG performance of 0 or 1, and a life expectancy greater than four months from date of randomization. The study exclusions included active cerebral disease, any bone metastases, history of secondary cancer unless disease-free for at least five years, open herpetic skin lesions, and primary ocular or mucosal melanoma.
The initial dose of talimogene laherparepvec was injected into one or more skin or subcutaneous tumors, followed three weeks later by a more concentrated formulation given every two weeks. The dosing was guided by the size of the lesion and could be increased in a predetermined manner if any injected lesion progressed.
The analysis of the data was performed by the Endpoint Assessment Committee (EAC), the FDA, and the investigators themselves using different methods. The durable response rate varied some by who was doing the analysis and the methods being used. Analysis of the results was also complicated by the number of people in the study who dropped out.
Even with these caveats, the results for talimogene laherparepvec stood out: 15.6% to 19.0% who received the therapy had durable response versus just 1.4% to 2.1% for the control group. The EAC and investigators agreed on about 85% of the assessments.
Overall survival was the secondary endpoint. The researchers used an event-driven analysis: Once 290 patients had died, they analyzed the data. They found that 189 of the 295 (64%) patients in the treatment arm of the study had died compared with 101 of 141 (72%) in the control arm. Estimates of overall survival in months were 23.3 months for the talimogene laherparepvec group versus 18.9 months for the control arm.
Adverse events occurred in almost all patients in both arms of the study, but a larger proportion of the patients treated with genetically modified HSV-1 had grade 3 events (28.1% versus 16.5 % in the control group). The adverse events in the treatment group included fatigue, chills, pyrexia, nausea, influenza-like illness, and injection-site pain and were consistent with treatment with a viral vaccine with a proposed immunological mechanism of action.
Of special interest is the possible viral shedding from the patients in the active arm. Since this is a live virus that is designed to replicate, it is expected to have biological properties similar to wild type HSV-1, including the ability to shed and potential for transmission and lifelong symptomatic reactivation. There are limited data on this issue, but of course it remains a concern for anyone who may come in close contact with these patients.
The FDA hasn’t approved talimogene laherparepvec. The agency doesn’t always follow the recommendation of its advisory committees. But if Amgen’s new therapy does get the go-ahead from the FDA, it will probably cause a considerable amount of angst for payers.
There are now more than 20 drugs approved for melanoma, including three—ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda)—that are designed to enlist the patient’s own immune system against their melanoma. Immunotherapy, once adventurous, is now an increasingly crowded field. It is also tearing gaping holes in many budgets. Pharmaceutical manufacturers are pricing these ingenious therapies so the annual cost is in the low six figures.
In the clinical practice, it’s likely that patients will receive one very expensive drug followed by another and then perhaps another. I predict that in the very near future, sequential melanoma treatment could cost $500,000.
And as a society, we have not addressed the question of how much each additional month of life with a metastatic malignancy is worth. Given the current state of our national debt and other priorities, can our society afford spending that much?
Immunotherapy will make the balancing act of managing care so that people get the treatment they want at the best possible cost even more difficult. It again proves that Tomorrow’s Medicine will ensure job security for decisionmakers in all health disciplines!