Back Back
T-VEC for Melanoma
Newly Approved: T-VEC for Melanoma After Resection

Released: January 11, 2016

Expiration: January 09, 2017

Activity Information

Activity

Progress
1
Course Completed
Continue

A 79-year-old white male presented with a 2.05-mm, nonulcerated, BRAF wild-type melanoma on the anterior right leg just above the ankle. His past medical history included coronary artery disease treated by coronary stenting and peripheral vascular disease requiring a right lower extremity femoral-popliteal bypass 3 years ago. He was treated by wide local excision and sentinel lymph node biopsy, which was negative. Six months later, he developed multiple in-transit metastases in the right leg extending from the primary site to just below the knee. The lesions were completely excised by a surgical oncologist but recurred 4 months later with the emergence of 17 new metastases in the right leg extending from below the knee to the ankle (Figure 1). The surgical oncologist referred the patient for medical oncology evaluation.

Figure 1. Multiple new in-transit melanoma metastases of the right lower extremity after several wide excisions.

General Approach to Local and Regionally Advanced Melanoma Treatment
This patient represents a significant clinical challenge. Whereas surgical excision with negative margins represents the standard of care for the treatment of primary melanoma, the treatment of satellitosis and in-transit metastases is more controversial. Treatment decisions depend on the location, number, and temporal pattern of tumor occurrence. Surgical management with re-excision to clear margins is possible, but often the tumor will recur. When disease recurrence happens quickly, as in the patient presented, long-term survival is unlikely. Isolated limb perfusion and infusion represent other possible therapeutic options. These procedures are indicated for extremity melanoma in which the major limb blood supply can be isolated for local drug delivery (axillary for the upper extremity and femoral for the lower extremity). Perfusion uses a surgical approach in which the artery and vein are isolated for delivery of anticancer agents (most commonly melphalan chemotherapy) and drug collection, respectively. This approach avoids systemic exposure to chemotherapy and allows high-dose drug delivery with localized toxicity. Perfusion is more difficult when patients have had previous surgical procedures, such as lymphadenectomy, and when tumor extends to and above the inguinal or axillary basins. Infusion accomplishes isolated extremity treatment using interventional access, thereby avoiding a surgical procedure but requiring specialized expertise. Limb perfusion/infusion have been associated with high clinical response rates but not with OS.

Systemic therapy can also be considered for the treatment of these patients, which in melanoma would include dacarbazine, high-dose IL-2, BRAF/MEK inhibitors if the melanoma harbors a mutation in BRAF, ipilimumab, nivolumab, pembrolizumab, or participation on a clinical trial. Many melanoma oncologists, however, would prefer to withhold systemic therapy when the disease is isolated to an extremity skin/soft tissue site with no evidence of visceral metastases. This avoids the considerable toxicity associated with systemic therapy, prevents emergence of drug resistance (eg, for the BRAF inhibitors), and maintains an armamentarium of agents for those patients who develop progressive disease at a later time. Another approach to these patients is local treatment in which therapy is directed to accessible tumors. There have been many strategies evaluated during the past 3 decades for local therapy of melanoma, including injection of BCG, cytokines (eg, IL-2, IL-12), PV-10, and native or genetically modified oncolytic viruses. In general, these approaches have resulted in limited therapeutic responses and have been associated with acceptable safety profiles and evidence for induction of melanoma-specific immune responses in some patients. In 2015, the first prospective, randomized phase III clinical trial of an oncolytic virus for the treatment of melanoma demonstrated an improvement in durable response rate. The oncolytic virus, termed talimogene laherparepvec (T-VEC), was approved by the FDA for the treatment of melanoma recurrent after primary resection and located in the skin, soft tissue, and lymph nodes.

T-VEC Oncolytic Virus Immunotherapy
T-VEC is an attenuated HSV-1 that has been rendered less pathogenic by deletion of virulence genes and enhanced for immunogenicity by encoding human GM-CSF. The virus is thought to mediate antitumor activity through 2 distinct mechanisms. First, the virus preferentially replicates within cancer cells, resulting in a direct lytic effect, and release of progeny virus allows continued infection of other tumor cells and release of tumor-associated antigens and signals that help to initiate a systemic antitumor immune response against the cancer cells. The expression of local GM-CSF was designed to further promote this process by attracting and maturing dendritic cells, which in turn activate virus- and tumor-specific T cells.

The prospective, randomized phase III OPTiM trial compared intralesional T-VEC vs recombinant, subcutaneous GM-CSF in 436 patients with unresectable stage IIIB/C or IV melanoma. In this pivotal trial, compared with GM-CSF, T-VEC was associated with significantly improved durable (2.1% vs 16.3%, respectively; P < .001) and objective response rates (5.7% vs 26.4%, respectively; P < .001). Median OS also improved with T-VEC vs GM-CSF (23.3 vs 18.9 months, respectively; P = .051), especially for patients with stage III or IV M1a disease and patients receiving T-VEC in the first-line setting. The most common adverse events associated with T-VEC were fatigue, chills, fever, nausea, influenzalike symptoms, and local injection-site reactions. Based on these data, the FDA approved T-VEC for patients with melanoma recurrent after surgery with cutaneous, subcutaneous, or nodal disease.

Integrating T-VEC Into Clinical Practice
Our patient case represents a common clinical challenge in having multiple recurrent melanoma isolated to a single extremity. The likelihood of long-term benefit with further surgical intervention is limited. His history of peripheral vascular disease also makes surgical management and isolated limb perfusion/infusion more difficult. Thus, systemic or local therapy may be the best possible approach. Because the patient is elderly and the disease is relatively low volume, local approaches may be better suited for this patient. To receive effective treatment while keeping adverse event rates low and maintaining a high quality of life, the patient elected T-VEC treatment.

In general, treatment begins with a measurement of all accessible lesions (by clinical examination or ultrasound guidance). At the first treatment visit, patients receive a low-dose of 106 pfu/mL by direct injection with a total injection volume of 4 cc and based on lesion size. Three weeks later, allowing time for seronegative patients to convert, the patients are treated with 108 pfu/mL, and this continues every 2 weeks until all lesions are gone, there is symptomatic disease progression requiring other therapy, or adverse events limit further injections. Of interest, in clinical trials, just more than 50% of patients had disease progression prior to achieving best objective response, suggesting that continued treatment in the face of asymptomatic progression is warranted.

The discussed patient received his first 3 injections into 5 lesions (the largest tumors), with reported mild fever and chills on the evening of treatment, which resolved with acetaminophen. Three weeks after treatment, he had a 50% reduction in tumor volume, but 2 new lesions appeared (Figure 2). He was asymptomatic so the 2 new lesions were injected, and he experienced similar albeit milder fever and chills for 24 hours after injection. After 2 more injections, he had only minimal induration remaining at all sites, and random biopsies revealed no evidence of melanoma. He has now experienced a complete response (Figure 3), and full body imaging has been conducted every 3 months without evidence of disease recurrence at 6 months.

Figure 2. Right lower extremity after 3 intralesional injections of T-VEC.

Figure 3. Right lower extremity after intralesional injections of T-VEC in new lesions.

Other Considerations When Prescribing T-VEC
Although T-VEC is typically well tolerated, even in elderly patients with significant comorbidities (such as in this case report), several important considerations exist when using T-VEC in the clinic. As a live, replicating virus, T-VEC requires specialized storage and handling procedures: It must be maintained at -70°C until its use, needs to be thawed and prepared in a sterile biosafety cabinet, and should be delivered in a dedicated examination room using universal precautions. The virus is eliminated by 10% bleach solution, but standard operating procedures and terminal cleaning of ambulatory sites where patients with T-VEC are treated need to be instituted for safe management of patients and staff. Additional training for staff preparing and handling the virus is also needed, with specific attention on education for patients and close household contacts.

To date, there are no reports of transmission of T-VEC to household contacts, but several healthcare providers have been accidentally infected, largely due to inadvertent injection during drug handling or administration. The virus is susceptible to antiviral agents such as acyclovir and famciclovir, and all accidental infections resolved rapidly with antiviral treatment. Communication with local biosafety and infection control committees may help establish a program for T-VEC in the ambulatory setting.

Concluding Thoughts
The approval of T-VEC represents a new therapeutic option for patients with melanoma, but as with any new form of treatment, clinicians and patients should understand the benefits and risks involved in treatment. Of interest, several combination clinical trials of T-VEC and other immunotherapy agents such as pembrolizumab and ipilimumab are in progress. But, to date, there are few data on how best to sequence T-VEC in relationship to other treatment options. At present, T-VEC seems most appropriate for patients with locally recurrent melanoma where surgical excision is either not technically feasible or not likely to be associated with long-term survival. This approach may be especially appropriate for patients who are elderly, with other comorbid conditions, and who do not have extensive visceral metastases. Although T-VEC represents another effective option for patients with inoperable melanoma and their prescribing physicians, further investigation is needed to better define the optimal integration of T-VEC into clinical management.

Please let me know in the comments how you would treat this patient or if you have used T-VEC in your own clinical practice.

Continue

Poll

1.
How would you treat this patient in your clinical practice?
Submit