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Talimogene laherparepvec (T-VEC): The first oncolytic virus in the treatment of unresectable melano

Tuesday, November 1, 2016   (0 Comments)
Posted by: Elizabeth Maynard
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Author: Chris Dorian, PCP PharmD Class of 2019
Faculty Advisor: Nicole Schroeder PharmD,BCPS,BCCCP, Assistant Prof. Clinical Pharmacy

 Talimogene laherparepvec (T-VEC): The first oncolytic virus in the treatment of  unresectable melanoma

Background:

It has been estimated that by the end of 2016, almost 77,000 people in the United States will be diagnosed with melanoma.  This estimation does not include new in situ cases that are not reported in outpatient clinics.  Melanoma, like most cancers, has a rising incidence rate each year.  The overall rate has increased significantly with 33% in males and 23% in females from 2002-2006.  The lifetime risk of developing cutaneous melanoma is 1 in 34 for women and 1 in 53 for males.  Risk factor for melanoma are include both genetic and environmental. The primary environmental cause is exposure to ultraviolet radiation.   Melanoma leads to 50,000 annual deaths worldwide.  A caucasian individual is 10-20 times more likely to develop a cutaneous melanoma than an African American individual. Many patients are genetically predisposed, because they already have genetic mutation in melanocytes. The mechanism of melanoma involves loss of function mutation in tumor suppressor genes.  70% of all cutaneous melanomas have mutations or deletions affecting cell cycle regulatory gene cyclin-dependent kinase inhibitor 2A (CDKN2A). A similar gene, CDK4 will also lead to loss of function in tumor suppressor genes.  Mutations in the germline cells can also predispose an individual to melanoma development. 2,4

Diagnosis and Treatment:

Patients typically present with cutaneous melanoma.   The American Academy of Dermatology Diagnosis recommends using ABCDEs for ease of diagnosing a potentially cancerous lesion.  “asymmetry (benign lesions are usually symmetric); border irregularity (most nevi have clear-cut borders); color variegation (benign lesions usually have uniform light or dark pigment); diameter >6 mm (the size of a pencil eraser); and involving (any change in size, shape, color, or elevation or new symptoms such as bleeding, itching, and crusting).”3

The most common treatment for nonmetastatic melanoma is surgery to remove the tumor, hence all melanomas of stage II or lower are treated with a wide excision, cutting the tumor and erring on the side of caution to remove more tissue to prevent the chance of some cancerous cells surviving.4  Standard treatment can consist of radiation therapy or chemotherapy, often cytotoxic drugs, which have many side effects.  Emerging in the literature, however, are many immunotherapies. Many cytokines used by the immune system are given systemically or locally to increase responses.  Monoclonal antibodies have been used since the 1980s to treat cancer. One such treatment commonly used in melanoma treatment is ipilimumab(Yervoy) which binds to cytotoxic T-lymphocyte-associated protein 4(CTLA-4) to prevent T-cell downregulation and enhance the response.. This is often combined with nivolumab(OPD1VO) which binds to PD1 again prevents downregulation and creates an increased T-cell response. 

Talimogene laherparepvec (T-VEC)         

Approval was granted by the FDA in October of 2015. “Talimogene laherparepvec (T-VEC) is a first-inclass oncolytic virus” 5  It is a modified Herpes virus and has been genetically engineered to harm tumor cells, but not normal cells.5  Genes deletions and addition to encode for granulocyte macrophage colony stimulating factor, which is believed to increase immune response and proliferation.  Overall, these modification are thought to have enhanced the CD8+ T cell response and reduction in CD4+ FoxP3+ T regulatory cells. This leads to an enhanced ability of the body to destroy the tumor.6

Eligible patients were 18 years of age, had stage IIIB to IV melanoma, and at least one lesion greater than 10mm in diameter. During the trial, 2 patients were assigned to Talimogene Laherparepvec for every 1 patient assigned to receive recombinant GM-CSF. The drug was injected directly into the lesions. The primary end point was durable response rate . This was the rate of complete response(CR) plus partial response (PR) lasting  more than 6 months. Ultrasound, palpation, computed tomography, and positron emission tomography  supplemented visual inspection and dermatoscopy to assess tumor remission. An interesting pearl is that even lesions which were not injected showed in increased response to T-VEC, strong evidence it was effective in creating T-cells specific to the tumor. Additionally, it should be noted the response to T-VEC may be slower, but the results are superior. The mean response time was longer and less clear for T-VEC, but overall survival four years out was 11.3% higher.

Dosing and Administration

Talimogene laherparepvec (T-VEC) is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Initial treatment injections aim for the largest lesions first.6 Local anesthetics can be used, but should be primarily around the tumor, as to not alter the pH of the tumor microenvironment.7  Exactly how much medication is injected into each lesion is dependent on the size of the lesion.  A maximum of up to 4mL of T-VEC can be injected in one treatment visit.  It may not be possible to inject all lesions at each treatment visit or over the full course of treatment with the limit of 4mL per visit.   Previously injected and/or uninjected lesion(s) may be treated at subsequent visits.  The reduced initial dose enables the patient to develop systemic immunity to any Herpes Simplex Type 1 that may mutate back to wild type HSV1. This is superseded only by any new lesion which arise, which must be treated, then treat the existing lesion in descending size order. Subsequent treatments may start three weeks after the first regimen.  (This is to allow systemic immunity to HSV1 to occur.) All subsequent treatments are spaced two weeks apart.7  The minimum treatment length is six months, or when all lesions disappear. There is no established upper limit regarding how long patients can be treated with T-VEC at this time.

Conclusion:

For the treatment of melanoma, surgery is the gold standard of care, however, for metastasized tumors, further treatments is needed. The efficacy of ipilimumab (Yervoy) and nivolumab (OPD1VO) and Talimogene laherparepvec and GM-CSF have both been proven effective in metastatic melanoma. Many immunotherapies are becoming available for malignancies and may well be guiding the treatments in the future.

 

Table 1. Dosing and Administration of Talimogene laherparepvec (T-VEC)

Lesion Size1

Amount to inject2,3

Dosage Form4

≤ 0.5cm

0.1mL

Based on Visit Number

0.5cm - 1.5cm

0.5mL

Based on Visit Number

1.5cm - 2.5cm

1mL

Based on Visit Number

2.5cm - 5cm

2mL

Based on Visit Number

>5cm

4mL

Based on Visit Number

1 Lesion size is based on longest dimension; when lesions are clustered together, inject them as a single lesion

2 Maximum volume (per treatment visit, for all injected lesions combined): 4 mL

3 Inject largest lesion(s) first; inject remaining lesion(s) based on lesion size until maximum injection volume is reached or all lesions have been treated

4The initial dose uses the 106 PFU/mL concentration suspension, and subsequent doses 108 PFU/mL concentration.

 

Table 2. Summary of Talimogene Laherparepvec (Imlygic)4,8

Indication

Non resectable melanoma (localized lesions)

Adult Dosing

See Table 1. Administration of Talimogene laherparepvec (T-VEC)

No Dosing Adjustments for renal or hepatic impairment

Contraindications

Any immunocompromised condition; pregnancy

Drug Interactions

Antiherpetic antivirals may decrease efficacy of T-VEC

Most Common Adverse Drug Reactions

Fever, chills, nausea, cellulitis, injection site reactions,fatigue

Product Availability

Imlygic: 106 (1 million) PFU/mL (1 mL); 108 (100 million) PFU/mL (1 mL)

Storage

Prior to use, intact vials should be stored at -90°C to -70°C, thawed for approximately 30 minutes, and not shaken prior to use.

Monitoring Parameters

The patient should also be monitored for injection site complications and immune system dysfunction related to the high levels of GM-CSF potentially being produced.8

 

References

1.     Handbook of Nonperscription Drugs 18E. American Pharmacist’s Association. 2015.

2.     Kasper D, Jameson J, Hauser S et al. Harrison's Principles of Internal Medicine 19/E (Vol.1 & Vol.2). McGraw-Hill Education / Medical; 2015.

3.     American Academy of Dermatology website www.aad.org Accessed June 14, 2016

4.     Coit DG, Thompson JA, Algazi A, et al. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14(4):450-73.

5.     Hu JCC, Coffin RS, Davis CJ: A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res 12:6737-6747, 2006

6.     Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25):2780-8.

7.     Drug Information Monograph Talimogene Laherparepvec (Lexi-Drugs) Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571. Accessed August 23, 2016.

8.     Hoffner B, Iodice GM, Gasal E. Administration and Handling of Talimogene Laherparepvec: An Intralesional Oncolytic Immunotherapy for Melanoma. Oncol Nurs Forum. 2016;43(2):219-26.

 


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