Talimogene Laherparepvec (Imlygic)

Number: 0900

Policy

Note: Requires Precertification.

Precertification of talimogene laherparepvec (Imlygic) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Imlygic, call (866) 752-7021, or fax (866) 267-3277.

  1. Aetna considers talimogene laherparepvec (Imlygic) medically necessary for the treatment of unresectable, limited resectable, or incompletely resectable cutaneous, subcutaneous, and nodal lesions in members with melanoma.

    Aetna considers continuation of talimogene laherparepvec (Imlygic) medically necessary for an indication outlined above when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

  2. Aetna considers talimogene laherparepvec in combination with other immune therapies (e.g., ipilimumab and pembrolizumab) experimental and investigational for the treatment of melanoma and other cancers.

  3. Aetna considers talimogene laherparepvec experimental and investigational for the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

    1. Merkel cell carcinoma
    2. Neuroendocrine cancer
    3. Non-melanoma skin cancers
    4. Solid tumors (e.g., bladder, brain including glioblastoma, breast, colon, head and neck, kidney, liver, lung, mesothelioma, ovary, pancreas, prostate, and sarcoma). 

Dosing Recommendations

Talimogene laherparepvec is available as Imlygic in 106 (1 million) plaque‐forming units (PFU) per mL, and 108 (100 million) PFU per mL for injection, in single‐use vials (1 mL).

The total injection volume for each treatment visit should not exceed 4 mL for all injected lesions combined. It may not be possible to inject all lesions at each treatment visit or over the full course of treatment. Per labeling, previously injected and/or uninjected lesion(s) may be injected at subsequent treatment visits. The initial recommended dose is up to 4 mL of Imlygic at a concentration of 106 (1 million) PFU per mL. The recommended dose for subsequent administrations is up to 4 mL of Imlygic at a concentration of 108 (100 million) PFU per mL.

Source: Amgen, 2019

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Imlygic is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.
  • Limitations of use: Imlygic has not been shown to improve overall survival or have an effect on visceral metastases.

Compendial Uses

  • Limited resectable or unresectable stage III melanoma with clinical satellite/in-transit metastases
  • Unresectable distant metastatic melanoma (extracranial lesions)
  • Limited resectable or unresectable local satellite/in-transit recurrence of melanoma
  • Unresectable or incomplete resection of nodal occurrence in patients with melanoma

Although complete surgical excision of early stage of melanoma may be curative, metastatic melanoma continues to be a major therapeutic challenge.  Advances in understanding the molecular pathways that promote tumorigenesis and the interactions between melanoma cells and the immune system have resulted in the approval of several newly targeted agents (dabrafenib, trametinib, and vemurafenib) and immunotherapy strategies (e.g., ipilimumab) for the treatment of advanced disease.  Oncolytic virus immunotherapy is a new approach that uses native or attenuated live viruses to selectively kill melanoma cells and induce systemic tumor-specific immune responses.  A variety of viruses are now in clinical development with the attenuated oncolytic herpes virus encoding granulocyte-macrophage colony stimulating factor (GM-CSF), known as talimogene laherparepvec (T-VEC), demonstrating an improvement in durable response rate in patients with advanced melanoma compared with GM-CSF alone.  A major advantage of T-VEC and related agents is the limited toxicity and ability to use each individual tumor as a source of antigen to generate a highly specific anti-tumor immune response.  Talimogene laherparepvec is injected directly into the melanoma lesions, where it replicates inside cancer cells and causes the cells to rupture and die.  These agents are easily administered in the out-patient setting and may be a reasonable option for patients with limited metastatic tumor burden, those with a good performance status and without extensive prior treatment, and in those who cannot tolerate more difficult therapeutic regimens (Dharmadhikari et al, 2015).

Imlygic (talimogene laherparepvec) is a live, attenuated herpes simplex virus type 1 oncolytic viral therapy that has been genetically modified to replicate within tumors and produce an immunostimulatory protein called granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Talimogene laherparepvec causes lysis of tumors, followed by release of tumor‐derived antigens, which together with virally derived GM‐CSF may promote an antitumor immune response. However, the exact mechanism of action is unknown.

Imlygic (talimogene laherparepvec) is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.The indication is approved based on demonstration of improved durable response rate (DRR) in a phase 3, multicenter, open‐label, randomized trial (OPTiM Trial) in 436 previously treated and untreated patients with stages IIIB, IIIC, and IV melanoma that surgically unresectable.

Johnson et al (2015) noted that T-VEC is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma.  Pre-clinical studies have shown that T-VEC preferentially infects melanoma cells and exerts anti-tumor activity through directly mediating cell death and by augmenting local and even distant immune responses.  Talimogene laherparepvec has now been assessed in phase II and III clinical trials and has demonstrated a tolerable side-effect profile and promising efficacy, showing an improved durable response rate and a trend toward superior overall survival (OS) compared to GM-CSF.  Despite these promising results, responses have been uncommon in patients with visceral metastases.  The authors stated that T-VEC is currently being evaluated in combination with other immune therapies (ipilimumab and pembrolizumab) with early signs of activity.

Kohlhapp et al (2015) stated that T-VEC is the first-in-class oncolytic virus immunotherapy for the treatment of cancer; it has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents.

In a randomized open-label, phase III clinical trial, Andtbacka and colleagues (2015) compared T-VEC with GM-CSF in patients with unresected stage IIIB to IV melanoma.  Patients with injectable melanoma that was not surgically resectable were randomly assigned at a 2:1 ratio to intralesional T-VEC or subcutaneous GM-CSF.  The primary end-point was durable response rate (DRR; objective response lasting continuously greater than or equal to 6 months) per independent assessment.  Key secondary end-points included OS and overall response rate (ORR).  Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3 %; 95 % confidence interval [CI]: 12.1 % to 20.5 %) than GM-CSF (2.1 %; 95 % CI: 0 % to 4.5 %]; odds ratio, 8.9; p < 0.001).  Overall response rate was also higher in the T-VEC arm (26.4 %; 95 % CI: 21.4 % to 31.5 % versus 5.7 %; 95 % CI: 1.9 % to 9.5 %).  Median OS was 23.3 months (95 % CI: 19.5 to 29.6 months) with T-VEC and 18.9 months (95 % CI: 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95 % CI: 0.62 to 1.00; p = 0.051).  The effectiveness of T-VEC was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease.  The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia.  The only grade 3 or 4 AE occurring in greater than or equal to 2 % of T-VEC-treated patients was cellulitis (2.1 %).  No fatal treatment-related AEs occurred.  The authors concluded that T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial; T-VEC was well-tolerated and resulted in a higher DRR (p < 0.001) and longer median OS (p = 0.051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease.  They stated that T-VEC represents a novel potential therapy for patients with metastatic melanoma.

On October 27, 2015, the Food and Drug Administration (FDA) approved talimogene Laherparepvec (Imlygic) for the treatment of melanoma lesions in the skin and lymph nodes.  A treatment course with Imlygic consists of a series of injections into the melanoma lesions.  After the initial injection, a second dose is administered 3 weeks later, followed by additional doses every 2 weeks for at least 2 months, unless other treatment is needed or until there are no remaining injectable lesions to treat.  The FDA approval of Imlygic was based on the findings of the phase III clinical trial by Andtbacka et al (2015).  However, Imlygic has not been shown to improve OS or to have an effect on melanoma that has spread to the brain, bone, liver, lungs, or other internal organs.  The most common side effects observed in clinical study participants were chills, fatigue, fever, flu-like symptoms, nausea, and pain at the injection site.  Because Imlygic is a modified live oncolytic herpes virus therapy, herpes virus infection can also occur.  Given this, Imlygic should not be given to individuals with suppressed immune systems or who are pregnant.

Imlygic (talimogene laherparepvec) should not be used in persons with hypersensitivity to talimogene laherparepvec or any of its components, women who are pregnant or lactating and have not been apprised of the potential hazard to the fetus and neonate, persons of reproductive potential (Nonclinical and clinical studies have not been established), persons less than 18 years of age (safety and efficacy have not been established), and persons with renal and hepatic impairment (pharmacokinetic studies have not been established).

Warnings and Precautions

  • Accidental Exposure to Imlygic (talimogene laherparepvec): Accidental exposure may lead to transmission of Imlygic (talimogene laherparepvec) and herpetic infection. Accidental needle stick and splash back to the eyes have been reported in healthcare providers during preparation and administration. In the event of an accidental exposure to treatment, exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant. If signs or symptoms of herpetic infection develop, the exposed individuals should contact their healthcare provider for appropriate treatment. Patients should avoid touching or scratching injection sites or their occlusive dressings, as doing so could lead to inadvertent transfer of Imlygic (talimogene laherparepvec) to other areas of the body.
  • Herpetic Infection: Herpetic infections (including cold sores and herpetic keratitis) have been reported in patients. Disseminated herpetic infection may also occur in immunocompromised patients. Patients who develop suspicious herpes‐like lesions should follow standard hygienic practices to prevent viral transmission. Patients or close contacts with suspected herpetic infections should also contact their healthcare provider to evaluate the lesions. Imlygic (talimogene laherparepvec) is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of Imlygic (talimogene laherparepvec). Therefore, consider the risks and benefits of treatment before administering antiviral agents to manage herpetic infection.
  • Injection Site Complications: Necrosis or ulceration of tumor tissue may occur during treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds. Impaired healing at the injection site has been reported. Imlygic (talimogene laherparepvec) may increase the risk of impaired healing in patients with underlying risk factors (e.g., previous radiation at the injection site or lesions in poorly vascularized areas). One patient had an amputation of a lower extremity 6 months after injection due to an infected non‐healing wound. This wound area had been treated with surgery and radiation prior to treatment and had previous wound complications.
  • Immune‐Mediated Events: Immune‐mediated events, including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported. Consider the risks and benefits of Imlygic (talimogene laherparepvec) before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune‐mediated events.
  • Plasmacytoma at Injection Site: A plasmacytoma has been reported in proximity to the injection site after administration of treatment in a patient with smoldering multiple myeloma.
  • Use in pregnancy: Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with Imlygic
  • Lactation: Discontinue drug or nursing.

Merkel Cell Carcinoma

Blackmon and colleagues (2017) reported the cases of 2 elderly, frail patients with loco-regionally advanced, surgically incurable Merkel cell carcinoma (MCC) who refused cytotoxic chemotherapy and consented to receive intra-tumoral talimogene laherparepvec (TVEC) off-label as first-line drug therapy.  In these 2 cases, disease was rapidly progressive with appearance of multiple new nodules within a few weeks.  Intra-tumoral TVEC not only led to regression of injected nodules but prevented development of new metastases loco-regionally and distantly over periods of 6 to 11 months in cases 1 and 2, respectively.  Patient 1 achieved a clinical complete response (CR) and patient 2 partial responses (PR) persisting for more than 5 and 7 months after the last TVEC dose, respectively.  Serologic testing failed to confirm Merkel cell polyomavirus (MCPyV) exposure in both patients, but a negative result did not exclude virus-associated MCC, and insufficient tissue was available for immunohistochemical viral large T-antigen detection.  Thus, whether the cases of MCC reported here were virus-positive or virus-negative was uncertain.  However, MCPyV shared no homology with herpes simplex type 1 comprising TVEC, and recent clinical experience indicated comparable response to immunotherapy among viral-positive and viral-negative MCC.  The authors concluded that these findings coupled with the emerging role for immunotherapy in advanced MCC indicate the need for prospective trials of TVEC alone or combined with blockade of the PD-1/PD-L1 immune checkpoint in both viral-positive and viral-negative advanced MCC.  The authors stated that a phase II clinical trial of TVEC with or without hypo-fractionated radiotherapy for melanoma, MCC, or other solid tumors with skin metastasis was opened to accrual.

Mucosal Melanoma of the Urethra

Frohlich and colleagues (2020) stated that mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis.  Immune checkpoint inhibition has so far only been assessed in a limited number of mucosal melanoma patients and, in contrast to response in cutaneous melanoma, was associated with disappointing response rates.  The oncolytic viral immunotherapy T-VEC has recently been approved for treatment of locally advanced or unresectable melanoma.  T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumor response.  The rationale to use T-VEC in this case was an expected augmentation of immunogenicity by tumor lysis to overcome primary resistance of a mucosal melanoma to immune checkpoint blockade.  These investigators reported the first case of an advanced mucosal melanoma of the urethra treated with intralesional application of T-VEC.  This case entailed a 78-year old woman who was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intra-vaginal mucosal metastases.  Shortly after surgical resection of the tumor mass, intra-vaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed.  The patient was treated with pembrolizumab and obtained a stable disease lasting for 30 weeks.  However, upon checkpoint inhibition the patient developed a loco-regional progressive disease featuring bleeding intra-vaginal metastases, while nodal metastases remained stable.  These researchers stopped treatment with pembrolizumab and administered T-VEC directly into the intra-vaginal mucosal metastases.  After 5 injections T-VEC yielded a PR with clinical regression of the injected mucosal metastases.  Disease remained stable for 16 weeks under bi-weekly T-VEC treatment; thereafter, the patient showed disease progression in nodal metastases.  T-VEC was discontinued.  Immunotherapy with pembrolizumab was re-started but failed to achieve a response.  Finally, targeted therapy with imatinib was induced in presence of a druggable c-KIT mutation, leading to a considerable response of all tumor sites that is still ongoing.  The authors concluded that T-VEC represented an effective and well-tolerated therapeutic option for patients with loco-regionally advanced mucosal melanoma, which should be addressed in interventional clinical trials.  These researchers stated that in combination with immunotherapy, T-VEC has the potential of synergistic effects to overcome the specific primary resistance of mucosal melanoma to immune checkpoint blockade. 

The authors stated that they were aware of the limitation of this work being a single-case study, which did not allow general conclusions to be drawn.  To what extent T-VEC or targeted therapy can induce an immune response that may help to overcome primary resistance to immune checkpoint blockade should therefore be examined in clinical trials for the rare subtype of mucosal melanoma.  Recruiting a sufficient number of patients suffering from mucosal melanoma for a clinical trial is presumed to be time-consuming.  This emphasizes the great necessity of publication of case-series and case reports regarding this rare tumor type.

Neuroendocrine Cancer

Kloker and colleagues (2019) stated that metastatic neuroendocrine cancer still constitutes a palliative situation, lacking promising therapeutic options.  Oncolytic virotherapy, a novel type of virus-based immunotherapy, lyses tumor cells using genetically engineered viruses thereby activating the immune system to induce an optimized anti-tumor response that could bring down tumor masses to a stage of minimal residual tumor disease.  The oncolytic vector talimogene laherparepvec has already shown excellent safety profiles in clinical studies and has become the first ever FDA/EMA-approved oncolytic virus (OV).  These researchers presented a first pre-clinical assessment of this state-of-the-art OV, using a panel of human neuroendocrine tumor/neuroendocrine carcinoma (NET/NEC) cell lines.  Cytotoxicity, transgene expression, and viral replication patterns were studied.  Furthermore, the anti-proliferative activity was compared to everolimus and also interactions between the OV and everolimus were evaluated.  Moreover, virostatic effects of ganciclovir (GCV) on replication of T-VEC were assessed and electron microscopic pictures were taken to comprehend viral envelopment and details of the replication cycle of T-VEC in human neuroendocrine cancer.  It could be shown that T-VEC infected, replicated in, and lysed human NET/NEC cells exhibiting high oncolytic efficiencies already at quite low virus concentrations.  Interestingly, everolimus was not found to have any relevant impact on rates of viral replication, but no additive effects could be proved using a combinatorial therapy regimen.  On the other hand, GCV was shown to be able to limit replication of T-VEC, thus establishing an important safety feature for future treatments of NET/NEC patients.  The authors concluded that T-VEC opened up a promising novel therapeutic option for NET/NEC patients, warranting its further pre-clinical and clinical development.

Solid Tumors

Taguchi and associates (2017) noted that oncolytic virus therapy has been recognized as a promising new therapeutic option for cancer.  Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells.  Notably, TVEC (talimogene laherparepvec, formerly called OncoVEXGM-CSF), an oncolytic herpes simplex virus type 1, was approved by the FDA for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016.  The effectiveness of many types of oncolytic viruses against urological cancers have been investigated in pre-clinical studies during the past 10 years, and some have already been tested in clinical trials.  For example, a phase-I clinical trial of the third-generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016.  These researchers summarized the current status of clinical trials of oncolytic virus therapy in patients with the 3 major urological cancers:
  1. prostate,
  2. bladder, and
  3. renal cell cancers.

In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials.  The authors believed that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future.

In addition, according to ClinicalTrials.gov, there are clinical trials on the use of talimogene laherparepvec for various types of solid tumors (e.g., bladder, breast, head and neck, kidney, liver, pancreas, prostate, and sarcoma).

Fountzilas and associates (2017) stated that oncolytic virotherapy uses an array of replication-competent viruses that have been adapted to amplify and spread preferentially at sites of tumor growth.  In 1991, a genetically modified HSV-1 virus led to tumor control without associated encephalitis when administered intra-cranially in a murine glioma model.  Talimogene laherparepvec (T-VEC) was first described in 2003 and approved by the FDA in October 2015 to treat advanced melanoma.  Although T-VEC remains the only FDA-approved oncolytic virotherapy at the time of this writing, clinical trials are underway with a wide variety of other modified viruses including vaccinia virus, adenovirus, parvovirus, reovirus, coxsackie virus, measles, poliovirus, Newcastle disease virus, Seneca valley virus and vesicular stomatitis virus.  Naturally occurring viruses have diverse tissue tropism making some more advantageous than others in different tumor histologies.  Since neutralization by anti-viral antibodies is a significant impediment to repetitive dosing of oncolytic virotherapy, sequential use of immunologically non-cross-reactive viruses will likely be more effectives.  Oncolytic viruses are in clinical trials treating a broad array of malignancies including melanoma, sarcoma, glioblastoma, myeloma, mesothelioma and carcinomas of the breast, lung, colon, prostate, kidney, liver, pancreas, bladder, ovary, and head and neck.  The authors noted that systemic delivery of oncolytic virotherapy is another major goal to markedly extend the spectrum of applicable tumor types and stages for this burgeoning drug class.  Several oncolytic viruses have been administered intravenously in human clinical trials with occasional encouraging results supporting feasibility.  To overcome circulating anti-viral antibodies, intravenous delivery of infected carrier cells to transport oncolytic viruses to tumor sites has shown success in murine models.  Thus, oncolytic virotherapy is a strategically attractive class of immunotherapeutic that is sure to rapidly expand in the clinic using a variety of viral platforms to treat a wide array of malignancies both loco-regionally and systemically as both monotherapy and in combinations with checkpoint inhibitors.

Saha and colleagues (2018) noted that oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are a new class of cancer therapeutic, which selectively replicate and kill cancer cells, while inducing an inflammatory micro-environment, immuno-virotherapy. An oHSV (talimogene laherparepvec) has been approved for the treatment of advanced melanoma.  Glioblastoma (GBM) is an almost always lethal primary tumor in the brain that is highly immunosuppressive and posited to contain GBM stem-like cells (GSCs).  Immune checkpoint blockade has revolutionized therapy for some cancers, but not GBM.  These researchers have used a syngeneic GSC-derived orthotopic GBM model (005) to develop immunotherapeutic strategies.  Curative therapy required oHSV expressing IL-12 in combination with 2 checkpoint inhibitors, anti-PD-1 and anti-CTLA-4.  This response required CD4+ and CD8+ T cells, and macrophages in a complex interplay.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Talimogene laherparepvec (Imlygic) :

CPT codes covered if selection criteria are met:

11900 Injection, intralesional; up to and including 7 lesions
11901     more than 7 lesions

Other CPT codes related to the CPB:

96401, 96405 - 96406 Chemotherapy administration, subcutaneous, intramuscular or intralesional

HCPCS codes covered if selection criteria are met:

J9325 Injection, talimogene laherparepvec, per 1 million plaque forming units

ICD-10 codes covered if selection criteria is met :

C43.0 - C43.9 Malignant melanoma of skin

ICD-10 codes not covered for indications listed in the CPB (not an all inclusive):

C7A.00 - C7A.8 Malignant neuroendocrine tumors

Talimogene laherparepvec (Imlygic) in combination with other immune therapies:

HCPCS codes not covered for indications listed in the CPB:

J9228 Injection, ipilimumab, 1 mg [not covered in combination with Imlygic]
J9271 Injection, pembrolizumab, 1 mg[not covered in combination with Imlygic]

ICD-10 codes not covered for indications listed in the CPB (not an all inclusive list):

C00.0 - C42.9, C44.0 - C76.8, C80 - C96.9 Malignant neoplasms
C78.00 - C78.39, C78.7, C78.89, C79.00 - C79.02, C79.31 - C79.32, C79.51 - C79.52 Secondary malignant neoplasm of internal organs

The above policy is based on the following references:

  1. Ahn DH, Bekaii-Saab T. The continued promise and many disappointments of oncolytic virotherapy in gastrointestinal malignancies. Biomedicines. 2017;5(1).
  2. Amgen Inc. Imlygic (talimogene laherparepvec) suspension for intralesional injection. Prescribing Information. v1. Thousand Oaks, CA: Amgen; revised October 2015.
  3. Amgen Inc. Imlygic (talimogene laherparepvec) suspension for intralesional injection. Prescribing Information. Thousand Oaks, CA: Amgen, revised October 2019.
  4. 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):2780-2788.
  5. Blackmon JT, Dhawan R, Viator TM, et al. Talimogene laherparepvec for regionally advanced Merkel cell carcinoma: A report of 2 cases. JAAD Case Rep. 2017;3(3):185-189.
  6. Chesney J, Puzanov I, Collichio F, et al. Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma. Br J Cancer. 2019;121(5):417-420.
  7. Dharmadhikari N, Mehnert JM, Kaufman HL. Oncolytic virus immunotherapy for melanoma. Curr Treat Options Oncol. 2015;16(3):326.
  8. Fountzilas C, Patel S, Mahalingam D. Review: Oncolytic virotherapy, updates and future directions. Oncotarget. 2017;8(60):102617-102639.
  9. Frohlich A, Hoffmann F, Niebel D, et al. Talimogene laherparepvec in advanced mucosal melanoma of the urethra upon primary resistance on immune checkpoint inhibition: A case report. Front Oncol. 2020;10:611. 
  10. Hamid O, Hoffner B, Gasal E, et al. Oncolytic immunotherapy: Unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66(10):1249-1264.
  11. Harrington KJ, Kong A, Mach N, et al. Talimogene laherparepvec and pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (MASTERKEY-232): A multicenter, phase 1b study. Clin Cancer Res. 2020;26(19):5153-5161.
  12. Hu J, Masoud SJ, Ravichandran S, et al. Retreatment with talimogene laherparepvec for advanced melanoma. Immunotherapy. 2020;12(16):1167-1172.
  13. Johnson DB, Puzanov I, Kelley MC. Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. Immunotherapy. 2015;7(6):611-619.
  14. Kelly CM, Antonescu CR, Bowler T, et al. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab: A phase 2 clinical trial. JAMA Oncol. 2020;6(3):402-408.
  15. Kloker LD, Berchtold S, Smirnow I, et al. The oncolytic herpes simplex virus talimogene laherparepvec shows promising efficacy in neuroendocrine cancer cell lines. Neuroendocrinology. 2019;109(4):346-361. 
  16. Kohlhapp FJ, Zloza A, Kaufman HL. Talimogene laherparepvec (T-VEC) as cancer immunotherapy. Drugs Today (Barc). 2015;51(9):549-558.
  17. National Comprehensive Cancer Network (NCCN). Cutaneous melanoma. NCCN Clinical Practice Guidelines in Oncology, version 2.2019. Fort Washington, PA: NCCN; 2019.
  18. National Comprehensive Cancer Network (NCCN). Imlygic. NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2020.
  19. National Institutes of Health. ClinicalTrials.gov. talimogene laherparepvec / United States. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=talimogene+laherparepvec&cntry1=NA%3AUS&state1=&Search=Search#wrapper. Accessed September 21, 2017.
  20. Saha D, Martuza RL, Rabkin SD. Oncolytic herpes simplex virus immunovirotherapy in combination with immune checkpoint blockade to treat glioblastoma. Immunotherapy. 2018;10(9):779-786.
  21. Taguchi S, Fukuhara H, Homma Y, Todo T. Current status of clinical trials assessing oncolytic virus therapy for urological cancers. Int J Urol. 2017;24(5):342-351.
  22. U.S. Food and Drug Administration (FDA). FDA approves first-of-its-kind product for the treatment of melanoma. FDA Press Release. Silver Spring, MD: FDA; October 27, 2015.