Talimogene Laherparepvec (Imlygic)

Number: 0900

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses talimogene laherparepvec (Imlygic) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of talimogene laherparepvec (Imlygic) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of talimogene laherparepvec (Imlygic), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Melanoma

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

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of talimogene laherparepvec (Imlygic) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

3. Related Policies

   1. CPB 0815 - Ipilimumab (Yervoy)
   2. CPB 0890 - Pembrolizumab (Keytruda)

Dosage and Administration

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.

Refer to full prescribing information for Imlygic for preparation and administration instructions.

Source: Amgen, 2022

Experimental and Investigational

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

2. 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. Nuclear protein in testis (NUT) carcinoma (NC)
   5. Solid tumors (e.g., bladder, brain including glioblastoma, breast, colon, head and neck, kidney, liver, lung, mesothelioma, ovary, pancreas, prostate, and sarcoma).

3. Aetna considers talimogene laherparepvec (T-VEC) plus nivolumab experimental and investigational for the treatment of melanoma.

4. Aetna considers talimogene laherparepvec (T-VEC) plus pembrolizumab experimental and investigational for the treatment of melanoma.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
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]
J9299	Injection, nivolumab, 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

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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.

Compendial Uses

• Limited resectable or unresectable stage III melanoma with clinical satellite/in-transit metastases or with nodal lesions
• Widely disseminated distant metastatic melanoma
• Limited resectable or unresectable local satellite/in-transit recurrence of melanoma

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) 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).

According to the prescribing information, Imlygic carries the following contraindications:

• Immunocompromised patients
• Pregnant patients

Per the prescribing information, Imlygic carries the following 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 the Injection Site: Consider the risks and benefits in patients with multiple myeloma or in whom plasmacytoma develops during treatment.
• Obstructive Airway Disorder: Use caution when injecting lesions close to major airways.
• Hepatic Hemorrhage from Transcutaneous Intrahepatic Route of Administration: Imlygic is not indicated for treatment via transcutaneous intrahepatic route of administration.

The most commonly reported adverse drug reactions (≥ 25%), per the prescribing information, included: fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain.

Refer to full prescribing information for Imlygic for use in specific populations.

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.

Breast Cancer

Kai et al (2021) stated that T-VEC is an immunotherapy that generates local tumor lysis and systemic anti-tumor immune response. Ina phase-II clinical trial, these researchers examined the effectiveness of intra-tumoral administration of T-VEC as monotherapy for inoperable loco-regional recurrence of breast cancer. T-VEC was administered intratumorally at 106 PFU/ml on day 1 (cycle 1), 108 PFU/ml on day 22 (cycle 2), and 108 PFU/ml every 2 weeks thereafter (cycles 3 or more). A total of 9 patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved CR or PR. The median number of cycles administered was 4 (range of 3 to 8); 7 patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median PFS and OS were 77 days (95 % CI: 63 to NA) and 361 days (95 % CI: 240 to NA). Two patients received 8 cycles with clinically SD as the best response. The most common grade-2 or higher AE was injection site reaction (n = 7, 78 %). The authors concluded that future studies could examine if combining intratumoral T-VEC with concurrent systemic therapy would produce better outcomes. The authors stated that the main drawback of this study was that evaluation of tumor tissues was not possible since none of the patients completed the study. Evaluation of alterations in the immune micro-environment of the injected and non-injected sites, including sites of distant disease, may provide valuable insights regarding the effectiveness of T-VEC.

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 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.

Franke et al (2023) noted that T-VEC i(a modified herpes simplex virus, type 1) is administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, T-VEC can be an elegant alternative to systemic immunotherapy. In this study, a total of 10 patients with metastatic melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute. These researchers collected data on response, AEs, and baseline characteristics. For response evaluation, they employed clinical evaluation with photography, 3-monthly positron emission tomography/computed tomography (PET/CT) using 18F-fluoro-2-D-deoxyglucose, and histological biopsies. Median age at baseline was 78.2 (35 to 97) years with a median follow-up of 11.6 months. Of these 10 patients, 5 had a CR, 3 had a PR, 1 had stable disease (SD) and 1 showed progressive disease (PD) as their best response. Best ORR was 80 %. Median progression-free survival (PFS) was 10.8 months (95 % CI: 2.2 to 19.4). Grade-1 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms, and injection site pain. PET-CT and histological biopsies proved to be clinically useful tools to examine treatment response for T-VEC monotherapy, confirming pathologic complete response (pCR) or PD to stage IV disease requiring systemic treatment. ORR for T-VEC monotherapy for melanoma in the head and neck region at the authors’ institute was 80 % with 50 % achieving a CR. The authors concluded that this real-world data demonstrated promising results and suggested T-VEC could be an alternative to systemic therapy in this select, mostly elderly patient population.

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.

Cilento et al (2022) noted that Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous tumor of neuroendocrine cell origin, which can grow rapidly and metastasize early. Localized disease is treated with surgery and radiotherapy (RT). Disease that reaches a more advanced stage can be treated with a variety of different therapeutic modalities including surgery, RT, chemotherapy, radionuclide therapy, immunotherapy, and intralesional therapy. These investigators reported on the case of a patient who had exhausted all local and systemic therapeutic options and who subsequently had an exceptional response to intralesional injection of T-VEC. Moreover, these researchers stated that while the initial experience of the use of T-VEC focused predominantly on cutaneous melanoma, there have now been a small number of cases described in the literature of durable benefit from T-VEC in patients with MCC, either used following an immune checkpoint inhibitor or concurrently in combination with a checkpoint inhibitor. They noted that clinical trials including patients with MCC are underway including a study through the Memorial Sloan Kettering Cancer Center examining T-VEC with or without RT for melanoma, MCC, or other solid tumors. The authors stated that further studies are needed to better define the optimal sequencing and use of T-VEC with immunotherapy for patients with advanced disease.

Casale et al (2022) stated that MCC is a rare neuroendocrine neoplasm, warranting surgical excision with sentinel lymph node biopsy (SLNB). In later stages, adjuvant chemotherapy and RT are needed due to its aggressive malignant behavior. These researchers described the case of a 62-year-old woman who presented with multi-focal recurrence of MCC and was not a candidate for immunotherapy or surgery. The patient underwent 4 treatments of intra-tumoral T-VEC and demonstrated a CR with no histologic evidence of remaining MCC on 4 scouting biopsies. The authors concluded that although T-VEC therapy is currently approved for the treatment of advanced stage melanoma, it is still being examined for use in MCC.

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.

Nuclear Protein in Testis (NUT) Carcinoma (NC)

Kloker et al (2022) stated that nuclear protein in testis (NUT) carcinoma (NC) is a rare and extremely aggressive form of cancer, usually presenting with intra-thoracic or neck manifestations in adolescents and young adults. With no established standard therapy regimen and a median OS of only 6.5 months, there is a huge need for innovative therapeutic options. As NC is genetically driven by a single aberrant fusion oncoprotein, it is generally characterized by a low tumor mutational burden; therefore, making it immunologically cold and insusceptible to conventional immunotherapy. Recently, these researchers have shown that OVs are able to specifically infect and lyse NC cells; thus, turning an immunologically cold tumor micro-environment into a hot one. These investigators reported an intensive multi-modal treatment approach using for the 1st time an OV (T-VEC) together with the immune checkpoint inhibitor pembrolizumab as an add-on to a basic NC therapy (cytostatic chemotherapy, radiation therapy, epigenetic therapy) in a patient suffering from a large thoracic NC tumor that exhibited an aberrant, unique BRD3:NUTM1 fusion. This case showed for the 1st time the feasibility of this innovative add-on immune-virotherapy regimen with a profound, repetitive and durable replication of T-VEC that is instrumental in achieving tumor stabilization and improvement in the patient´s quality of life (QOL). Furthermore, a previously unknown BRD3:NUTM1 fusion gene was discovered that lacks the extra-terminal domain of BRD3.

Soft-Tissue Sarcoma

Monga et al (2021) noted that soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care (SOC) pre-operative external beam RT (EBRT) followed by surgical resection are associated with local and distant relapses. In pre-clinical studies, oncolytic virotherapy in sarcoma has demonstrated anti-tumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. T-VEC is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma. In a phase-IB/II clinical trial, these researchers examined a novel combination of T-VEC with EBRT administered pre-operatively in patients with locally advanced STS of the extremities and trunk. A total of 30 patients with primary STS greater than 5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved T-VEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were carried out. No dose-limiting toxicity (DLT) was observed; AEs were similar to those reported in previous studies with T-VEC. One patient with myxoid liposarcoma exhibited a PR; 7 of the 29 (24 %) evaluable patients achieved 95 % pathological necrosis. None of the patients developed a herpes infection due to the treatment; 8 of the 29 (27 %) patients developed post-operative wound complications, which was consistent with previous studies. None of the patients developed local recurrence following surgical resection of the primary sarcoma. The 2-year PFS and OS were 57 % and 88 %, respectively. Caspase-3 demonstrated increased expression of both in T-VEC-treated tissue samples as compared with control samples treated with RT alone. The authors concluded that pre-operative intratumoral T-VEC with concurrent EBRT for locally advanced STS was safe and well-tolerated. Combinational treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of T-VEC in sarcoma tumor tissue and should be examined in future studies. Moreover, these researchers stated that a trial examining greater dose level of T-VEC corresponding to the tumor size and various combination strategies should be considered.

The authors stated that this study had several drawbacks. First, a fixed T-VEC dose was administered irrespective of tumor size. Whether this was an appropriate approach was not examined. This drawback could perhaps be overcome by evaluating phased dose escalations of T-VEC plus pre-operative EBRT based on sarcoma size (e.g., 4-ml of T-VEC in tumors 5 to 10 cm in size, 8-ml of T-VEC in tumors greater than 10 cm). An ongoing trial is evaluating the 8-ml dose of intratumoral TVEC in combination with pre-operative RT; and is currently enrolling patients. Second, standard EBRT doses were employed. Perhaps hypo-fractionated dosing of EBRT regimens that result in greater tumor cell killing and immune responses may elicit a better immune response. Third, despite careful ultrasound (US)-guided injection to ensure good T-VEC distribution to every tumor region, the drug effect could not be confirmed histologically in all parts of the tumor specimens. Whether good drug distribution within the tumor is important to elicit more potent anti-tumor immune responses remains to be determined. Visceral-site T-VEC injections could be considered for metastatic disease. Given the possibility of delayed responses with immunotherapy, as observed in 1 of the subjects, allowing continued treatment despite first progression may be considered, provided there are limited symptoms. Addition of other immune stimulants, such as systemic anti-PD-137–39 or intratumoral TLR 9 receptor agonists, could be considered for more robust localized immune responses. A recent study of T-VEC in combination with pembrolizumab in locally advanced or metastatic STS showed promising objective responses and the combination is being examined in select sarcoma subtypes. Exploring T-VEC in combination with anti-PD1 together with RT, which can further enhance immunotherapy effects, may be a very valuable approach to be studied in future clinical trials. Radiographic responses determined by comparing pre-treatment and pre-operative imaging (MRI or CT) did not correspond to pathological necrosis in all cases, which again highlighted the lack of good radiographic disease assessment in the neoadjuvant therapeutic space.

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.

Talimogene Laherparepvec Plus Nivolumab for Melanoma

Rohaan et al (2022) noted that studies examining neoadjuvant treatment with immune checkpoint inhibitors (ICI) in patients with melanoma have shown high clinical and pathologic response rates. Treatment with T-VEC is approved for patients with unresectable stage IIIB-IVM1a melanoma and has the potential to make tumors more susceptible for ICI. Combined ICI and intralesional T-VEC has already been examined in patients with unresectable stage IIIB-IV disease; however, no data are available yet on the potential benefit of this combinational therapy in neoadjuvant setting. In a single arm, single-center, phase-II clinical trial, these researchers aim to show an improved major pCR rate, either pCR or near-pCR, up to 45 % in 24 patients with resectable stage IIIB-IVM1a melanoma upon neoadjuvant combinational treatment with systematic nivolumab and intralesional T-VEC. Participants will receive 4 courses of T-VEC up to 4 ml (1st dose as seroconversion dose) and 3 doses of nivolumab (240 mg flat dose) every 2 weeks, followed by surgical resection in week 9. The primary endpoint of this trial is pathologic response rate; secondary endpoints are safety, the rate of delay of surgery and event-free survival (EFS). Furthermore, prognostic and predictive biomarker research and health-related QOL (HR-QOL) evaluation will be carried out. The authors concluded that intralesional T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma in combination with ICI. However, the potential clinical benefit of T-VEC plus ICI in the neoadjuvant setting remains unknown. This is the 1st trial examining the safety and effectiveness of neoadjuvant treatment of T-VEC and nivolumab followed by surgical resection in patients with stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity.

Talimogene Laherparepvec Plus Pembrolizumab for Melanoma

Chesney et al (2022) stated that the combination of T-VEC and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging CR rate (CRR) in patients with advanced melanoma in a phase-Ib clinical trial. In an international, randomized, double-blind, multi-center, phase-III clinical trial, these researchers examined the safety and effectiveness of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. Patients with stage IIIB-IVM1c unresectable melanoma, naive to anti-programmed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at 4 × 10[6] or less plaque-forming unit (PFU) followed by 4 × 10[8] or less PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary endpoints were PFS per modified Response Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and OS. Secondary endpoints included ORR per mRECIST, CRR, and safety. These investigators reported the primary analysis for PFS, the 2nd pre-planned interim analysis for OS, and the final analysis. A total of 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio [HR], 0.86; 95 % CI: 0.71 to 1.04; p = 0.13) or OS (HR, 0.96; 95 % CI: 0.76 to 1.22; p = 0.74) compared with placebo-pembrolizumab. The ORR was 48.6 % for T-VEC-pembrolizumab (CRR 17.9 %) and 41.3 % for placebo-pembrolizumab (CRR 11.6 %); the durable response rate was 42.2 % and 34.1 % for the arms, respectively. Grade-3 or higher treatment-related AEs occurred in 20.7 % of patients in the T-VEC-pembrolizumab arm and in 19.5 % of patients in the placebo-pembrolizumab arm. The authors concluded that T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

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References