Information below provided by the Pharmaceutical Company.

Talimogene laherparepvec (IMLYGIC^™, OncoVEXGM-CSF)

Agent Description

Talimogene laherparepvec is a modified HSV-1 containing the gene coding for human GM-CSF. Wild type HSV-1 is an alpha herpes virus that can infect a wide range of cell types. HSV-1 consists of a large double-stranded linear DNA genome of approximately 152 kb that is packaged into an icosahedral nucleocapsid approximately 125 nm in diameter. HSV-1 is an enveloped virus with an amorphous structure between the nucleocapsid and envelope known as the tegument that contains virus proteins important in the early stages of the infection process. The size of the complete virion varies but the average virion diameter is 186 nm, or approximately 225 nm if the glycoprotein spikes are included.

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Mechanism of Action

Intralesional administration of talimogene laherparepvec results in oncolysis of cells within injected tumors. Iterative viral replication within permissive tumor tissue results in lytic cell destruction and local release of progeny virus as well as of tumor cell antigens. GM-CSF, the product of the viral transgene, is also produced locally to recruit and stimulate antigen presenting cells which, in addition to relevant tumor-derived antigens, are required for the initiation of a systemic antitumor immune response. Overall, this strategy is expected to result in the destruction of injected tumors via oncolysis and un-injected sites of disease (including micro-metastases) via a systemic antitumor immune response, to curtail tumor progression and to reduce local and distant tumor recurrence.

Classification

Genetically modified oncolytic virus

Molecular Target

N/A

Monograph

Talimogene laherparepvec is an intralesionally delivered virally-based oncolytic immunotherapy comprised of a genetically engineered herpes simplex virus type 1 (HSV-1) that selectively replicates in tumor tissue. The genes encoding neurovirulence factor ICP34.5 and ICP47 are functionally deleted in the virus allowing for selective replication in tumor cells, while the gene for human granulocyte macrophage colony-stimulating factor (GM-CSF) is inserted enabling stimulation of cellular immune responses. T-VEC enables both direct tumor lysis at the site of injection as well as enhancement of a systemic immune response by expression of GM-CSF in the tumor microenvironment to recruit and activate antigen presenting cells required for a T cell-mediated anti-tumor response.

Preclinical data: In vitro studies of cytopathic effects and in vivo studies of efficacy in numerous tumor types, have been conducted with talimogene laherparepvec and its murine analog, OncoVEXmouseGM-CSF. Talimogene laherparepvec lyses a variety of in vitro human tumor cell lines in culture including colorectal cancer (HT29), breast cancer (MDA-MB-231), glioblastoma astrocytoma (U-87 MG), prostate adenocarcinoma (LNCaP), and malignant melanoma (SK-MEL-28) tested at a multiplicity of infection (MOI) between 0.1 and 5; essentially all tumor cells were killed less than 48 hours following infection in vitro.

Talimogene laherparepvec affects not only the tumors into which it is injected, but also distant non-injected tumors, demonstrating a systemic beneficial effect from local administration. Talimogene laherparepvec suppresses tumor recurrence upon re-challenge with the same tumor type and remains effective when animals have undergone previous exposure to wild-type HSV implying that pre-existing antibodies to HSV do not preclude the drug’s activity.

In mice injected with OncoVEXmouseGM-CSF, immunophenotyping demonstrated increases in activated T cells (CD69+), and treatment-related decrease in CD3+ T cells in the injected tumor-draining lymph node possibly due to trafficking of T-cell to tumor. Increases in NK T cells were seen in injected and non-injected tumor draining lymph nodes as well as the spleen. Additionally, treatment increases tumor-specific cytotoxic T lymphocyte responses in mice. Splenocytes from CT26 tumor bearing mice were isolated and treated with Talimogene laherparepvec or vehicle control. Splenocytes were cultured in the presence of mitomycin C to arrest tumor cell growth and allow for expansion of T-cells specific to tumor. The T-cells were purified and put into a killing cell assay with either the same tumor or a distant tumor. Results indicated T-cells from Talimogene laherparepvec treated animals have a more specific and robust capability of killing tumor cells.

Talimogene laherparepvec has been tested to evaluate the combined effects of either radiation (Investigators Brochure-Report 4648-00019) or chemotherapy (Investigators Brochure-Report 4648-00022) in preclinical studies. Both combinations were well tolerated.

Preclinical testing of the combination of Talimogene laherparepvec and anti-PD-1 has been tested in MC38 contralateral tumor bearing mice. Murine versions of Talimogene laherparepvec and anti-PD-1 were administered intralesionally and both injected tumor and contralateral noninjected tumor were observed. Mice demonstrated 80% complete regression of tumor in injected lesions with 20% complete regression in noninjected lesions. Additionally, the combination of Talimogene laherparepvec and anti-PD-1 increased co-receptor expression (both PD-1 and PD-L1) on CD8+ T cells in peripheral blood (Amgen data on file).

In vitro testing results with Talimogene laherparepvec in a variety of cell lines as part of the pediatric preclinical testing program (PPTP) showed oncolytic activity against the pediatric solid tumor cell lines evaluated (Amgen data on file). A range of sensitivity was observed, with the Ewing sarcoma and neuroblastoma cell lines being most sensitive and the rhabdomyosarcoma cell lines showing higher IC50 values. Leukemia and lymphoma cell lines did not respond to Talimogene laherparepvec. Additionally, Amgen conducted a study to test the sensitivity of human pediatric osteosarcoma cell lines to Talimogene laherparepvec. Specifically, 7 pediatric osteosarcoma cell lines were treated with Talimogene laherparepvec and all showed susceptibility to Talimogene laherparepvec mediated oncolysis in a concentration dependent fashion (Amgen data on file).

Clinical Experience:

Nine clinical studies have been or are being conducted in several advanced tumor types (advanced solid tumors, melanoma, squamous cell cancer of the head and neck [SCCHN], and pancreatic cancer), with over 400 subjects treated with talimogene laherparepvec. These studies include a phase 1 study (001/01) in various advanced solid tumors (n = 30), a phase 1/2 study (004/04) in SCCHN (n = 17), a phase 1 study (005/04) in pancreatic cancer (n = 17), a phase 2 study (002/03) in melanoma (n = 50), and a phase 2 extension study (002/03 E) in subjects from the phase 2 melanoma study for whom further treatment was considered to be warranted by the investigator (n = 3). Additionally, the primary analysis of the phase 3 study (005/05) in melanoma was recently completed (n = 292 subjects treated with talimogene laherparepvec), and an extension to that study (005/05E) is ongoing (n = 25). An ongoing Phase1b/2 study of ipilimumab with or without talimogene laherparepvec in Stage IIIB-IV melanoma is ongoing, and 19 subjects have been treated with talimogene laherparepvec in the Phase 1b portion. Finally, a non-interventional registry study (009/07) is ongoing to investigate the long-term survival and safety of subjects previously treated with talimogene laherparepvec in prior clinical trials.

In the open-label, randomized, phase 3 study of talimogene laherparepvec versus subcutaneously administered GM-CSF in stage IIIB, IIIC, and IV unresectable melanoma, talimogene laherparepvec or GM-CSF was administered until CR, clinically significant PD, intolerable side effects, 12 months of therapy without an objective response, or withdrawal of consent (OPTiM study, Study 005-05). The primary endpoint of the study was DRR, defined as the rate among subjects with an objective response (CR or partial response [PR]) lasting continuously for 6 months and starting any time within 12 months of initiating therapy. Primary analysis of the OPTiM study showed a statistically significant difference between the rate of durable response among subjects treated with talimogene laherparepvec (16%; 95% confidence interval [CI]: 12%, 21%). versus those treated with GM-CSF (2%; 95% CI: 0%, 5%) (p-value <0.0001). Responses were seen in both injected and non-injected lesions including visceral metastases. At the primary analysis of the secondary endpoint of overall survival (OS), median OS was 23.3 months in subjects treated with talimogene laherparepvec, compared with 18.9 months for subjects treated with GM-CSF (HR 0.79; 95% CI: 0.62, 1.00; p-value 0.051). Most common side effects were fatigue, chills, and pyrexia. Serious adverse events occurred in 26% of the talimogene laherparepvec subjects and 13% of the GM-CSF subjects. No ≥ grade 3 adverse events occurred in ≥ 2% of subjects in either arm.

A phase 1b/2 study combining talimogene laherparepvec with the checkpoint inhibitor ipilimumab in advanced melanoma is being conducted (ClinicalTrials.gov NCT01740297). Talimogene laherparepvec is administered by intralesional injection at up to 4 mL of 106 plaque forming units (PFU)/mL for the first dose, then up to 108 PFU/mL 3 weeks later and every 2 weeks thereafter. Ipilimumab is administered at a dose of 3 mg/kg every 3 weeks as 4 infusions starting 5 weeks after the initial dose of talimogene laherparepvec. Preliminary results indicate at least 7 objective responses (4 CR, 3 PR), including 1 CR in a subject with lung metastasis, among the first 18 subjects evaluable for response. Median time to response was 2.0 months and most patients responded within 11 weeks of therapy initiation. Median tumor follow-up time was 35.5 weeks. There were no dose-limiting toxicities and no increased toxicities beyond what would be expected from either agent alone. These data, although preliminary, suggest higher CR and OR rates than either agent alone.

Over 400 subjects have received talimogene laherparepvec (with doses from 104 to 108 PFU/mL) across 9 studies (Investigators brochure- Table 6-3). Overall, most adverse events reported in subjects administered talimogene laherparepvec are non-serious and most commonly include flu-like symptoms and injection site reactions. There has been no fatal treatment related adverse events. Most fatal adverse events reported in subjects administered talimogene laherparepvec were reported in the setting of disease progression.

Package insert: http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/imlygic/imlygic_pi.ashx

Studies of Interest

Areas of Interest:

• Injectability
  • Study proposals in settings with a defined injectable solid tumor and where sufficient injections (4-6 injections) can be achieved. Proposals can be in settings with injectable tumor but requiring interventional radiology or endoscopic/brochospcopic administration (e.g., pelvic or mediastinal lymph nodes) or involve an alternative method of administration (e.g., intravesical, intrepleural).
• Combinations in other injectable tumor types
  • Combination studies with approved chemotherapy, targeted therapy or immunotherapy in a new indication of interest (e.g., lung cancer, bladder, prostate cancer, gastroesophageal cancers)
  • Combination studies with other modalities such as radiotherapy or chemoradiotherapy (e.g. HNSCC, lung cancer, cervical, anal cancer, rectal) or with other locoregional therapies (e.g. ILI/ILP, electrochemotherapy) in melanoma.
• Monotherapy
  • In other injectable tumor types, such as skin/subcutaneous metastases of various tumor types (e.g. non-melanoma) or uveal/ocular melanoma with cutaneous disease
• Studies to understand mechanism of action

Areas NOT of Interest:

• Proposals that involve systemic injections (e.g., intravenous)
• Proposals that replace an established potential curative treatment (but can be an add-on)
• Proposals that involve pediatric tumors
• Proposals that involve injection in brain tumors (i.e., glioblastoma multiforme) or brain metastases
• Proposals in combination with any unapproved drug
• Proposals in immunocompromised patient populations

Information collaborator would like included in investigator proposals

Amgen is considering proposals for drug only support.