Talimogene laherparepvec

Talimogene laherparepvec

Transmission electron micrograph of an unmodified herpes simplex virus
Clinical data
Pregnancy category	TBD
Legal status	US: ℞-only
Routes of administration	Injection
Identifiers
CAS Number	1187560-31-1
ChemSpider	none

Talimogene laherparepvec (tal im' oh jeen la her" pa rep' vek), often simply called "T-VEC" is a cancer-killing (oncolytic) virus studied for the treatment of melanoma and other advanced cancers. The drug was developed by BioVex, Inc. under the name OncoVEX^GM-CSF. It was acquired by Amgen in 2011.^[1]

With the announcement of positive results in March 2013, T-VEC became the first oncolytic virus to be proven effective in a Phase III clinical trial.^[2]

In October 2015, the US FDA approved T-VEC, with the brand name Imlygic, for the treatment of melanoma in patients with inoperable tumors.^[3]

In Jan 2016 it was approved in Europe for some inoperable melanoma.^[4]

Approvals and indications

In October 2015, the US Food and Drug Administration approved the injectable formulation of T-VEC, with the brand name Imlygic, for the treatment of melanoma in patients with inoperable tumors.^[3]

In Jan 2016 the European Commission (EC) approved Imlygic for adult patients with unresectable melanoma that is regionally or distantly metastatic — Stage IIIB, IIIC and IVM1a — and with no brain, bone, lung, or other visceral disease.^[4]

Mechanism of action

T-VEC was engineered from herpes simplex virus 1 (HSV-1), a relatively innocuous virus that normally causes cold sores. A number of genetic modifications were made to:

• Attenuate the virus (so it could no longer cause herpes)
• Increase selectivity for cancer cells (so it destroys cancer cells while leaving healthy cells unharmed)
• Secrete the cytokine GM-CSF (a protein naturally secreted in the body to initiate an immune response)

T-VEC has a dual mechanism of action, destroying cancer both by directly attacking cancer cells and also by helping the immune system to recognize and destroy cancer cells. T-VEC is injected directly into the patient’s tumors. The virus invades both cancerous and healthy cells, but it is unable to replicate in healthy cells and thus they remain unaffected. Inside a cancer cell, the virus is able to replicate, secreting GM-CSF in the process. Eventually overwhelmed, the cancer cell lyses (ruptures), destroying the cell and releasing new viruses, GM-CSF, and an array of tumor-specific antigens (pieces of the cancer cell that are small enough to be recognized by the immune system).^[5]

The GM-CSF attracts dendritic cells to the site. Dendritic cells are immune cells that process and present antigens to the immune system so that the immune system can then identify and destroy whatever produced the antigen. The dendritic cells pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells. Now the T cells are essentially "programmed" to recognize the cancer as a threat. These T cells lead an immune response that seeks and destroys cancer cells throughout the body (e.g., tumors and cancer cells that were not directly injected with T-VEC).^[5][7]

In this way, T-VEC has both a direct effect on injected tumors and a systemic effect throughout the entire body.^[8] Because the adaptive immune system "remembers" a target once it has been identified, the effect of an oncolytic virus like T-VEC may be durable (e.g., prevent relapse). For this reason T-VEC is injected into just enough tumors to start the immune process.

Clinical trials

Melanoma

Clinical efficacy in unresectable melanoma has been demonstrated in phase II and phase III clinical trials.

The phase II clinical trial was published in 2009. 50 patients with advanced melanoma (most of whom had failed previous treatment) were treated with T-VEC. The overall response rate (patients with a complete or partial response per RECIST criteria) was 26% (16% complete responses, 10% partial responses). Another 4% of patients had a surgical complete response, and another 20% had stable disease for at least 3 months. On an extension protocol, 3 more patients achieved complete responses, and overall survival was 54% at 1 year and 52% at 2 years—demonstrating that responses to T-VEC were durable.^[6]

Consistent with other immunotherapies, some patients exhibited initial disease progression before eventually responding by generating the full immune response. Responses were seen in both injected and uninjected tumors (including those in visceral organs), demonstrating systemic immunotherapeutic effects. Treatment was well tolerated, with only Grade 1 or 2 drug-related side effects, most commonly mild flu-like symptoms.^[6]

Phase III OPTiM trial

This global, randomized, open-label trial compared T-VEC with subcutaneously administered GM-CSF (2:1 randomization) in 430 patients with unresectable stage IIIB, IIIC or IV melanoma. The primary endpoint was durable response rate (DRR), defined as a complete or partial tumor response lasting at least 6 months and starting within 12 months of treatment.^[2]

Amgen announced the initial results of the Phase III OPTiM trial on Mar. 19, 2013. T-VEC was shown to offer superior benefits in metastatic melanoma. DRR was achieved in 16% of patients receiving T-VEC compared with only 2% in the GM-CSF control group (P<.0001). The greatest benefit was seen in stage IIIB or IIIC melanoma, with a 33% DRR vs 0% with GM-CSF. The objective response rate (any response) with T-VEC was 32%, with 17% of patients experiencing a complete response (complete disappearance of melanoma throughout the body). This demonstrated that T-VEC has a systemic immune effect that destroys distant, uninjected tumors.^[9]

The most common side effects with T-VEC were fatigue, chills and fever.

Further survival data were presented later in 2013. It showed that for patients who hadn't previously been treated for their melanoma (half the trial patients) death risks were reduced by 51% and that for patients who were treated before the melanoma had spread to their organs (also half of the trial patients; stages 3b, 3c and IV M1a) death risk was reduced by 44%, which were statistically significant results (p<0.001).^[9]

The success of T-VEC in the OPTiM trial represents the first Phase III proof of efficacy for a virus-based oncolytic immunotherapy.

Further results were reported in 2015 (leading to US and EU approvals). The results showed a durable response rate (DRR) in patients with Stage IIIB, IIIC and IVM1a melanoma of 25.2%, versus 1.2% in patients treated with GM-CSF.^[4] Also: The median overall survival (OS) for the Imlygic-treated patients treated was 41.1 months, versus 21.5 months in those given GM-CSF.^[4]

Other trials for melanoma

T-VEC has also been tested in melanoma in combination with ipilimumab (data presented at ASCO 2014^[10] and 2015^[11]) and pembrolizumab (data presented at SMR 2015^[12]) with in both cases response rates of over 50% being seen, with no increased toxicity as compared to the use of either drug alone.

Head and neck cancer

Clinical efficacy in squamous cell cancer of the head and neck (SCCHN) was demonstrated in a Phase II trial. A Phase III trial was started but terminated without explanation.^[13]

The Phase II trial results were announced in 2009 and published in 2010. 17 patients with stage III or IVA SCCHN received one of 4 different doses of T-VEC along with concomitant cisplatin and radiotherapy. 93% of patients had a pathological complete response confirmed by neck resection. 82% of patients had a complete or partial radiologic response per RECIST criteria. The remaining patients had stable disease, with no patient (0%) experiencing disease progression. At the median post-treatment follow-up of 29 months, all (100%) patients continued to show loco-regional control with disease-specific survival at 82%. T-VEC was well tolerated and had a similar safety profile to that seen in the melanoma trials (Grade 1 or 2 side effects only, the most common being mild flu-like symptoms). 77% of patients remained relapse-free as of 2010.^[14][15]

A 2010 Phase III trial in SCCHN was initiated by BioVEX.^[13] After Amgen acquired T-VEC in, they halted the trial due to the "changing therapeutic landscape for patients with SCCHN"— presumably the discovery of HPV status as a major prognostic risk factor in SCCHN.^[16]

Other cancers

Clinical activity was observed in Phase I studies including patients with pancreatic, breast and colorectal cancers.^[17][18] Because it is an immunoresponsive tumor, renal cell carcinoma is also a potential target.^[19]

Tolerability

T-VEC has generally been well tolerated. The majority of adverse events were mild or moderate (Grade 1 or 2). The most common side effects are mild fatigue, chills, or fever. In the Phase III OPTiM trial, the most common serious side effect was cellulitis, reported in only 2.1% of patients.^[6][9][15]

External links

• Imlygic
• Imlygic full prescribing information

See also

• Virotherapy
• Oncolytic virus
• Oncolytic herpes virus
• Oncolytic adenovirus

References