Talimogene laherparepvec

Talimogene laherparepvec

Transmission electron micrograph of an unmodified herpes simplex virus
Clinical data
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  • TBD
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administration		 Injection
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CAS Number 1187560-31-1
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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 OncoVEXGM-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 demonstrated effective in a Phase III clinical trial.[2]

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

In January 2016 it was approved in Europe for some inoperable melanomas.[4]

Approvals and indications

The injectable formulation of T-VEC is approved for the treatment of melanoma in patients with inoperable tumors in the US.[3]

Imlygic is approved in Europe 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:

Summary of genetic modifications[5][6]
Modification Result
Use of new HSV-1 strain (JS1) improved tumor cell killing ability compared with other strains
Deletion of ICP34.5 prevents HSV infection of non-tumor cells, providing tumor-selective replication
Deletion of ICP47 enables antigen presentation
Earlier insertion of US11 increases replication and oncolysis of tumor cells
Insertion of human GM-CSF gene enhances anti-tumor immune response by recruiting and stimulating dendritic cells to tumor site

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 them. T-VEC is injected directly into tumors. The virus invades both cancerous and healthy cells, but it is unable to replicate in healthy cells, leaving them unaffected. Inside a cancer cell, the virus is able to replicate, secreting GM-CSF in the process. Eventually overwhelmed, the cancer cell ruptures (lyses), destroying the cell and releasing new viruses, GM-CSF, and tumor-specific antigens (pieces of the cancer cell that are 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 the antigen source. The dendritic cells pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells. This programs the T cells to recognize the cancer cells 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 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 durable responses.[6]

Consistent with other immunotherapies, some patients exhibited initial disease progression before eventually 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]

T-VEC offered 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 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 had been treated before metastasis (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 OPTiM trial was the first Phase III proof of efficacy for a virus-based oncolytic immunotherapy.

Results reported in 2015 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] 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 melanoma trials

T-VEC was tested in melanoma in combination with ipilimumab [10][11] and pembrolizumab.[12] Both cases produced response rates of over 50%, 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]

In the Phase II trial 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 experiencing disease progression. At the median post-treatment follow-up of 29 months, all 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 Phase III trial was initiated in 2010 by BioVEX.[13] After Amgen acquired T-VEC in, they halted the trial due to the "changing therapeutic landscape for patients"— presumably the discovery of HPV status as a major prognostic risk factor.[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]

Tolerance

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 2.1% of patients.[6][9][15]

External links

See also

References

  1. ↑ [ Amgen buys a cancer drug maker. New York Times
  2. 1 2 Amgen press release. Amgen announces top-line results of phase 3 talimogene laherparepvec trial in melanoma. Mar 19, 2013. Available here
  3. 1 2 "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015.
  4. 1 2 3 4 Metastatic Melanoma Therapy, Imlygic, Now Available in EU
  5. 1 2 3 Liu BL, Robinson M, Han Z-Q, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Therapy. 2003;10:292–303 . Available here
  6. 1 2 3 4 Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor–encoding, second-generation oncolytic herpesvirus in patents with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-5771. Available here
  7. ↑ Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. 2010;17(3):718-30. Available here
  8. ↑ Núñez MA. Tumor killer viruses. Mapping Ignorance. January 9, 2013. Available here
  9. 1 2 3 Andtbacka RHI, Collichio FA, Amatruda T et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol 31, 2013 (suppl; abstr LBA9008). Available here
  10. ↑ Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.
  11. ↑ Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.
  12. ↑ A multicenter, open-label trial of talimogene laherparepvec (T-VEC) plus pembrolizumab vs pembrolizumab monotherapy in previously untreated, unresected, stage IIIB-IV melanoma.
  13. 1 2 ClinicalTrials.gov. Study of safety and efficacy of OncoVEXGM-CSF With cisplatin for treatment of locally advanced head and neck cancer. NLM Identifier: NCT01161498. Available here.
  14. ↑ Harrington K, Hingorani M, Tanay M, et al. A phase I/II dose escalation study of OncoVexGM-CSF and chemoradiotherapy in untreated stage III/IV squamous cell cancer of the head and neck. J Clin Oncol. 2009;27:15s(suppl; abstr 6018). Available here
  15. 1 2 Harrington K, Hingorani M, Tanay M, et al. Phase I/II study of oncolytic HSVGM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin Cancer Res. 2010;16:4005-4015. Available here
  16. ↑ Amgen press release. Amgen's second quarter 2011 revenue increased 4 percent to $4.0 billion. Jul 29, 2011. Available here.
  17. ↑ Chang KJ, Senzer NN, Binmoeller K, Goldsweig H, Coffin R. Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer (ca). J Clin Oncol. 2012;30(suppl; abstr e14546). Available here
  18. ↑ Hu JCC, Coffin RS, Davis CJ, et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12:6737-6747. Available here
  19. ↑ American Cancer Society. Kidney cancer (adult) - renal cell carcinoma: What's new in kidney cancer research and treatment? Last revised: 1/18/2013. Available here
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