By: Gabrielle Plaia, PharmD Candidate Class of 2016
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On Oct. 27 2015, the Food and Drug Administration announced the approval of talimogene laherparepvec, referred to by its brand name ImlygicTM, with an indication for local treatment of melanoma lesions that cannot be removed completely by initial surgery. The drug was created by Amgen.1 This drug is the first of its kind – a genetically modified, live oncolytic herpes simplex virus type 1 (HSV-1) therapy.2 The drug is injected directly into the lesions and then proceeds to work by replicating inside tumors. It then causes the lysis of individual cells causing a rupture of tumors, which may in turn cause an anti-tumor response, though the exact mechanism of action is not known.3
The trial that paved the way for the approval of ImlygicTM is referred to as OPTiM, a phase 3 multicenter, open-label, randomized clinical trial. This trial set out to compare ImlygicTM to an immunostimulatory protein called granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 individuals with advanced melanoma with lesions unable to be removed by surgery.4 Due to the modification of HSV-1, ImlygicTM can replicate within tumors and to produce GM-CSF. The released GM-CSF combined with Imlygic’sTM tumor-lysing ability and release of tumor-derived antigens, may promote an antitumor immune response. This is only a proposed mechanism of action, since, as previously stated, the true mechanism of action is not known.2
The melanoma lesions of these patients were treated with ImlygicTM (295 patients) or GM-CSF (141 patients) for six months or until injectable lesions ceased to exist. The primary endpoint of this study was a durable response rate (DRR), which is defined as complete or partial response for at least six months, and beginning at any point within twelve months of initiating therapy. OPTiM found that 16.3% of patients treated with ImlygicTM reached a durable response rate, as opposed to 2.1% of patients treated with GM-CSF, which was statistically significant.4 Additionally, in the primary survival analysis of OPTiM, the median overall survival was calculated as 23.3 months in patients with ImlygicTM as opposed to 18.9 months in those treated with GM-CSF, although this did not achieve statistical significance. There was no improvement in overall survival or effect on melanoma spreading to other regions with the use of Imlygic.4
In April of 2015, the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 22-1 in favor of approval of ImlygicTM, then known as oncolytic immunotherapy T-VEC.5 A final approval decision was scheduled for October 27th, 2015 – and on that date the drug was then set to be marketed, a few days after approval by the European Medicines Agency.6
Risks associated with ImlygicTM include common side effects observed in the OPTiM trial – fatigue, chills, pyrexia, flu-like symptoms and injection site pain.1,2 A more serious possible adverse event of ImlygicTM therapy is cellulitis at the injection site. Due to the nature of its mechanism as a modification of herpes simplex virus 1, infection with herpes may occur.1 ImlygicTM should therefore not be used as treatment in certain patient populations, such as those on immunosuppressants, pregnant women, and otherwise immunocompromised individuals. Additional risks include impaired wound healing. Overall, in the OPTiM trial, there was a marginally higher percentage of patients treated with ImlygicTM (99.3%) as opposed to GM-CSF (95.3%) who had treatment-emergent adverse effects.4
Potential benefits with this agent are reflected in the results in the OPTiM study. In comparison to GM-CSF, there was a 4.4 month increase in median survival rate with Imlygic therapy, although this was not statistically signficant.4 A greater percent of patients had reached a complete or partial response rate as well. The results of OPTiM are a representation of what will hopefully be exemplified in a broader patient population of individuals with advanced melanoma, which is incredibly difficult to treat. This genetically modified oncolytic viral therapy not only provides an additional treatment modality in those with unresectable melanoma, but it paves the way for what could become a pivotal class of drugs in the constantly-advancing landscape of cancer immunotherapy.
SOURCES:
- Food and Drug Administration. FDA Approves First-Of-Its-Kind Product For The Treatment Of Melanoma. 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm. Accessed November 24, 2015.
- Lexicomp. Talimogene Laherparepvec. (Lexi-Drugs). Lexicomp website. Available at http://http://online.lexi.com.jerome.stjohns.edu:81/lco/action/doc/retrieve/docid/patch_f/5909571. Accessed November 24, 2015.
- Amgen. FDA approves Imlygic™ (Talimogene Laherparepvec) as first oncolytic viral therapy in the US. 2015. Available at: http://www.multivu.com/players/English/7414056-amgen-imlygic-fda-approval/. Accessed November 24, 2015.
- Kaufman HL, Bines SD. OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 2010;6(6):941-9. doi: 10.2217/fon.10.66. Accessed November 24, 2015.
- Broderick J. FDA Panels Support Approval of T-VEC in Melanoma. OncLive. http://www.onclive.com/web-exclusives/FDA-Panels-Support-Approval-of-T-VEC-in-Melanoma. Published April 29, 2015. Accessed November 24, 2015.
- Nelson R. FDA Approves Imlygic, First Oncolytic Viral Therapy in the US. Medscape. http://www.medscape.com/viewarticle/853345. Published 10/27/2015. Accessed November 24, 2015.
