Talimogene laherparepvec is an oncolytic treatment used in the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma. It is a genetically administered herpes simplex virus 1 (HSV-1) that expresses human cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) with antitumor and immune-stimulating activities. It specifically replicates within tumor cells and causes lysis. It was approved by the FDA in 2015 under the market name Imlygic.
In general, talimogene laherparepvec has been modified so that it can infect and multiply inside melanoma cells [rx]. The drug subsequently uses the melanoma cells’ own machinery to multiply, eventually overwhelming the melanoma cells and killing them [rx]. Alternatively, although talimogene laherparepvec also enters healthy cells, it is not designed to multiply inside them [rx].
Mechanism of action
Talimogene laherparepvec is an oncolytic immunotherapy that is derived from Herpes Simplex Virus type-1 (HSV-1) [rx]. It has been modified to replicate within tumor cells and to produce the immune response stimulatory protein, human GM-CSF (granulocyte-macrophage colony-stimulating factor) [rx]. The medication causes the death of tumor cells and the release of tumor-derived antigens [rx]. It is believed that together with GM-CSF, talimogene laherparepvec can promote a systemic anti-tumor immune response and an effector T-cell response [rx]. Mice subjects involved in talimogene laherparepvec treatment studies that had complete regression of their primary tumors following therapy were resistant to subsequent tumor rechallenge [rx].
The genetic modifications to talimogene laherparepvec from HSV-1 include deletion of the ICP34.5 and ICP47 genes [rx]. Whereas anti-viral immune responses defend normal cells following infection by talimogene laherparepvec, tumors have been shown to be susceptible to injury and cell death from ICP34.5-deficient HSV-1 derived viruses, including talimogene laherparepvec [rx]. Moreover, deletion of ICP47 prevents the down-regulation of antigen presentation molecules in the targeted tumor cells and increases the expression of the HSV US11 gene, thereby enhancing the talimogene laherparepvec viral replication in tumor cells and increasing chances of tumor cell injury and death [rx].
Although the talimogene laherparepvec virus is specifically modified to infect and multiply inside melanoma cells and uses melanoma cells’ own machinery to multiply, the medication is not designed to multiply inside healthy cells, which it is also capable of entering [rx].
Talimogene laherparepvec has been genetically modified to replicate within tumors and to produce the immune stimulatory protein GM-CSF (granulocyte-macrophage colony-stimulating factor). The medication causes lysis of tumors, followed by the release of tumor-derived antigens, which together with virally derived GM-CSF may promote an anti-tumor immune response in the body.
- This medication is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable, cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after the initial surgery. Elsewhere, the EMA notes that the agent is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral diseases.
- Talimogene laherparepvec is delivered by injecting it directly into tumors, thereby creating a systemic anti-tumor immune response.[rx] In the US, talimogene laherparepvec is FDA-approved to treat Stage IIIb-IVM1c melanoma patients for whom surgical intervention is not appropriate and with tumors that can be directly injected; the EMA-approved population in Europe is for Stage IIIb-IVM1a.[rx][rx]
- Talimogene laherparepvec has been shown to extend survival in patients with Stage IIIb-IVM1a melanoma and patients who have not received prior systemic therapy for melanoma.[rx]
Use in Cancer
Talimogene laherparepvec is approved to treat:
- Melanoma in the skin and lymph nodes that cannot be removed by surgery. It is used as a local treatment in patients whose disease has recurred (come back) after being treated with surgery.
Talimogene laherparepvec is also being studied in the treatment of other types of cancer.
- a herpes simplex infection
- a patient who is producing milk and breastfeeding
Strengths: 1 mpfu/mL; 100 mpfu/mL
Melanoma – Metastatic
- Up to 4 mL at a concentration of 10(6) [1 million] plaque-forming units (PFU) per mL by intralesional injection.
- The largest lesion(s) should be injected first.
- The remaining lesion(s) should be prioritized for injection based on lesion size.
- Up to 4 mL at a concentration of 10(8) [100 million] PFU per mL by intralesional injection 3 weeks after initial treatment.
- New lesions that developed since initial treatment should be injected first.
- The remaining lesion(s) should be prioritized for injection based on lesion size.
All Subsequent Treatments (including Reinitiation):
- Up to 4 mL at a concentration of 10(8) [100 million] PFU per mL by intralesional injection 2 weeks after previous treatment.
- New lesions that developed since previous treatment should be injected first.
- The remaining lesion(s) should be prioritized for injection based on lesion size.
- Maximum Dose: The total injection volume for each treatment visit should not exceed 4 mL for all injected lesions combined.
Duration of Therapy:
- At each treatment visit: Lesions should be injected until maximum injection volume is reached or until all injectable lesion(s) have been treated.
- Full treatment course: At least 6 months unless another treatment is required or until there are no injectable lesions to treat.
The injection volume should be based on lesion size (lesions clustered together should be treated as a single lesion):
- Greater than 5 cm: Up to 4 mL
- Greater than 2.5 cm to 5 cm: Up to 2 mL
- Greater than 1.5 cm to 2.5 cm: Up to 1 mL
- Greater than 0.5 cm to 1.5 cm: Up to 0.5 mL
- 0.5 cm or less: Up to 0.1 mL
- This drug should be injected into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.
- Previously injected and/or uninjected lesion(s) may be injected at subsequent treatment visits.
- It may not be possible to inject all lesions at each treatment visit or over the full course of treatment.
- This drug should only be administered by intralesional injection; IV administration should not be used.
- The manufacturer’s product information should be consulted for administration technique instructions.
- This drug should be stored and transported at -90 to -70 degrees Celsius (-130 to -94 Fahrenheit).
- The thawed drug should be protected from light and stored in its original vial and carton in a refrigerator at 2 to 8 degrees Celsius (36 to 46 Fahrenheit) for no longer than 12 hours for the 10(6) [1 million] PFU per mL vial, and no longer than 48 hours for the 10(8) [100 million] PFU per mL vial.
- Vials left in the refrigerator longer than the specified times should be discarded.
- This drug should be thawed immediately prior to administration; the manufacturer’s product information should be consulted for thawing instructions.
- Healthcare providers who are immunocompromised or pregnant should not handle, prepare, or administer this drug, and should not come into direct contact with injection sites, dressings, or body fluids of treated patients.
- Personal protective equipment (gown or lab coat, safety glasses or face shield, gloves) should be worn while preparing or administering this drug.
- Accidental drug exposure (especially contact with skin, eyes, and mucous membranes) should be avoided and exposed wounds should be covered before handling.
- If accidental occupational exposure occurs, the affected area should be flushed with clean water for at least 15 minutes.
- If exposure to broken skin or needle sticks occurs, the affected area should be cleaned thoroughly with soap and water and/or a disinfectant.
- All drug spills should be treated with a virucidal agent (e.g., 1% sodium hypochlorite) and blotted with absorbent materials.
- All materials that come in contact with this drug should be disposed of in accordance with universal biohazard precautions.
- Treatment with this drug should be reinitiated if new unresectable cutaneous, subcutaneous, or nodal lesions appear after a complete response.
- This drug has not been shown to improve overall survival or have an effect on visceral metastases.
- There is no clinical overdose experience with this drug; suspected overdoses should be treated symptomatically with supportive measures instituted as required.
- This drug is provided as a sterile frozen suspension in 1 mL single-use vials in 2 different dose strengths: 10(6) [1 million] PFU per mL (light green cap) for the initial dose only, and 10(8) [100 million] PFU per mL (royal blue cap) for all subsequent doses.
- Each drug vial may contain residual components of VERO cells including DNA, protein, and trace quantities of fetal bovine serum.
Following are some recommendations on how to prevent spreading this drug to other areas of your body and to your close contacts; talk to your healthcare provider about other ways to prevent accidental drug exposure.
- Avoid direct contact between your treatment sites/dressings/bodily fluids and your close contacts (for example, do not kiss a close contact if either person has an open mouth sore);
- Wear gloves while putting on or changing your dressings;
- Keep treatment sites covered with airtight and watertight dressings for at least 1 week after each treatment (or longer if the treatment site is weeping or oozing);
- Replace dressings right away if they come loose or fall off;
- Place all used dressings and cleaning materials in a sealed plastic bag before throwing them away in the garbage;
- Avoid touching or scratching your treatment sites.
Healthcare providers who are immunocompromised or pregnant should not prepare or administer IMLYGIC and should not come into direct contact with the IMLYGIC injection sites, dressings, or body fluids of treated patients [see Warnings and Precautions. Avoid accidental exposure to IMLYGIC and follow the below instructions for the preparation, administration, and handling of IMLYGIC: Wear personal protective equipment (protective gown or laboratory coat, safety glasses or face shield, and gloves) while preparing or administering IMLYGIC. Avoid accidental exposure to IMLYGIC, especially contact with skin, eyes, and mucous membranes. Cover any exposed wounds before handling. In the event of accidental occupational exposure (e.g., through a splash to the eyes or mucous membranes), flush with clean water for at least 15 minutes. In the event of exposure to broken skin or needle sticks, clean the affected area thoroughly with soap and water, and/or a disinfectant. Clean all surfaces that may have come in contact with IMLYGIC and treat all IMLYGIC spills with a virucidal agent such as 1% sodium hypochlorite or 70% isopropyl alcohol and blot using absorbent materials.Dispose of all materials that may have come in contact with IMLYGIC (e.g., vial, syringe, needle, co tton gauze, gloves, masks, or dressings) as biohazardous waste. Advise patients to place used dressings and cleaning materials into a sealed plastic bag and dispose of in household waste.
The Most Common
- unusual tiredness
- abdominal pain
- weight loss
- dry, cracked, itching, burning skin
- muscle or joint pain
- pain in arms or legs
- slowed healing of injection sites
- pain at the injection sites
- shortness of breath or other breathing problems
- pink, cola-colored, or foamy urine
- swelling of face, hands, feet, or stomach
- losing color in your skin, hair, or eyes
- warm, red, swollen, or painful skin around the injection area
- fever, sore throat, chills, or other signs of infection
- dead tissue or open sores on the injected tumors
- general feeling of discomfort or illness
- joint pain
- loss of appetite
- muscle aches and pains
- pain at the injection site
- runny nose
- sore throat
- trouble sleeping
- unusual tiredness or weakness
- Break in the skin, especially associated with blue-black discoloration, swelling, or drainage of fluid
- burning or stinging of the skin
- painful cold sores or blisters on the lips, nose, eyes, or genitals
- Abdominal or stomach pain
- difficulty having a bowel movement (stool)
- difficulty with moving
- muscle pain or stiffness
- pain in the arms or legs
- weight loss
Pregnancy and Lactation
FDA pregnancy category: Not Assigned
This drug is a live, attenuated Herpes Simplex Virus Type 1 (HSV-1). If a pregnant woman has an infection with primary or reactivated wild-type HSV-1, there is a potential for the virus to cross the placental barrier and also a risk of transmission during birth due to viral shedding. Women of childbearing potential should be apprised of the potential hazards to the fetus/neonate and advised to use an effective method of contraception to prevent pregnancy during treatment. Male patients should be instructed to use condoms when engaging in sexual activity to prevent the inadvertent transfer of this drug.
A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown. Excreted into animal milk: Data not available. The effects in the nursing infant and on milk production are unknown.
Talimogene laherparepvec injection comes as a suspension (liquid) to be injected by a doctor or nurse in a medical office. Your doctor will inject the medicine directly into tumors that are on your skin, just below your skin, or in your lymph nodes. You will receive a second treatment 3 weeks after the first treatment, and then every 2 weeks afterward. The length of treatment depends on how well your tumors respond to treatment. Your doctor may not inject all of the tumors at each visit.
Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with talimogene laherparepvec and each time you receive the injections. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.
Before receiving talimogene laherparepvec injection,
- tell your doctor and pharmacist if you are allergic to talimogene laherparepvec, any other medications, or any of the ingredients in the talimogene laherparepvec injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
- tell your doctor if you are taking any medications that weaken your immune systems such as anti-thymocyte globulin (Agam, Thymoglobulin), azathioprine (Azasan, Imuran), basiliximab (Simulect), belatacept (Nulojix), belimumab (Benlysta), cortisone, cyclosporine (Gengraf, Neoral, Sandimmune), dexamethasone, fludrocortisone, methotrexate (Otrexup, Rasuvo, Trexall), methylprednisolone (Depo-Medrol, Medrol, Solu-medrol), mycophenolate mofetil (Cellcept), prednisolone (Flopred, Orapred, Pediapred), prednisone (Rayos), sirolimus (Rapamune), and tacrolimus (Astagraf XL, Prograf, Envarsus XR). Many other medications may also weaken your immune system, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor will probably tell you not to receive talimogene laherparepvec if you are taking one or more of these medications.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: any antiviral medications such as acyclovir (Sitavig, Zovirax), cidofovir, docosanol (Abreva), famciclovir (Famvir), foscarnet (Foscavir), ganciclovir (Cytovene), penciclovir (Denavir), trifluridine (Viroptic), valacyclovir (Valtrex), and valganciclovir (Valcyte). These medications may affect how well talimogene laherparepvec works for you.
- tell your doctor if you have or have ever had leukemia (cancer of the white blood cells), lymphoma (cancer of a part of the immune system), human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), or any other condition that causes a weakened immune system. Your doctor will probably not want you not to receive a talimogene laherparepvec injection.
- tell your doctor if you have or have ever had radiation treatment in the area of melanoma tumors, multiple myeloma (cancer of the plasma cells in the bone marrow), any type of autoimmune disease (conditions in which the immune system attacks healthy parts of the body and causes pain, swelling, and damage), or if you have close contact with someone who is pregnant or has a weakened immune system.
- tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You should not become pregnant during your treatment with a talimogene laherparepvec injection. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while receiving a talimogene laherparepvec injection, call your doctor immediately. Talimogene laherparepvec injection may harm the fetus.
- you should know that talimogene laherparepvec injection contains a virus that could spread and infect other people. You should be careful to cover all the injection sites with airtight and watertight bandages for at least 1 week after each treatment, or longer if the injection site is oozing. If the bandages become loose or fall off, be sure to replace them right away. You should use rubber or latex gloves when bandaging the injection sites. You should be sure to put all cleaning materials, gloves, and bandages that were used for the injection sites into a sealed plastic bag and throw them away into the garbage.
- you should not touch or scratch the injection sites or bandages. This can spread the virus in the talimogene laherparepvec medication to other parts of your body. The people around you should be careful not to come into direct contact with your injection sites, bandages, or bodily fluids. Call your doctor immediately if you, or anyone around you, develops signs of herpes infection;: pain, burning, or tingling in a blister by your mouth, genitals, fingers, or ears; eye pain, redness, or tearing; blurry vision; sensitivity to light; weakness in arms or legs; extreme drowsiness; or mental confusion.