In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 27, 2015, talimogene laherparepvec (Imlygic) was approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. It is the first U.S. Food and Drug Administration–approved oncolytic virus therapy.
Supporting Efficacy Data
Approval was based on the finding of an improved durable response rate in an open-label phase III trial in which 436 patients with stage IIIB, IIIC, or IV melanoma considered to be unresectable were randomly assigned to receive talimogene laherparepvec (n = 295) or granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]).1,2
Talimogene laherparepvec was given via intralesional injection at an initial concentration of 106 plaque-forming units (PFU)/mL on day 1 followed by a concentration of 108 PFU/mL on day 21 and every 2 weeks thereafter at a dose of up to 4 mL per visit. The agent was injected into only cutaneous, subcutaneous, or nodal melanoma lesions. GM-CSF was given subcutaneously in 28-day cycles consisting of 125 μg/m2 daily for 14 days followed by 14 days with no treatment. Patients were to be treated for at least 6 months or until there were no injectable lesions.
Overall, patients had a mean age of 63 years, 57% were men, 98% were white, 70% had Eastern Cooperative Oncology Group performance status of 0, 70% had stage IV (27% M1a, 21% M1b, and 22% M1c), and 30% had stage III disease, 53% had received prior therapy for melanoma (other than surgery, adjuvant therapy, or radiation), and 58% were seropositive for wild-type herpes simplex virus 1 (HSV-1).
The durable response rate, defined as the proportion of patients with complete or partial response maintained continuously for ≥ 6 months, was 16.3% in the talimogene laherparepvec group vs 2.1% in the GM-CSF group (unadjusted relative risk = 7.6, P < .0001). Median time to response was 4.1 months (range = 1.2–16.7 months) in the talimogene laherparepvec group. Median overall survival was 22.9 vs 19.0 months (P = .116).
How It Works
Talimogene laherparepvec is a genetically modified live oncolytic herpes virus therapy designed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. It causes lysis of tumors, followed by release of tumor-derived antigens; this, together with virally derived GM-CSF, may promote an antitumor immune response. The exact mechanism of action is unknown.
How It Is Used
Talimogene laherparepvec is injected into cutaneous, subcutaneous, or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. The total injection volume for each treatment visit should not exceed 4 mL for all injected lesions combined.
The recommended starting dose is up to a maximum of 4 mL at a concentration of 106 PFU/mL. The second dose should be given 3 weeks after the first, and all subsequent treatments, including reinitiation, should be given at 2 weeks after the prior dose. For the second dose and all subsequent treatments, the recommended dose is up to 4 mL at 108 PFU/ mL. Recommended injection volume by lesion size is up to 4 mL for > 5 cm, up to 2 mL for > 2.5 cm to 5 cm, up to 1 mL for > 1.5 cm to 2.5 cm, up to 0.5 mL for > 0.5 cm to 1.5 cm, and up to 0.1 mL for ≤ 0.5 cm.
Treatment should continue for ≥ 6 months unless other treatment is required or until there are no injectable lesions to treat. Treatment should be reinitiated if new unresectable cutaneous, subcutaneous, or nodal lesions appear after a complete response.
In the phase III trial, the most common adverse events of any grade in talimogene laherparepvec recipients occurring at an incidence ≥ 5% higher vs GM-CSF recipients were fatigue (50% vs 36%), chills (49% vs 9%), pyrexia (43% vs 9%), nausea (36% vs 20%), and influenza-like illness (30% vs 15%). Grade ≥ 3 adverse events were of low incidence; the most common was cellulitis. Pyrexia, chills, and influenza-like illness were more frequent during the first 3 months of treatment but also occurred thereafter. Other adverse events in talimogene laherparepvec patients included glomerulonephritis, vitiligo, and oral herpes.
Talimogene laherparepvec carries warnings and precautions for accidental exposure to the agent, herpetic infections, injection-site complications, immune-mediated events, and plasmacytoma at the injection site.
Accidental exposure may lead to transmission of the agent and herpetic infection. Health-care providers and close patient contacts should avoid direct contact with injected lesions, dressings, or body fluids of treated patients. Health-care providers who are immunocompromised or pregnant should not prepare or administer the agent. If accidental exposure occurs, exposed individuals should clean the affected area.
Patients who develop herpetic infections should be advised to follow standard hygienic practices to prevent viral transmission. The risks and benefits of continuing treatment should be considered if persistent infection or delayed healing develops at the injection site.
Risks and benefits of treatment should be considered before starting treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events. Risks and benefits of treatment should be considered in patients with multiple myeloma or in whom plasmacytoma develops during treatment.
The agent is contraindicated in immunocompromised patients and in pregnant patients. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with talimogene laherparepvec. Breast-feeding women should discontinue treatment or nursing. ■
1. Imlygic (talimogene laherparepvec) suspension for intralesional injection prescribing information, Amgen, Inc, October 2015. Available at http://www.imlygic.com/. Accessed November 6, 2015.
2. Andtbacka RH, Kaufman HL, Collichio F, et al: Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33:2780-2788, 2015.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).