Talimogene Laherparepvec
Talimogene laherparepvec was approved by the US Food and Drug Administration in 2015.63 It shows a trend toward improved survival rates and a robust bystander effect.39 Talimogene laherparepvec is an oncolytic, immune-enhanced herpes simplex virus type 1, and its various genetic modifications include deletions of ICP34.5, ICP47, and insertion of GMCSF. Oncolytic viruses like talimogene laherparepvec are designed to selectively multiply in tumor cells.64 At least 9 virus groups are being investigated in clinical trials.65 Oncolytic viruses have direct effects on the metabolic processes of cancer cells. They selectively replicate in tumors, thereby destroying and infecting cancer cells due to their direct effects on the metabolic processes in the cell as well as their ability to induce immune responses that target the cancer cell. This action is thought to be aided by the activation of nuclear factor κB and the release of chemokines and cytokines from the cancer cell.65 Oncolytic viruses demonstrate limited systemic applicability due to the immune responses of the host, but they are suitable for intralesional injection. Specifically with talimogene laherparepvec, ICP47 deletion helps to prevent blocking antigen presentation and enhances virus growth and replication in tumor cells.38,66 Replacing the coding sequence for neurovirulence factor ICP34.5 with the human cytokine GMCSF enables talimogene laherparepvec to initiate a systemic antitumor response by enhancing immune response to tumor antigens.66 The most common adverse events seen with this agent are fatigue, chills, and pyrexia.49
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Senzer et al38 investigated the effectiveness of talimogene laherparepvec in study patients with stages 3 (n = 10) and 4 (n = 40) melanoma in a single-arm, phase 2 trial. Study patients received intralesional injections of either talimogene laherparepvec or GMCSF.38 The initial injection had a volume of up to 4 mL of 106 pfu/mL followed 3 weeks later by 4 mL of 108 pfu/mL, every 2 weeks, for up to 24 treatments.38 The protocol allowed injection with or without ultrasonographic guidance and included cutaneous, subcutaneous, and nodal lesions. An ORR based on Response Evaluation Criteria In Solid Tumors was 26% (CR rate, 8%; PR rate, 5%).38 After 1 and 2 years, the overall survival rates were 58% and 52%, respectively.38
Based on these data, a phase 3 study was conducted.14,39 This study randomized 436 patients 2:1 to intralesional talimogene laherparepvec (n = 295) or subcutaneous GMCSF (n = 141) and used the same talimogene laherparepvec regimen as the phase 2 trial.39 The ORRs were 26.4% for those assigned to talimogene laherparepvec and 5.7% for those assigned to GMCSF.39 The results showed a significant difference in durable response rates (ie, PR or CR rate for > 6 months), with 16.3% in the talimogene laherparepvec group and 2.1% in the GMCSF group (P < .001); durable response rates were higher in study patients with stage 3B/C melanoma (33% for the talimogene laherparepvec group vs 0% for those in the GMCSF group).39 Six previously unresectable study patients were converted to resectable. Fewer than 3% of study patients experienced grade 3/4 adverse events.39 For the entire patient population, the overall survival rates trended toward statistical significance (23.3 months for the talimogene laherparepvec group vs 18.9 months for the GMCSF group; P = .051).39
A subgroup analysis showed survival benefit in patients with stage 3B/C and 4 M1a disease, and the effect was stronger when talimogene laherparepvec was given as first-line therapy as opposed to second-line therapy or higher.
A lesion-level analysis of the phase 3 trial of 3,219 lesions in 286 patients showed a 50% reduction in 64% of the injected lesions, 32% of the uninjected nonvisceral lesions, and 16% of the uninjected visceral lesions.14 These findings indicate a bystander effect and, thus, a systemic immune response from the local injection of talimogene laherparepvec.14
A phase 1b study of talimogene laherparepvec added to ipilimumab in 19 participants suggested a higher CR rate for the combination than for either agent alone.40 Grade 3/4 adverse events occurred in 32%.40 Two study patients had possible immune-related grade 3/4 adverse events, and, of the 17 study patients with investigator-assessed response, the ORR was 41% (CR rate, 24%; PR rate, 18%) and stable disease was seen in 35%.40 Median time to response was 2.9 months (NCT01740297).
Topical Therapies
Topical therapies have shown some success in superficial lesions and are generally associated with low rates of morbidity.41,67-70 Typically, they are more suited for thinner lesions. Topical diphencyprone cream is a synthetic contact sensitizer that has been used to treat alopecia and warts.71,72 The largest trial to date was conducted by Damian et al,67 who studied 58 patients, 50 of whom were treated for more than 1 month. A total of 46% achieved CR and 46% achieved PR; however, the results of this study should be interpreted with caution, as the majority of results came from the same research group.67-70
Imiquimod is a toll-like receptor agonist approved by the US Food and Drug Administration for the treatment of genital warts, keratosis, and superficial basal cell carcinomas.73 A treatment regimen for melanoma has not been established, as the application of imiquimod ranges from once weekly to twice daily and from 2 to 88 weeks.74 Since 2000, it has been used for advanced melanoma in various case reports and small case series.6,75-77 The largest case series is of 5 patients treated with combination topical imiquimod/fluorouracil; a response was elicited in 44 of 45 lesions.77 Combined treatments with IL-2 and BCG have also been reported.41,57 More evidence is available for patients with lentigo maligna, including a large case reporting that more than 90% of study patients with lentigo maligna experience regression with daily or twice-daily application of an imiquimod cream.74,78
