Developments in Intralesional Therapy for Metastatic Melanoma

Patients with limited locoregional disease often have few symptoms. Consequently, physicians are less likely to recommend systemic or regional perfusion-based therapy that could expose asymptomatic patients to considerable toxicity. These patients may benefit from intralesional therapy, where the active agent is immediately injected into the tumor, exerting mainly local effects, with fewer adverse events than systemic or regional therapy.³ Intralesional therapies have been extensively studied, but effective agents have not been available until recently.⁶ However, similar to the rapid development of multiple new systemic treatments for stage 3/4 metastatic melanoma (nivolumab, ipilimumab, trametinib, dabrafenib, vemurafenib, pembrolizumab, cobimetinib, pegylated interferon), intralesional injections and topical therapies have seen major advances.8,9 Due to their rate of efficacy and relatively low toxicity profile, these treatment modalities may be promising in select patients with locoregional disease.³

Intralesional therapy was first reported in 1893 by Coley,¹⁰ which was prior to the report published by Handley¹¹ on wide local excision as the mainstay of melanoma treatment. Local therapy increases rates of efficacy and lowers rates of toxicity when compared with systemic administration by delivering an increased concentration of the drug locally.^3,12 A so-called “bystander effect” has been reported in select agents, including velimogene aliplasmid, 10% rose bengal, and talimogene laherparepvec, where noninjected (both visceral and nonvisceral) distant lesions respond to the locally injected drug.^9,13 Although the exact mechanism of action is under investigation, tumor antigens in the injected lesions may serve as an autologous vaccine, stimulating systemic immunity.^12,14 The occurrence of the bystander effect makes intralesional therapies appealing because local injections have been associated with a systemic reduction in tumor burden.¹⁵

Generally, lesions are treated using a 25- to 30-gauge needle using a “fanning” technique, where the needle is moved in multiple directions within the same lesion. Preferably, the same needle entry and needle stick are used to keep the number of needle tracks and cavities in the tumor limited to prevent in

tralesional injectate from leaking out and to maximize the delivered dose. Visible or palpable lesions can be injected in the ambulatory clinic, whereas deeper lesions can be injected using ultrasonographic guidance. Tumor response may be measured using caliper measurements, ultrasonography, or cross-sectional imaging (magnetic resonance imaging/computed tomography), depending on tumor size and location.9 Evidence suggests that subcutaneous lesions are less responsive than cutaneous lesions, and tumors with smaller bulk are more likely to regress under treatment.^16-18 Investigators have attempted to limit intralesional volumes to 1 mL or less to minimize the local adverse events that result from injecting higher volumes.¹⁶

This review will summarize the mechanisms of action, adverse-event profiles, and clinical data for all agents currently in use and of historic importance (Tables 1 and 2).^{9,12,13,16,18-41}