The US Food and Drug Administration has been rapidly approving new checkpoint inhibitors and targeted therapies for melanoma and other tumors. Recently, it approved the first intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of metastatic melanoma lesions in the skin and lymph nodes. Several other intralesional therapies (PV-10, interleukin-12 electroporation, coxsackievirus A21 [CVA21]) are entering later-stage testing. Locally injected agents have clearly shown their ability to produce local responses that can be durable. The possibility that they also stimulate a regional and even systemic immune response is exciting, as this potential effect may have utility in combination regimens; such regimens are an area of active research. Favorable responses with minimal toxicities in monotherapy trials have led to the first melanoma studies of T-VEC in combination with the cytotoxic T-lymphocyte–associated antigen 4 inhibitor ipilimumab and, separately, with the programmed death 1–blocking antibody pembrolizumab. Studies of PV-10 with pembrolizumab and of CVA21 with pembrolizumab are also being initiated. Preliminary analyses of the results of the first combination trials, which show higher response rates than with either agent alone, offer some optimism that these locoregional therapies will find application—as treatment for patients who cannot tolerate systemic immunotherapies, to alleviate locoregional morbidity, and perhaps even to “prime” the immune system.
Melanoma accounts for about 4.5% of new cancers (21.6% per 100,000) and 1.7% of all cancer deaths in the United States. The incidence of melanoma has been gradually increasing for several decades, with the annual rise averaging 1.4% per year over the last 10 years. It is estimated that the number of deaths from melanoma approached 10,000 in 2015.
After frustrating decades of little progress, the landscape of melanoma therapy was dramatically altered with the first report in 2010 of significantly improved overall survival with the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab, compared with a vaccine, and subsequently, compared with the then “standard” chemotherapeutic agent dacarbazine (DTIC). Following the US Food and Drug Administration (FDA) approval of ipilimumab the following year, approvals of other targeted therapies (against BRAF and MEK), and most recently, approvals and extended indications for other checkpoint inhibitors, especially the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, have constituted a revolution characterized by higher response rates and the potential for extended survival. Clearly, we are now in an era where new treatments are showing positive results and are becoming available at an unprecedented rate.
Why an Interest in Locoregional Therapies?
Direct treatment of cutaneous melanoma lesions is on a separate track from that of systemic therapies, with its rapid advances. However, interest in strategies focused on the direct treatment of cutaneous melanoma lesions has its own pedigree. Melanoma is unique in its propensity to produce cutaneous, subcutaneous, and nodal metastases. This unique pattern of metastatic spread affords us an opportunity to access the tumor and manipulate it for potential therapeutic benefit. Furthermore, while it is true that metastatic melanoma is a systemic disease—and also that mortality is not caused by dermal or subcutaneous lesions but rather by metastases to the liver, brain, lung, and other sites—locoregional disease is often disfiguring and painful, and locoregional therapy may provide clinical benefit.
A particular challenge is posed by the in-transit metastases that develop in 6% to 10% of patients with primary melanomas > 1.0 mm in Breslow thickness. In some patients, in-transit metastatic disease may remain indolent and regionally confined for years or decades. In these patients, clinical results with systemic therapy have been less than optimal, and locoregional therapeutic options, such as limb perfusion and intralesional treatments, have thus been explored.
Intralesional therapy for melanoma has a long history. The unique relationship of melanoma to the immune system has stimulated research in this area for many years. Murine experiments showed heightened host immune responses against transplanted experimental tumors after inoculation with bacillus Calmette-Guérin (BCG).[3,4] Dummer et al demonstrated BCG-induced increases in melan-A–specific cytotoxic T cells. Morton et al, in 1974, reported 7 years’ experience with 151 malignant melanoma patients who received BCG immunotherapy alone or as an adjunct to surgery. In lesions limited to skin, regression was 90% in injected lesions and 17% in uninjected lesions, with one-fourth of patients remaining disease-free for 1 to 6 years.
Enthusiasm for intralesional BCG therapy waned following reports of anaphylactic reactions; disseminated BCG mortality; and, in our own research, the occurrence of punctate abscesses in more than two-thirds of treated patients, as well as failure to impact outcomes. Other agents of mostly historical interest include intralesional interleukin (IL), interferon (IFN), and granulocyte-macrophage colony-stimulating factor (GM-CSF), which have not shown consistent or durable efficacy and have not been rigorously tested in randomized trials. Here we review agents that have been evaluated or are currently undergoing evaluation in the modern era of melanoma therapeutics.
Velimogene aliplasmid (Allovectin-7), a plasmid/lipid complex with human leukocyte antigen (HLA)-B7 and β2 microglobulin DNA encoding sequences, was granted orphan drug designation by the FDA back in 1999. HLA-B7 and β2 microglobulin are components of major histocompatibility complex class I (MHC-I), expression of which is often altered during cancer progression, allowing tumor cells to evade the immune system. A role in augmenting the immune system’s ability to recognize and target melanoma cells was hypothesized because velimogene aliplasmid increases HLA-B7 cytotoxic T-cell frequency fivefold, upregulates/restores MHC-I molecules, and induces a proinflammatory response.
The agent showed promise in a phase II trial, which was conducted in 133 patients with stage IIIB/C and IV M1a/b injectable cutaneous, subcutaneous, or nodal melanoma lesions. Complete responses (CRs) and partial responses (PRs) were reported in 3.2% and 8.7% of patients, respectively, with stable disease (SD) in 25% of the two patient cohorts combined. Time to death was significantly longer in responders than in nonresponders (P = .036). Of the patients with stage IV M1a/b disease, 21% (9/42) had responses in noninjected target lesions. However, the subsequent phase III Allovectin Immunotherapy for Metastatic Melanoma (AIMM) trial failed to show benefit. Among 390 patients with stage IIIB/IV M1a/b melanoma randomized 2:1 to velimogene aliplasmid or to intravenous DTIC or oral temozolomide (TMZ), the primary endpoint of response rate at ≥ 24 weeks was lower in the velimogene aliplasmid group at 4.6%, compared with 12.3% for DTIC/TMZ (P = .010). While the duration of response in the velimogene aliplasmid responders was marginally longer than with DTIC/TMZ (P = .066), overall survival was shorter (median, 18.8 months [95% CI, 16.6–21.3 months] vs 24.1 months [95% CI, 17.1–27.9 months]; P = .491). The velimogene aliplasmid program was discontinued.
Electroporation With Plasmid IL-12
With intratumoral electroporation, tumor cell pores are opened when a mild electrical current is introduced directly through an electrode. The intention is to thereby facilitate greater influx of a cytotoxic agent over a longer period of time than would occur with systemic administration of the same agent. Achieving high levels of IL-12 protein expression stimulates a local proinflammatory process, which leads to a targeted immune response; enhances the immune capacity of natural killer (NK) and T cells; and upregulates IFNγ, as well as antigen presentation and processing. With reduced systemic drug concentrations, side effects are minimized. This feature is of particular value with respect to IL-12, a cytokine that is toxic when given systemically.
Interim phase II results of first treatment with electroporation of IL-12 in 28 patients with advanced melanoma, after 24 weeks of treatment, reported at the American Society of Clinical Oncology 2014 Annual Meeting, revealed a 32.2% objective response rate (ORR; the primary endpoint), with a CR in 10.7%. Among lesion responses (n = 85), the CR rate was 45%, and the PR rate was 8%, with SD in 31%. Responses were observed in untreated lesions in 59.1% of evaluable patients (13/22).
The electroporation treatment produced no toxicity and no serious adverse events, aside from injection site pain (69.0%) and inflammation (20.7%). Grade 3 pain was reported in 1 patient.
An exploratory analysis showed that intratumoral NK cells doubled from pretreatment through day 11, and doubled again by day 39, with an increase in the frequency of activated circulating NK cells. In the phase II trial, a maximum of four treatment cycles at 12-week intervals were allowed. A planned expansion protocol in melanoma patients will evaluate increased treatment frequency.
In October 2015—around the same time that the FDA was granting several approvals and indication extensions to checkpoint inhibitors—the agency approved the oncolytic virus (herpes simplex virus 1)–derived therapy talimogene laherparepvec (T-VEC) for the treatment of melanoma lesions in the skin and lymph nodes. T-VEC encodes GM-CSF, and is thought to replicate in tumor cells, lysing cells in injected tumors. Antigen-presenting cells then take up the lysed cells. Local expression of GM-CSF may also evoke an enhanced adaptive antimelanoma response (Figure).
T-VEC was compared with GM-CSF in the phase III OPTiM study in 436 stage IIIB/C and IV melanoma patients who had injectable and unresectable disease. Durable response (complete or partial), the primary endpoint, was defined as a response lasting continuously for at least 6 months and begun within 12 months of initiation of therapy. Patients were randomized 2:1 (295:141) to intralesional T-VEC (initially, ≤ 4 mL × 106 pfu/mL; then after 3 weeks, ≤ 4 mL × 108 pfu/mL every 2 weeks) or subcutaneous GM-CSF (125 µg/m2 daily × 14 days every 28 days).
The durable response rate (DRR) in the intention-to-treat analysis was 2.1% in the GM-CSF arm and 16.3% in the T-VEC arm, a treatment difference of 14.1% (95% CI, 8.2%–19.2%; P < .0001). The ORR in the 141 patients who received GM-CSF was 5.7% (95% CI, 1.9%–9.5%). It was 26.4% in the 295 patients who received T-VEC (95% CI, 21.4%–31.5%; P < .0001), for a treatment difference of 20.8% (95% CI, 14.4%–27.1%; P < .0001). In the T-VEC responders, the CR rate was 41% (10.8% among all patients who received T-VEC; 0.7% for all patients who received GM-CSF). PR rates were 15.6% and 5.0%, respectively, for the entire T-VEC and GM-CSF arms.
In the stage IIIB/C melanoma patients with no disease spread to distant organs, the DRR was 33% for T-VEC compared with 0% for GM-CSF. Differences in DRRs between groups were smaller for stage IV patients (11% for T-VEC, 7% for GM-CSF).
With regard to median overall survival (OS), a secondary endpoint, T-VEC had a 4.4-month advantage over GM-CSF (23.3 months vs 18.9 months [hazard ratio (HR), 0.79 (95% CI, 0.62–1.00); P = .051]); this approached but did not achieve statistical significance.
The OPTiM investigators, in an analysis of lesion-level responses, reported that among 2,116 lesions in patients treated with T-VEC, tumor area decreases of ≥ 50% occurred in 64% of injected lesions, in 34% of uninjected nonvisceral lesions, and in 15% of uninjected visceral lesions.
The most common adverse event was fatigue (occurring in 50.3% of patients in the T-VEC arm, and in 36.2% of those in the GM-CSF arm), with chills (48.6% in the T-VEC arm; 8.7% in the GM-CSF arm) and pyrexia (42.8% in the T-VEC arm; 8.7% in the GM-CSF arm) the next most common. The only grade 3/4 event that occurred in ≥ 2% of patients was cellulitis (seen in 2.1% of the patients who received T-VEC).
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