Systemic Therapy for Melanoma
Nour Kibbi and Harriet Kluger
Systemic therapies, administered either intravenously, subcutaneously, or orally, are given to patients with melanoma that has been resected (adjuvant therapy) or has metastasized to distant organs and is unresectable and measurable by physical examination and/or imaging. Systemic therapies can either be generally targeted rapidly by dividing cells such as cancer cells (standard chemotherapy), inhibit driver mutations in tumor cells (targeted therapies), affect the tumor microenvironment (e.g., antiangiogenic therapies), or activate the immune system. In this chapter, we review systemic therapies administered in the adjuvant setting and in the setting of unresectable disease.
Until the past decade, systemic therapy options for melanoma were dismal, and no drug had shown an overall survival advantage in a randomized setting, other than high-dose interferon (IFN) administered to high-risk stage II or III patients (discussed in the next section); however, results of studies of adjuvant IFN were not consistently positive. Since 2011, however, a number of immune and targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) based on improvement in overall survival in randomized trials, providing hope to patients with high-risk resected or unresectable metastatic melanoma. Numerous newer therapies are currently being studied, geared at enhancing antitumor immunity, targeting additional driver mutations in tumor cells or both. Future directions are summarized in the Summary section.
ADJUVANT THERAPY FOR RESECTED, HIGH-RISK MELANOMA
The risk of metastatic disease among patients with resected primary melanoma ranges from 5% to 80%, depending on the stage of disease at presentation. Development of metastatic disease after resection of the primary tumor—and when appropriate, draining lymph nodes—is likely due to hematogenous or lymphatic tumor cell spread already present at the time of initial diagnosis, even if undetectable by physical examination or imaging studies. Adjuvant therapy is therefore administered with the hope of treating this microscopic disease. Studies of newer drugs in the adjuvant setting typically trail behind those conducted in the metastatic setting for two reasons: (a) drug activity can be determined more rapidly if tumor shrinkage by examination or imaging is the endpoint and is measurable within weeks, whereas, studies in the adjuvant setting take years to mature, and (b) not all patients with resected high-risk disease develop distant metastases, and drug toxicity is more acceptable in patients with unresectable disease than in patients who might be cured with surgery alone. With the plethora of newer therapies with demonstrated efficacy in unresectable disease, there will likely be an increase in the repertoire of available options for adjuvant therapy as well over the coming years, as described in the following sections.
The first cytokine to gain approval by the FDA for high-risk melanoma was high–dose IFN-α2B (Table 15.1). A number of studies have been conducted, most showing a benefit in relapse-free survival, but data on overall survival are conflicting; some studies showed an improvement in overall survival in patients treated with this therapy, while others did not. The dose and schedules used for the majority of the studies was 20 MU/m2 5 days per week for 4 weeks, then 10 MU/m2 three times per week for 48 weeks for maintenance/consolidation (1–3). Of note, this regimen is associated with a fair amount of toxicity and therefore remains controversial in terms of the risk–benefit ratio. A number of trials have assessed low or intermediate doses of IFN, and survival benefit was not demonstrated with lower doses, as reviewed (4). More recent trials have compared pegylated IFN to observation and similarly showed improved relapse-free survival, but no improvement in overall survival; this regimen similarly remains controversial (5). Another study showed that induction of autoantibodies or autoimmunity during treatment with IFN-α is associated with statistically significant improvements in relapse-free survival and overall survival in patients with high risk, resected melanoma (6). In a recent clinical study, high-dose IFN-α was also shown to be effective as neo-adjuvant therapy in patients with stage IIIB–C melanoma (7).
In conclusion, single-agent high-dose adjuvant IFN-α is a toxic regimen that might have a role in patients at high risk for developing overt metastasis, although different studies have yielded inconsistent results.
Adjuvant immune checkpoint inhibitors
Ipilimumab is a monoclonal antibody that inhibits cytotoxic lymphocyte antigen-4 (CTLA-4), one of the immune coinhibitory molecules located on the surface of T cells. CTLA-4 competitively blocks the costimulatory signals, which activate the antitumor T cell response (8). Inhibition of CTLA-4 results in increased activity and proliferation of cytotoxic T cells. Ipilimumab has been used extensively in patients with metastatic melanoma, and was approved for this indication by the FDA in 2011 based on superior survival in patients treated with ipilimumab compared with a peptide vaccine or dacarbazine (dimethyl triazeno imidazole carboxamide; DTIC) in randomized trials (see details in section “Immune Checkpoint Inhibitors”) (9,10). Two large randomized trials have been conducted with ipilimumab in the adjuvant setting in patients with high-risk stage III or resected stage IV disease. The first trial compared ipilimumab at a dose of 10 mg/kg every 3 weeks with a maintenance dose every 12 weeks for up to 3 years to placebo (11). Relapse-free survival was superior in the treatment arm, but long-term survival data are not available yet. Based on this result, the U.S. FDA approved this regimen in the adjuvant setting in 2015. Of note, the approved dose for patients with metastatic disease is 3 mg/kg, which has been shown to be better tolerated than the higher dose in the metastatic setting. Given that toxicities of 10 mg/kg ipilimumab can be considerable and life threatening, extreme caution must be taken when using this drug and close attention to potential symptoms of autoimmunity must be paid. Moreover, in mild-to-moderate risk patients, including some patients with lower-risk stage III disease, the risk/benefit ratio of adjuvant ipilimumab, particularly at the higher dose, is questionable.
A more recent clinical trial led by the Eastern Cooperative Oncology Group randomized patients with resected stage IIIB, IIIC, or M1a disease to receive ipilimumab 10 mg/kg, ipilimumab 3 mg/kg, or high dose of IFN. Relapse-free and overall survival data are not yet available, but a number of bowel perforations from uncontrolled colitis and deaths on the 10 mg/kg ipilimumab arm were reported, once again raising the question of whether the risk/benefit ratio favors use of adjuvant ipilimumab at 10 mg/kg (12).
Pembrolizumab and nivolumab are inhibitors of programmed-death 1 (PD-1) that similarly activate T cells. Both drugs have demonstrated benefit in the metastatic setting, as detailed in the section “Immune Checkpoint Inhibitors.” Moreover, the combination of ipilimumab and nivolumab is superior to either drug alone, as detailed in the following. Studies are ongoing in the adjuvant setting to determine whether inhibitors of PD-1 (NCT02362594 and NCT02388906, respectively) are superior to ipilimumab or high-dose IFN.
Other forms of adjuvant immune therapy
A number of vaccines have been studied in the adjuvant setting including BCG, dendritic cell vaccines, peptide vaccines, and autologous or allogeneic vaccines generated from patient tumors, DNA vaccines, and ganglioside vaccines. These approaches have not shown benefit in the randomized setting, as reviewed (4).
Targeted Therapies and Chemotherapy
A number of driver mutations have been identified in melanoma cells. These include mutations in BRAF and NRAS (also known as the neuroblastoma RAS viral oncogene), primarily in cutaneous melanomas, c-Kit in acral lentiginous or mucosal melanomas, and GNAQ/GNA11 in uveal melanomas (13). These driver mutations sometimes provide opportunities for pharmacologic inhibition, as detailed in the section “Molecular Targeted Therapy.” Drugs that target mutant BRAF have been approved for metastatic melanoma, while drugs that target c-Kit have been approved for other malignancies harboring c-Kit mutations and have been studied in c-Kit mutated metastatic melanoma. Given the activity of BRAF inhibitors in macroscopic, unresectable melanoma, these drugs are also being studied in the adjuvant setting. BRAF inhibitors are often combined with an inhibitor of MEK (MAPK/ERK kinase), a signaling mediator downstream of RAF. This prevents tumoral escape by providing an additional, downstream blockade of the mitogen-activated protein kinase (MAPK) pathway (detailed in the section “Molecular Targeted Therapy”). Survival in patients with metastatic disease on the combination treatment is superior, as detailed in the section “Molecular Targeted Therapy.” These drugs are therefore being studied in the adjuvant setting as well, either alone or in combination. Examples include the use of dabrafenib in COMbination with ADjuvant trametinib (COMBI-AD) (NCT01682083) trial of dabrafenib and trametinib compared with placebo and the BRAF Inhibitor in Melanoma (BRIM-8) (NCT01667419) study that compares the BRAF inhibitor vemurafenib with placebo in patients with high-risk resected stage III melanoma. Typically, the drugs are administered for 12 months in these trials, and patients are followed for relapse-free survival; results are pending. A study is being conducted in China for patients with resected c-Kit mutated melanoma comparing imatinib to IFN (NCT01782508), and results are similarly pending.
Chemotherapy has limited activity in unresected melanoma, and has also been studied in the high-risk adjuvant setting. Three randomized trials studied the role of chemotherapy in this setting; all were negative, as reviewed (4). Chemotherapy has also been studied in conjunction with immune therapy—so-called biochemotherapy. The rationale behind this approach is that chemotherapy might enhance antigen presentation to T cells, and the combination with immune stimulating drugs might result in synergism. While responses to biochemotherapy are quite frequent in the metastatic setting, these regimens are fairly toxic, and caution certainly needs to be taken in the adjuvant setting in which cures can be obtained in some patients by surgery alone. A randomized trial comparing high-dose IFN for 1 year to biochemotherapy was led by the Southwestern Oncology Group (S008). Toxicity in the biochemotherapy arm was not negligible, and although the relapse-free survival might be slightly superior, there was no overall survival benefit; this regimen is not currently being used (14).
SYSTEMIC THERAPY FOR METASTATIC MELANOMA
First introduced in the 1980s as the first antitumor immune therapy, interleukin-2 (IL-2) was a ground-breaking alternative to traditional chemotherapy regimens against melanoma (15). IL-2 is a cytokine predominantly secreted by antigen-stimulated CD4+ T cells, but also CD8+ cells and activated dendritic cells. IL-2 stimulates CD8+ T cell proliferation and memory differentiation. The initial studies in the 1980s using IL-2 demonstrated no clinical response (16). Rosenberg et al. then showed that the IL-2 could mediate tumor regression if it was administered at higher doses; in the early phase of the study, most patients were treated with IL-2 doses of 60,000 IU/kg every 8 hours, but patients subsequently received 3- or 10-fold higher doses (15). In the 1990s, phase II and III clinical trials using high-dose IL-2 suggested that 7% of patients could achieve complete responses (17). Subsequent studies suggested that up to 6% of patients could achieve complete response and 10% partial responses (18,19). Most importantly, many of these responses were durable, lasting years. Of note, the first trial using high-dose IL-2 in a randomized trial alone or with a peptide vaccine showed improved response rates of 22.1% in the combination therapy arm, compared with 9.7% in the group treated with IL-2 alone. However, the trial was underpowered to demonstrate improvement in overall survival, and took years to accrue due to narrow eligibility criteria.
The broad applicability of IL-2 is limited by its multiorgan toxicity and the need for high doses to achieve a clinical response. The predominant mechanism of toxicity is vascular leak, resulting in interstitial pulmonary infiltrates, acute kidney injury, and volume overload. As the potency and toxicity of the drug were better appreciated, alternative regimens were designed to minimize those effects, such as delivery of fewer doses (20). By contrast, lower doses and combinations with growth factors were unsuccessful (21,22). Ongoing work is underway to better understand what factors influence the response to IL2, and how they can be manipulated to enhance response rates (23).
Immune checkpoint inhibitors
Before 2011, the median survival of unresectable, advanced stage III or IV melanoma was about 8 to 10 months (24). In the following section, we present the exciting clinical trials that have revolutionized the treatment of metastatic melanoma.
The first immune checkpoint inhibitor to be developed was ipilimumab, a CTLA-4 inhibitor, as described previously in the section “Adjuvant Immune Checkpoint Inhibitors.” In the phase III study that gained FDA approval of ipilimumab for melanoma, the drug was administered at 3 mg/kg every 3 weeks for four doses to patients with advanced melanoma with or without the peptide vaccine, glyco-protein 100 (gp100) (9). Patients on the control arm received peptide vaccine alone. The median survival of patients treated with ipilimumab with or without gp100 was about 10 months compared with only 6.4 months in patients receiving peptide alone. More recent long-term follow-up suggests survival rates remain nearly flat after 3 years, with about 20% of the ipilimumab-treated patients alive (25). In another phase III trial, ipilimumab at the higher dose of 10 mg/kg was administered with DTIC and compared with DTIC plus placebo (10). The median survival of the combination therapy was 11.2 months compared with 9.1 months, although the toxicity of the combination was not insignificant.
The toxicity of ipilimumab is high with over 60% of patients experiencing immune-related adverse events (irAEs), of which 15% were grade 3 or higher, most commonly diarrhea and colitis (26). These resolved by 6 to 8 weeks with immune suppression, but residual symptoms (such as vitiligo or pain) were not uncommon. Attempts to predict best responders prior to initiation of treatment have been unsuccessful, and there is increasing interest in developing reliable biomarkers of response.
The second immune checkpoint to be recognized is the PD-1. PD-1 is a type I transmembrane protein expressed on the surface of multiple immune cells including T cells, B cells, and dendritic cells. PD-1 binds to one of two ligands, PD-L1 (also known as B7-H1) and PD-L2 (B7-DC), both expressed on melanoma cells (among other tumors) as well as antigen-presenting cells in the tumor microenvironment (27). This interaction inhibits cytotoxic T cell responses (including perforin-mediated cell death) against tumor cells. Therefore, PD-1, PD-L1, and PD-L2 inhibitors are thought to facilitate these cytotoxic antitumor responses. The two programmed death immune checkpoint inhibitors currently approved for melanoma are nivolumab and pembrolizumab, both antibodies against PD-1.
Overall survival rates for patients with metastatic melanoma treated in early phase trials with nivolumab were 62% at 1 year, 43% at 2 years, and 41% at 3 years (28,29). In a phase III trial comparing nivolumab to DTIC in BRAF wildtype melanomas, survival at 1 year was significantly better in the nivolumab group (73% vs. 42%) and overall response rate was 40% versus 14%, leading to approval of nivolumab in 2014 (30).
Approval for pembrolizumab came after a phase I trial compared different doses of pembrolizumab (2 and 10 mg/kg) in patients whose disease had not responded to ipilimumab (31). At the lower dose of 2 mg/kg, overall response rate was estimated at 26% and progression-free survival (PFS) at 24 weeks was 45%. One-year survival was estimated at 58%. In a phase II trial comparing pembrolizumab to investigator’s choice chemotherapy, pembrolizumab was far superior at 2 mg/kg; 6-month PFS was 34% in the pembrolizumab arm compared with only 16% in the chemotherapy arm (32). Moreover, pembrolizumab was better tolerated than chemotherapy with 9% serious adverse events reported, compared with 31%.
Toxicities associated with blockade of the PD-1 pathway are similar in spectrum but less frequent and severe than those seen with CTLA-4 inhibitors (33). In fact, the incidence of grade 3 or grade 4 adverse events were seen in only 9% of PD-1 inhibitors, compared with 14% of anti-CTLA-4 agents. Pneumonitis, observed in 3% of patients and fatal in almost a third of them, requires a high degree of vigilance on the part of health care providers. These irAEs may predict favorable antitumor responses (34), and studies suggest that immunosuppression to treat the irAEs does not dampen ongoing antitumor response (35).
Predictors of response to PD-1 inhibitors are being studied to improve patient selection. In the phase I nivolumab trial, tumor expression of PD-L1 correlated with response to therapy (33). Moreover, such tumors are almost always associated with the presence of tumor infiltrating lymphocytes (TILs) (36). However, neither PD-1 expression nor presence of TIL has been sufficiently sensitive or specific for clinical use and patient selection.
Since many of the anti-PD-1 trials followed the initial approval of anti-CTLA-4, some of the patients enrolled in the initial anti-PD-1 trials had been on ipilimumab and had not achieved durable responses. Head-to-head comparison of those two classes of drugs in the frontline setting was achieved in a phase III trial whose results were published in 2015 and suggested response rates were improved in the pembrolizumab groups, whether the drug was administered every 2 or 3 weeks (33.7% vs. 32.9%), compared with ipilimumab (11.9%) (37).
Since resistance to ipilimumab in the early trials did not preclude a response to anti-PD-1 therapy, the two checkpoint inhibitors are likely not cross-resistant, and it was possible that a synergistic antitumor response could be achieved with combination therapy. This was supported by the fact that the two classes of drugs inhibit nonredundant checkpoints and events in the cascade of T cell activation (38). A phase I trial of the combination revealed dramatic activity, albeit with a fair degree of autoimmune toxicity. A randomized phase II trial demonstrated superior activity to ipilimumab alone (39). A phase III trial comparing the combination of ipilimumab and nivolumab to either drug alone once again showed increased toxicity (40). Interestingly, in patients with PD-1-negative tumors, combination therapy was more effective than either agent alone, whereas tumors that were strongly PD-L1 positive had a similar response to monotherapy with nivolumab. Although the combination is now approved by the FDA, caution should be taken when using the combination as expertise in handling autoimmune toxicities, which can be severe and sometimes irreversible or fatal, is necessary.