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Adjuvant immunotherapy for melanoma
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Adjuvant immunotherapy for melanoma
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Literature review current through: Jul 2017. | This topic last updated: Jun 06, 2017.

INTRODUCTION — Surgical excision is the treatment of choice for early cutaneous melanoma and is curative in most cases. However, some patients will subsequently relapse with disseminated disease. High-risk features in the primary tumor and regional lymph node metastasis define patient subsets that are at increased risk for recurrent disease.

The use of adjuvant immunotherapy for high-risk melanoma will be reviewed here. The initial management of cutaneous melanoma and the management of patients with metastatic disease are discussed separately. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Overview of the management of advanced cutaneous melanoma".)

GENERAL APPROACH TO ADJUVANT THERAPY

Staging and prognosis — For patients who have undergone a complete resection of a cutaneous melanoma, the decision of whether or not to recommend adjuvant therapy depends upon the risk of disease recurrence, based upon the stage at diagnosis, along with a consideration of patient age, comorbidity, and personal preferences.

The extent and characteristics of the primary tumor and regional lymph node involvement allow classification of patients into different risk categories. The tumor, nodes, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) (table 1A-B and table 2A-B) incorporates the most important determinants of prognosis [1,2]. (See "Tumor node metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

For the primary tumor (T), increasing tumor thickness, an increased mitotic rate, and the presence of ulceration (ie, the loss of the epidermal layer overlying the primary tumor) are associated with an increased risk of relapse (figure 1).

The presence of lymph node involvement is associated with a significant increase in risk of recurrence, and this is further subdivided based upon the number and extent of lymph node disease (figure 2).

Specific recommendations regarding the use of adjuvant therapy are summarized in this section for different risk groups. The clinical trial supporting data are discussed below. (See 'Ipilimumab' below and 'Interferon alfa' below.)

Low-risk patients — The majority of patients diagnosed with melanoma present with stage I or IIA disease (≤2 mm in thickness with ulceration, or localized tumor ≤4 mm in thickness without ulceration). In these patients, surgery is usually curative, and adjuvant therapy is not indicated except in the context of a formal clinical trial [3].

High-risk node-negative (stage IIB or IIC) disease — Patients without lymph node involvement but with high-risk features in their primary tumor are at increased risk for recurrence and disease dissemination. High-risk primary tumors include those that are >4 mm thick, or >2 mm thick with ulceration. High-risk node-negative patients were excluded from the European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial, which compared ipilimumab with placebo [4,5]. (See 'Efficacy and toxicity' below.)

Options in this setting include both observation and high-dose interferon alfa (IFNa). Ipilimumab is not currently approved for patients with high-risk node-negative disease. (See 'Interferon alfa' below.)

High-risk stage III disease — For patients who have had a complete resection of stage III melanoma, recommendations regarding adjuvant therapy are based upon the extent of lymph node involvement:

For patients with macroscopic lymph node involvement, multiple lymph nodes involved, or a single node with >1 mm of microscopic disease, enrollment in a clinical trial evaluating a programmed cell death protein 1 (PD-1) inhibitor is the preferred approach. Ipilimumab (using the 10 mg/kg schedule) is an appropriate alternative when clinical trial participation is not feasible. Although no data are yet available on PD-1 inhibitors in the adjuvant setting, these agents (alone or in combination with ipilimumab) are significantly more effective than single-agent ipilimumab in the metastatic disease setting. (See 'Efficacy and toxicity' below and "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Anti-PD-1 monoclonal antibodies' and "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy'.)

Patients with microscopic involvement of ≤1 mm in a single lymph node were excluded from the EORTC 18071 trial. In this setting, high-dose IFNa or observation is an option. Ipilimumab is not currently approved for those with stage IIIA (<1 mm) disease. (See 'Interferon alfa' below.)

IPILIMUMAB — The use of ipilimumab as an adjuvant for resected high-risk melanoma is based upon the results of a large phase III trial in which ipilimumab significantly decreased the rate of recurrence and improved overall survival compared with placebo. Although there currently are no results directly comparing ipilimumab with interferon alfa (IFNa), the magnitude of the overall survival benefit with ipilimumab (on the 10 mg/kg schedule) has made this the preferred agent for patients with stage III disease.

Efficacy and toxicity — In the European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial, 951 patients were randomly assigned to either ipilimumab or placebo [4,5]. All patients had stage III melanoma, and 80 percent had stage IIIB or IIIC disease. The other 20 percent had stage IIIA disease with melanoma >1 mm diameter in the sentinel lymph node.

Treatment with ipilimumab was given at a dose of 10 mg/kg every three weeks for four doses, then every three months for three years unless toxicity or relapse prevented its continuation. Placebo was given on the same schedule.

The primary endpoint of the trial was relapse-free survival (RFS); overall survival and distant metastasis-free survival (DMFS) were secondary endpoints. Results were updated at a median follow-up of 5.3 years [5]:

RFS was significantly better with ipilimumab compared with placebo (five-year RFS 40.8 versus 30.3 percent, hazard ratio [HR] 0.76, 95% CI 0.64-0.89).

DMFS was significantly better with ipilimumab (five-year DMFS 48.3 versus 38.9 percent, HR 0.76, 95% CI 0.64-0.92).

Overall survival was significantly prolonged with ipilimumab (five-year overall survival 65.4 versus 54.4 percent, HR 0.72, 95% CI 0.58-0.88, p = 0.001). This benefit was seen despite the use of various systemic therapies in patients who subsequently developed recurrent disease.

Toxicity associated with adjuvant ipilimumab was significant. Adverse events of any grade were observed in 98.7 percent of patients treated with ipilimumab, including 54.1 with grade 3 or 4 adverse events. Grade 3 or 4 immune-related adverse effects occurred in 41.6 percent of patients and led to treatment discontinuation or, rarely, death. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

The most common immune-related adverse events included dermatologic, gastrointestinal, endocrine, and hepatic toxicity (grade 3 or higher in 4.2, 16.8, 7.8, and 10.9 percent of patients, respectively).

There were five treatment-related deaths in patients treated with ipilimumab (three due to colitis, one to myocarditis, and one to multiorgan failure associated with Guillain-Barré syndrome).

Quality of life was assessed using the EORTC Quality of Life Questionnaire version 3.0 (QLQ-C30) [6]. There was a statistically significant decrement in global health status both during and after induction therapy, but the difference did not exceed the clinically relevant threshold.

A second phase III trial in the adjuvant setting is comparing ipilimumab at one of two doses (the 10 mg/kg dose used in the EORTC 18071 trial or the standard 3 mg/kg dose approved for patients with stage IV disease) with high-dose IFN (E-1609, NCT01274338). It has overall survival and RFS as coprimary endpoints.

An unplanned exploratory analysis of the E-1609 trial was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting [7]. This was based on a 3.1 year follow-up of 773 concurrently randomized patients treated with ipilimumab at either 3 or 10 mg/kg. Toxicity was lower with the 3 mg/kg schedule compared with the 10 mg/kg schedule (all grade 3-4 adverse events 36.6 versus 56.5 percent and grade 3-4 immune-related adverse events 18.8 versus 34.0 percent). There was no difference in the three-year RFS (42.3 and 42.6 percent, respectively, HR 1.0), but longer follow-up is required.

Dose of ipilimumab — Based upon the initially reported results of the EORTC 18071 trial [4], ipilimumab was approved at a dose of 10 mg/kg for use as an adjuvant. The dose used in this trial (10 mg/kg) is different from the dose used for metastatic disease (3 mg/kg) and is associated with increased toxicity. However, in patients with metastatic disease, ipilimumab on the 10 mg/kg schedule has been shown to produce a superior three-year overall survival rate compared with ipilimumab 3 mg/kg (31 versus 23 percent) in patients with stage IV disease [8]. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Dose and schedule'.)

Therefore, until more data are available to support equivalent results in the adjuvant setting, the ipilimumab 10 mg/kg regimen is preferred over the lower-dose regimen that is approved for patients with distant metastases.

Interferon versus ipilimumab — There currently are no data from randomized trials comparing ipilimumab with IFNa.

The phase III trial comparing ipilimumab with placebo demonstrated an improvement in RFS, DMFS, and overall survival similar to what has been reported in high-dose IFN trials (ECOG 1684 and Intergroup E1694) [9-11]. However, the benefit with ipilimumab on overall survival was seen despite the potentially confounding use of various systemic therapies with proven benefits on overall survival in patients who subsequently developed recurrent disease. Approximately one-half of patients who relapsed received either a BRAF inhibitor or additional checkpoint inhibitor therapy. Further, the convenience and general tolerability of the ipilimumab regimen are superior to that of the high-dose IFN regimen.

INTERFERON ALFA — Prior to the development of ipilimumab checkpoint inhibitor immunotherapy, high-dose interferon alfa (IFNa) was the only option for adjuvant treatment of high-risk melanoma that had demonstrated an improvement in overall survival. Approaches to improve the therapeutic index of high-dose IFNa have included the use of pegylated IFN, the combination of IFNa with various chemotherapy regimens, and the use of low or intermediate doses of IFNa [12-17]. However, none of these approaches were shown to be superior to high-dose IFNa in terms of overall survival.

High-dose IFNa — The use of high-dose IFNa is supported by the results of the Eastern Cooperative Oncology Group (ECOG) 1684 and Intergroup E1694 trials, as well as a meta-analysis that included results from trials with various schedules and doses of IFNa [18].

ECOG 1684 — In the ECOG trial (ECOG 1684), 287 patients with melanomas >4 mm in depth (stage IIB), or subclinical or clinically apparent regional node involvement (stage III) were randomly assigned to one year of high-dose IFNa-2b or close observation [11]. The IFNa treatment schedule consisted of intravenous therapy at a dose of 20 million units/m2 five days per week for four weeks, followed by 10 million units/m2 subcutaneously three times weekly for an additional 11 months.

At a median follow-up of nearly seven years, the following statistically significant benefits were noted with IFNa:

A nine-month prolongation in relapse-free survival (RFS; median 1.7 versus 1 years), with an 11 percent absolute increase in RFS at five years (37 versus 26 percent).

A one-year prolongation in median survival (3.8 versus 2.8 years), with a 9 percent absolute increase in survival at five years (46 versus 37 percent).

In a subsequent analysis, the improvement in overall survival was no longer statistically significant [10]. Treatment benefit appeared to be confined to patients with lymph node involvement, with a doubling of RFS in these subgroups. Although patients without nodal involvement (T4NO stage IIB (table 1A-B)) did not appear to benefit, there were too few patients in this subgroup to make any meaningful assessment.

Intergroup E1694 — Intergroup E1694 trial compared high-dose IFNa-2b with the GM2-KLH vaccine in resected stage IIB and III melanoma patients, the same population studied in ECOG 1684 and 1690 [9]. The trial was closed prematurely when interim analysis disclosed significantly worse RFS and overall survival for patients treated with the GM2-KLH vaccine compared with high-dose IFNa (hazard ratio [HR] 1.47 and 1.52, respectively).

The general interpretation of this trial was that the GM2-KLH vaccine was no worse than observation and that the vaccine thus served as a control group for the high-dose IFNa. A subsequent trial found that the vaccine did not improve or significantly hinder overall survival compared with observation alone.

Toxicity — Administration of adjuvant high-dose IFNa is associated with numerous adverse effects, including acute constitutional symptoms, chronic fatigue, myelosuppression, and neurologic and psychologic effects, which are experienced to some degree by the majority of patients (table 3) [19].

Granulocytopenia occurs in the majority of patients and may be severe enough in 20 to 60 percent to warrant dose modification. Infections are uncommon, suggesting a different mechanism of myelosuppression than that seen with cytotoxic chemotherapy.

Liver toxicity resulted in two early deaths in ECOG 1684 but has not been a cause of death in the United States cooperative group trials since vigilant monitoring and dose modification guidelines were mandated.

Fatigue is common and was present in 70 to 100 percent of patients in large trials. Fatigue can increase in severity with duration of therapy and can be debilitating.

Mild to moderate depression and impaired cognitive function are commonly reported, while mood instability (alternating mania and depression) occurs less often. A history of mood or psychiatric disorders is a risk factor for neuropsychiatric effects. The use of antidepressants (either therapeutically or prophylactically) may facilitate completion of the full planned course of therapy.

Thyroid dysfunction (both hypothyroidism and hyperthyroidism) may appear during the course of IFNa therapy. It typically is autoimmune in nature and usually resolves within 6 to 12 months of stopping treatment. Studies suggest that thyroid dysfunction may be associated with a significantly enhanced chance of therapeutic benefit.

Patients should be monitored closely during therapy. During the initial four-week induction period with IFNa, this should include weekly blood counts, liver function tests, and metabolic panels. These should then be repeated on a monthly basis for patients being treated on the high-dose IFNa regimen.

The majority of these effects can be managed with appropriate supportive care and/or dose reduction if toxicity is severe [19]. Most adverse reactions resolve with treatment discontinuation. However, a high-dose IFNa regimen for one year can be associated with significant side effects. Significant toxicities include hepatotoxicity, fatigue, depression, and autoimmune phenomena, particularly affecting the thyroid. The incidence of key toxicities is summarized in the table (table 3).

Pegylated interferon alpha — Pegylated IFNa was developed to decrease the frequency with which IFNa is administered while maintaining a high level of exposure. Pegylated IFNa was evaluated as an adjuvant following primary resection of melanoma in two phase III trials.

In the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial in patients with stage III melanoma, there was no difference in overall survival, although the seven-year RFS was significantly increased with pegylated IFNa compared with observation [20]. This trial led to the US Food and Drug Administration (FDA) approval of pegylated IFNa for adjuvant treatment of patients with stage IIIA melanoma.

In a second trial in patients with high-risk disease, there was no significant difference in the five-year distant metastasis-free survival, disease-free survival, or overall survival [21].

Based on this information and its FDA approval, pegylated IFNa is an alternative option to standard high-dose IFN for adjuvant therapy for patients with resected stage III melanoma. However, given their overall survival benefits, either ipilimumab or high-dose IFN would be preferable treatments.

ANTI-PD-1 ANTIBODIES — Checkpoint inhibition using nivolumab or pembrolizumab, which target the programmed cell death protein 1 (PD-1), significantly prolongs overall survival compared with ipilimumab in patients with metastatic melanoma. Both of these agents are being studied in the adjuvant setting. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Programmed death 1 protein' and "Principles of cancer immunotherapy".)

However, there are no data to support their use outside a clinical trial setting. Ongoing trials in the adjuvant setting include the following:

A phase III trial comparing nivolumab with ipilimumab has completed enrollment for patients who have had complete resection of stage IIIB/C or IV melanoma (NCT02388906). Results are pending.

A phase III trial comparing pembrolizumab with placebo has also completed accrual for patients with high-risk stage III melanoma following complete resection (NCT02362594).

A phase III cooperative group trial (NCT02506153, Southwest Oncology Group S1404) comparing pembrolizumab with high-dose interferon or high-dose ipilimumab is ongoing in patients with high-risk stage III or IVA disease following complete resection.

EXPERIMENTAL APPROACHES — Alternative approaches that have been studied as an adjuvant following surgical resection include:

Biochemotherapy – Intensive biochemotherapy was evaluated as an alternative to high-dose interferon alfa (IFNa) in a phase III cooperative group trial (S0008) and may constitute an alternative to high-dose IFNa in carefully selected patients [13]. The trial randomly assigned 432 patients with high-risk melanoma to either three cycles of cisplatin, vinblastine, dacarbazine, interleukin-2 (IL-2), and IFNa given over a nine-week period or to high-dose IFNa for one year.

At a median follow-up of 7.2 years, the biochemotherapy regimen significantly prolonged relapse-free survival (RFS; median 4.0 versus 1.9 years and five-year RFS rate 48 versus 39 percent, hazard ratio [HR] 0.75, 95% CI 0.58-0.97). However, there was no significant difference in overall survival (five-year rate 56 percent for both treatment arms, HR 0.98, 95% CI 0.74-1.31). The toxicity profiles of the two regimens differed substantially. For the biochemotherapy regimen, grade 3 or 4 toxicity was observed in 76 percent of cases and consisted primarily of hematologic and gastrointestinal toxicity. Neurologic, psychiatric, and hepatic toxicities were the most frequent with high-dose IFNa. Biochemotherapy toxicities were limited to the nine-week treatment period, while IFNa toxicities were distributed across the year of treatment.

Bevacizumab – In a phase III trial in which 1343 patients with stage IIB, IIC, or III disease were randomly assigned to one year of bevacizumab (7.5 mg/kg every three weeks) or observation, there was a statistically significant increase in the disease-free interval [22,23]. However, there was no significant difference in overall survival, the primary endpoint of the trial, at a median follow-up of six years.

BRAF mutant melanoma – For patients with BRAF mutant melanoma, agents being evaluated in the adjuvant setting include vemurafenib (NCT01667419) and the combination of dabrafenib plus trametinib (NCT01682083).

GM-CSF – Granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to demonstrate a benefit in a multicenter trial in 815 patients with high-risk stage III or completely resected stage IV melanoma [24]. There was no statistically significant difference in either overall survival or RFS compared with placebo. There was also no benefit associated with the use of the peptide vaccine.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Patients who have undergone a definitive resection of cutaneous melanoma generally do well. However, subsets of patients at increased risk of recurrence can be defined based upon the characteristics of the primary tumor (thickness, mitotic rate, ulceration) or the presence of lymph node metastases. Patients should be enrolled in formal clinical trials whenever feasible. (See 'General approach to adjuvant therapy' above.)

For patients with stage III melanoma (table 1A-B and table 2A-B) at high risk of recurrence due to the presence of macroscopic lymph node involvement, multiple lymph node involvement, or a single lymph node with >1 mm tumor involvement, participation in a clinical trial evaluating an anti-programmed cell death protein 1 (PD-1) checkpoint inhibitor (nivolumab, pembrolizumab) is preferred. If clinical trial participation is not feasible, we suggest ipilimumab (using the 10 mg/kg schedule) rather than interferon alfa (IFNa) (Grade 2B). (See 'High-risk stage III disease' above and 'Ipilimumab' above and 'Interferon versus ipilimumab' above.)

Although there currently are no data on the use of anti-PD-1 checkpoint inhibitors in an adjuvant setting, these agents have significantly prolonged overall survival compared with ipilimumab in patients with metastatic disease. (See 'Anti-PD-1 antibodies' above and "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Anti-PD-1 monoclonal antibodies'.)

While adjuvant ipilimumab is approved at a dose of 10 mg/kg every three weeks for four doses, followed by ipilimumab every three months for three years in the absence of serious toxicity or progressive disease, this dose is more toxic and not definitively more effective than 3 mg/kg every three weeks for four doses, which is the schedule used in patients with metastatic disease. While stronger evidence supports the use of the 10 mg/kg dose, there are currently inadequate data to require the selection of this dose over the 3 mg/kg dose in the adjuvant setting. (See 'Dose of ipilimumab' above.)

Patients with stage III disease but ≤1 mm involvement of a single lymph node were excluded from the phase III trial that established the efficacy of ipilimumab. Adjuvant immunotherapy with high-dose IFNa, and observation are options in this setting. (See 'High-risk stage III disease' above and 'Interferon alfa' above.)

Patients at increased risk of recurrence with stage II melanoma (primary tumor >4 mm, or >2 mm with ulceration) were also excluded from the phase III ipilimumab trial. Adjuvant immunotherapy with high-dose IFNa can be considered in this setting. (See 'High-risk node-negative (stage IIB or IIC) disease' above and 'Interferon alfa' above.)

For patients at low risk of recurrence (no lymph node involvement and tumor ≤4 mm in thickness without ulceration or ≤2 mm in thickness with ulceration, stage IIA (table 1A-B and table 2A-B)), there is a high probability of cure. There is no evidence that adjuvant therapy improves the prognosis, and adjuvant therapy is not indicated. (See 'Low-risk patients' above.)

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REFERENCES

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