What is the role of adjuvant systemic therapy in patients with resected stage II and stage III melanoma?

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Introduction

Despite adequate surgical treatment patients with resected stage II or III melanoma have a risk of both local and distant recurrence. The risk of relapse and death can be estimated based on tumour clinicopathological features, including but not limited to primary tumour Breslow thickness and ulceration, size and number of involved lymph nodes and the presence or absence of in-transit metastases (see What are the clinical features of melanoma and how do atypical melanomas present?) The purpose of adjuvant systemic therapy is to eradicate occult metastatic disease, thus reducing the risk of relapse and improving overall survival. In the setting of resected stage II or III melanoma, there have been randomised controlled studies (RCT) examining the role of, nivolumab, pembrolizumab, combination dabrafenib/trametinib, vemurafenib, ipilimumab, interferon-α, chemotherapy, vaccines and levamisole.

Randomised trials of chemotherapy, vaccines, levamisole and vemurafenib did not identify a survival benefit.[1] Ipilimumab and interferon-α (IFN-α) have both been shown to improve relapse-free and overall survival patients with resected stage III melanoma in RCTs (and meta-analyses for IFN), however the excessive toxicity of ipilimumab, and minimal overall survival benefit with interferon, mean that they are not considered standard therapy for most melanoma patients.

Recently, the initial results of three adjuvant RCTs of highly active drugs in metastatic melanoma, suggest that nivolumab, pembrolizumab and combination dabrafenib/trametinib are likely to soon replace other treatments as new standards of care.[2][3] These studies showed a significant improvement in relapse-free survival (RFS) (over ipilimumab for nivolumab and placebo for pembrolizumab and dabrafenib/trametinib), and mature analyses of overall survival are awaited.

Neither nivolumab, pembrolizumab nor combination dabrafenib/trametinib has been trialled in the setting of resected stage II melanoma and as such the activity of these agents in stage III cannot be extrapolated to patients with stage II melanoma. The nivolumab RCT[3] included patients with resected stage IV disease and it may be considered in patients considered for treatment after resection of stage IV disease (see For patients with distant metastases, when is surgical therapy indicated?)


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Systematic review evidence

Twenty-four RCTs and seven meta-analyses were identified examining the adjuvant treatment of resected stage II and III melanoma. The only agents to have been found to have benefit over placebo are pembrolizumab, ipilimumab, interferon-α-2b (IFN-α), pegylated interferon-α-2b (Peg IFN-α) and combination dabrafenib/trametinib. Nivolumab was shown to be superior to ipilimumab.

Of note a second adjuvant study in BRAF mutant melanoma (BRIM-8) has been undertaken which randomized patients to either single agent vemurafenib or placebo treatment for 1 year.[4] Preliminary results have been presented, however to date results have not been published (NCT01667419). Unlike the recent adjuvant drug trials, BRIM-8 included patients with resected stage IIC melanoma. This study did not meet its primary endpoint of improving RFS in patients with resected stage IIIC melanoma. In patients with resected stage IIC, IIIA and IIIB melanoma, RFS was greater in patients treated with vemurafenib vs placebo (HR 0.54; 0.0010), however this result was not considered statistically significant because of the prespecified hierarchical prerequisite for primary relapse free survival analysis in patients with resected IIIC disease.

Combination dabrafenib and trametinib in BRAF mutant melanoma

In patients with unresectable stage III and IV melanoma, whose tumours are BRAF V600 mutant, combination dabrafenib and trametinib improves survival compared with single agent dabrafenib or vemurafenib (see Does systemic drug therapy improve progression free, overall survival in unresectable stage IIIC and stage IV melanoma?) (which in turn improves survival over chemotherapy).[2] In the adjuvant setting, the double blind RCT Combi-AD included patients with resected stage III (AJCC IIIA, [sentinel node deposit >1mm diameter], IIIB and IIIC) BRAF V600E/K melanoma and randomised patients to 12 months of treatment with combination dabrafenib/trametinib or matched placebo.[2]

After a median follow-up of 2.8 years, dabrafenib/trametinib improved RFS over placebo; the 3 year RFS was 58% with dabrafenib/trametinib group versus 39% with placebo (HR 0.47; P<0.001).[2] Similarly, OS was improved; the 3-year OS rate was 86% versus 77%, respectively (HR 0.57; P = 0.0006). This OS result did not cross the prespecified interim analysis boundary, and the study is powered for a final survival analysis with further follow-up. The benefit of dabrafenib/trametinib was consistent across multiple subgroups tested, including mutation type (V600E vs V600K) and AJCC sub-stage (lymph node tumour burden and primary tumour ulceration status).[2]

Adverse events were reported in 97% of patients treated with adjuvant dabrafenib/trametinib versus 88% of patients on the placebo arm.[2] Grade 3/4 adverse events occurred in 41% of patients treated on the combination arm versus 14% on the placebo. Consistent with data from patients with advanced disease, the most common adverse events with dabrafenib/trametinib were pyrexia and fatigue, most commonly grade 1 or 2. In the dabrafenib/trametinib group 26% had adverse events leading to treatment discontinuation, 38% leading to a dose reduction and 66% leading to a dose interruption.[2] Back to top

Nivolumab

In patients with unresectable (metastatic) stage III or IV melanoma, nivolumab is associated with superior efficacy and improved safety as compared to ipilimumab. The double blinded phase III RCT CA209-238 included patients with resected stage IIIB/C or stage IV melanoma (AJCC 7th edition), randomised to 12 months treatment with either nivolumab (3mg/kg 2 weekly) or ipilimumab (10mg/kg) (see Does systemic drug therapy improve progression free, overall survival in stage IIIC unresectable and stage IV melanoma?).[3] The study cohort was predominantly resected stage III melanoma (81%), including 29% of patients with micrometastatic disease detected by sentinel lymph node biopsy.

At first analysis and after a minimum follow-up of 18 months, nivolumab was associated with an improvement in RFS; the 12-month RFS was 70.5% for with nivolumab and 60.8% with ipilimumab (HR 0.65; P<0.001).[3] Nivolumab was superior to ipilimumab across all subgroups including stage IIIB/C and stage IV disease, BRAF mutant and wildtype melanoma, and PD-L1 positive and negative subgroups. Initial data are too immature for an OS analysis.

Consistent with studies in the advanced setting, nivolumab was associated with a favourable safety profile compared with ipilimumab, and similar to that seen when used in the metastatic setting.[3] The rate of treatment related adverse events was 85.2% with nivolumab versus 95.8% with ipilimumab, and grade 3/4 toxicity was 14.4% versus 45.9%, respectively. There were two treatment-related deaths in the ipilimumab arm versus with no treatment related deaths in the nivolumab cohort.[3] Back to top

Ipilimumab

Ipilimumab was the first systemic therapy shown to improve overall survival in advanced melanoma.[5] The RCT, EORTC 18071, compared ipilimumab to placebo in resected stage III melanoma. Stage IIIA patients required sentinel nodal metastasis diameter >1mm, and patients with in-transit metastasis or prior adjuvant radiotherapy were excluded.[5] 951 patients were randomised one to one to ipilimumab (10mg/kg for 4 doses 3 weekly then a maintenance regime of 3 monthly for up to 3 years) or a matched placebo.[5]

Recurrence free survival (RFS), the primary endpoint, was improved in those treated with ipilimumab. Five-year RFS was 40.8% in the ipilimumab and 30.3% in the placebo arm (HR 0.76; P<0.001), and 5-year overall survival (OS) was 65.4% and 54.4%, respectively (HR 0.72; P = 0.001).[6] Subsequent therapy in those who recurred was roughly similar in both arms, but given the timing of the trial, only a small proportion of patients received BRAF/MEK inhibitors and anti-PD-1 therapy post-relapse.[6]

Ipilimumab had 54% grade 3/4 toxicity compared to 26% in the placebo arm, only a minority (40%) of patients received more than the four induction doses of ipilimumab, and only 13% received all three years of ipilimumab treatment. There were five treatment-related deaths ipilimumab arm, three related to colitis, one myocarditis and one Guillain-Barre syndrome. The general consensus among clinicians is that this treatment was associated with significant toxicity however there was no clinically significant difference in quality of life between both groups.[7]

Of note, the dose of ipilimumab used in this trial was higher (10mg/kg) than the TGA/PBS approved dose in the metastatic setting (3mg/kg), which is given without maintenance dosing. While a RCT in the metastatic setting has shown 10mg/kg to be more efficacious but also more toxic than 3mg/kg,[8] a subsequent RCT of adjuvant ipilimumab at 10mg/kg; 3mg/kg or high dose IFN (NCT01274338) should clarify the best dose of ipilimumab in this setting. However, given the superiority and favourable toxicity profile of nivolumab over ipilimumab (see above) the results of this subsequent study are unlikely to change practice. Back to top

IFN-α

Multiple randomised phase III trials have examined the role of IFN as an adjuvant treatment for the management of resected stage II and III melanoma.[9][1] Various dosing strategies have been examined including high-dose (20 MU/m2), intermediate-dose (5–10 MU), low-dose (1–3 MU) regimens and Peg IFN.

The results of the ECOG 1684 (E1684) study of high dose IFN-α (20MU/m2) 5 days a week for 4 weeks, followed by 11 months of maintenance treatment (10MU/m2 3 days a week) versus routine follow-up for the treatment of resected stage III melanoma led to the TGA approval and PBS listing of this regimen. The E1684 regimen improved relapse free survival (RFS, median 1.72 years compared with 0.98 years), with initial analysis suggesting an improvement in OS.[10] Subsequent analysis, including pooling data from E1684 and ECOG 1690 (E1690), treated with the same regimen, failed to confirm an improvement in OS.[11]

A meta-analysis of 17 RCTs found IFN-α improved RFS (HR = 0.83; P value < 0.00001).[9] Analysis from 15 of these studies identified an improvement in OS (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). This equates to an absolute improvement in OS of approximately 2–3%. Despite multiple studies examining different doses and durations of treatment no IFN regimen was found to be superior.[9]

There is conflicting evidence regarding the impact of the number and size of nodal melanoma burden on the efficacy of interferon. Patients with microscopic nodal disease benefited the most in the E1684 trial, whereas those with 2–3 positive nodes benefited in the E1690 trial, and those who were node-negative benefited in the E1694 trial.[10][12][13] A retrospective analysis of EORTC 18952 and 18891 suggested a greater benefit of IFN-α in those with ulcerated primaries.[14]

IFN-α treatment is associated with significant toxicity, which is reversible on cessation of treatment. Common toxicities include flu like symptoms (fevers, fatigue, myalgia), hepatotoxicity and depression.[15]

One study examined the role of IFN-α exclusively in resected stage II melanoma and reported OS, when adjusted for prognostic factors OS was significantly improved by treatment with IFN (HR 0.70; 95% CI 0.50-0.99, P=0.046).[16] Patients enrolled in this study did not undergo a sentinel node biopsy and as such, it is unclear if the results are applicable in the current era.

Overview of additional evidence (non-systematic review relevant literature)

Pembrolizumab

Like nivolumab, pembrolizumab is associated with superior survival and efficacy when compared to ipilimumab in patients with unresectable stage IIIC or stage IV melanoma (see Does systemic drug therapy improve progression-free, overall survival in unresectable stage IIIC and stage IV melanoma?). The double blind phase III RCT MK3475-054 included patients with resected stage III (AJCC 7th Addition IIIA, [sentinel node deposit >1mm diameter], IIIB and IIIC) melanoma and randomised patients to 12 months of treatment with pembrolizumab or matched placebo.[17]

After a median follow-up of 15.1 months, pembrolizumab improved RFS over placebo; the 12 month RFS was 75% with pembrolizumab versus 61% with placebo (HR 0.57; P<0.001). Pembrolizumab was superior to placebo across the all subgroups including AJCC substage, BRAF mutant and wildtype melanoma, and PD-L1 positive and negative subgroups. Initial data are too immature for an OS analysis.

The toxicity profile of Pembrolizumab was consistent with studies in the metastatic setting. The rate of treatment related adverse events was 77.8% with pembrolizumab versus 66.1% with placebo, and grade 3/4 toxicity was 14.7% versus 3.4%, respectively. There was one treatment-related death in the pembrolizumab arm due to myositis.


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Evidence summary and recommendations

Evidence summary Level References
Combination dabrafenib and trametinib treatment for one year in resected IIIA (nodal deposit >1mm diameter), IIIB, IIIC BRAF V600E/K melanoma improves RFS compared to placebo (HR 0.47; P<0.001). II [2]
Nivolumab for one year in resected IIIB, IIIC, IV melanoma improves RFS compared to ipilimumab (10mg/kg) (HR 0.65; P<0.001). II [3]
Pembrolizumab for one year in resected IIIA (nodal deposit >1mm diameter), IIIB, IIIC melanoma improves RFS compared to placebo (HR 0.57; P<0.001). II [17]
Ipilimumab (10mg/kg for 4 doses followed by 3 monthly maintenance treatment for 3 years) in resected IIIA (nodal deposit >1mm diameter), IIIB, IIIC melanoma improves RFS (HR 0.76, P<0.001) and OS (HR 0.72; P=0.001) compared to placebo. II [5]
Adjuvant IFN-α in resected stage II, III melanoma improves RFS (HR 0.83; P<0.00001) and overall survival (HR 0.91; P=0.003) compared to observation. I [9]
Evidence-based recommendationQuestion mark transparent.png Grade
All patients with resected stage III melanoma should discuss the benefits, potential toxicities and out-of-pocket costs of adjuvant systemic therapy with an experienced melanoma medical oncologist who is part of a multidisciplinary melanoma team, including the role of clinical trials.
C


Evidence-based recommendationQuestion mark transparent.png Grade
Patients with BRAF V600E/K resected stage III melanoma may be considered for 12 months adjuvant treatment with combination dabrafenib/trametinib.

Note: Adjuvant dabrafenib/trametinib is not TGA approved or PBS listed

B


Evidence-based recommendationQuestion mark transparent.png Grade
Patients with resected stage IIIB/C or IV melanoma may be considered for 12 months adjuvant treatment with nivolumab.

Note: Adjuvant nivolumab is not PBS funded.

B


Evidence-based recommendationQuestion mark transparent.png Grade
Patients with resected stage III melanoma may be considered for 12 months adjuvant treatment with pembrolizumab.

Note: Adjuvant pembrolizumab is not TGA approved or PBS funded.

B


Evidence-based recommendationQuestion mark transparent.png Grade
Patients for whom adjuvant nivolumab, pembrolizumab or dabrafenib/trametinib is not appropriate or is not available, routine follow-up may be appropriate. Patients may consider treatment with IFN-α after discussion with a medical oncologist regarding the associated toxicity and potential benefit.
B


Evidence-based recommendationQuestion mark transparent.png Grade
Ipilimumab is not recommended because it has inferior efficacy and greater toxicity than nivolumab.
B


Evidence-based recommendationQuestion mark transparent.png Grade
Outside of a clinical trial adjuvant systemic therapy is not recommended for patients with resected stage II melanoma.
C



Practice pointQuestion mark transparent.png

Patients should be treated in a medical oncology facility with a melanoma multidisciplinary team and experience in using immunotherapy and BRAF/MEK inhibitors.


Practice pointQuestion mark transparent.png

At present neither dabrafenib/trametinib or pembrolizumab are TGA approved for adjuvant therapy and neither dabrafenib/trametinib, nivolumab or pembrolizumab are PBS funded. As such, enrolment in a clinical trial should be discussed.


Practice pointQuestion mark transparent.png

There are no data comparing combination dabrafenib/trametinib and nivolumab/pembrolizumab in patients whose tumours are BRAF V600 mutant, as such individual patient discussions are required for patients whose tumours are BRAF mutant.


Practice pointQuestion mark transparent.png

For those with stage III melanoma not able to receive dabrafenib/trametinib, nivolumab or pembrolizumab (or a clinical trial), interferon may be considered, but given the minimal overall survival benefit and significant toxicity, routine follow-up is usually preferred. See How should patients at each stage of melanoma be followed after initial definitive treatment?

The use of adjuvant systemic therapies in the Australian setting

At present, the only PBS-funded adjuvant treatment in Australia is IFN-α. Adjuvant IFN-α confers a small improvement in absolute OS but also has significant toxicity and as such for many patients the option of routine follow-up is considered favourable to IFN-α. Given the superiority of nivolumab over ipilimumab in the CA209-238 study, and the toxicity of ipilimumab, ipilimumab does not have a current role in the adjuvant treatment of melanoma in Australia, and is unlikely to have one in the future.

At present nivolumab is TGA approved but not PBS reimbursed and combination dabrafenib/trametinib and pembrolizumab are neither TGA approved or PBS reimbursed for the adjuvant treatment of resected melanoma. Enrolment in a clinical trial remains an alternative to routine follow-up for many patients. Self-funded adjuvant therapy is an option, however should be considered in the context of a multidisciplinary team involving a medical oncologist experienced in melanoma treatment.


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Appendices


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  1. 1.0 1.1 Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Cancer 2006 Apr 1;106(7):1431-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16511841.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 2017 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28891408.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28891423.
  4. Maio M, Lewis K, Demidov L, Mandalà M, Bondarenko I, Ascierto PA, et al. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 2018 Feb 21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29477665.
  5. 5.0 5.1 5.2 5.3 Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 2016 Nov 10;375(19):1845-1855 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27717298.
  6. 6.0 6.1 Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015 May;16(5):522-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25840693.
  7. Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, et al. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol 2017 Feb 2 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28162999.
  8. Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2017 Mar 27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28359784.
  9. 9.0 9.1 9.2 9.3 Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev 2013 Jun 18;6:CD008955 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23775773.
  10. 10.0 10.1 Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996 Jan;14(1):7-17 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8558223.
  11. Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004 Mar 1;10(5):1670-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15014018.
  12. Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000 Jun;18(12):2444-58 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10856105.
  13. Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001 May 1;19(9):2370-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11331315.
  14. Eggermont AM, Suciu S, Testori A, Kruit WH, Marsden J, Punt CJ, et al. Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer 2012 Jan;48(2):218-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22056637.
  15. Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dréno B, et al. Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer 2008 Mar 1;112(5):982-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18236459.
  16. Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998 Jun 27;351(9120):1905-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9654256.
  17. 17.0 17.1 Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 2018 Apr 15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29658430.