Elsevier

European Journal of Cancer

Volume 86, November 2017, Pages 101-105
European Journal of Cancer

Current Perspective
The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients

https://doi.org/10.1016/j.ejca.2017.09.014Get rights and content

Highlights

  • Adjuvant therapy with nivolumab in stage IIIB/C–IV melanoma patients is superior to adjuvant therapy with ipilimumab.

  • Adjuvant therapy with the combination of dabrafenib and trametinib is superior to placebo in stage IIIA(>1 mm)/B/C melanoma patients.

  • These findings will put an end to the use of adjuvant ipilimumab.

  • Adjuvant interferon remains an option only for patients with ulcerated melanoma.

Abstract

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C–IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node–positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.

Section snippets

Background

The history of establishing effective adjuvant therapies in high-risk melanoma patients until recently has been marred by a lack of drugs that are effective in advanced melanoma [1]. Now that we have active drugs, the situation has changed dramatically. Ugurel et al. [2] published an important 2017-update of the pooled analysis regarding the currently approved active treatment regimens in advanced melanoma. They demonstrated that chemotherapy regimens are least effective, followed by ipilimumab

The 2017 new landscape

The European Organisation for Research and Treatment of Cancer (EORTC) trial 18071 demonstrated in 2015 that ipilimumab adjuvant therapy prolonged relapse-free survival (RFS) significantly, which led to its approval by the Food and Drug Administration in 2015 [3]. In 2016, a similarly significant prolongation of distant metastasis-free survival (DMFS) and overall survival (OS) was shown [4]. Toxicities, especially immune-related adverse events, were significant and led to drug-related deaths in

Nivolumab for all melanoma patients

Nivolumab adjuvant therapy in resected stage IIIB/IIC/IV patients demonstrated in the Checkmate-238 trial clears superiority over adjuvant therapy with ipilimumab [6]. Patients received nivolumab at 3 mg/kg for 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for the first four doses and then every 12 weeks for a total duration of 1 year. The primary end-point was RFS, which was significantly better for nivolumab at 18 months with an RFS of 65% versus 53% for ipilimumab (hazard ratio [HR]: 0.65;

Dabrafenib plus trametinib combination for BRAF-mutant patients

The COMBI-AD trial compared dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) for up to a year with placebo in stage III (IIIA > 1 mm, IIIB/C) patients. Superiority was demonstrated for primary end-point RFS (HR: 0.47; p < 0.00001) and secondary end-points DMFS (HR: 0.51; p < 0.001) and for OS (HR: 0.57; p = 0.0006). RFS rates at 1 year were 88% versus 66%; at 2 years 67% versus 44% and at 3 years 58% versus 39% for the combination and placebo, respectively. Also DMFS

Only a role for IFN in patients with ulcerated melanoma

Approved adjuvant therapies with IFN are high-dose IFN (alfa2b used in the USA and EU), based on the Eastern Cooperative Oncology Group (ECOG) 1684 trial [20]; low-dose IFN (alfa2a used in the EU), based on the French adjuvant trial [21] and pegylated IFN (alfa2b used in the USA and Switzerland), based on EORTC 18991 trial [22], [23]. In the EORTC adjuvant trials 18952 and 18991, patients were stratified by ulcerated or non-ulcerated primary melanoma status, which led to interesting findings

Staging and the importance of CLND in SN-positive patients

The prognosis of SN-positive patients depends on tumour load in the SN and especially on the number of positive nodes identified in completion lymph node dissection (CLND). It has been demonstrated by the DECOG and the MSLT-2 trial that CLND does not improve outcomes [31], [32]. These results will reduce the number of CLNDs but thereby will also lead to a loss of prognostic information that is crucial in making decisions about adjuvant therapy. This will initiate intensive discussions. A

What is next?

Neoadjuvant use of highly active drugs such as nivolumab, or its combination with ipilimumab, and the use of a BRAF/MEK combination is a very attractive research concept for patients with palpable nodal stage III disease. Both approaches have been reported to yield 40–50% pathologic complete responses and overall response rates of close to 100% [33], [34]. Thereby, this approach may facilitate surgery and reduce the indication for radiotherapy and potentially will result in increased

Conflict of interest statement

None declared.

References (35)

Cited by (50)

  • Future Treatments in Melanoma

    2022, Oral and Maxillofacial Surgery Clinics of North America
  • Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial

    2019, European Journal of Cancer
    Citation Excerpt :

    The outcomes of the dermatologic cooperative oncology group (DECOG) and the multicenter selective lymphadenectomy trial II (MSLT-II) trials have demonstrated that CLND does not improve outcome in SN-positive patients [23,24]. It would therefore be logical to conclude that CLND is no longer obligatory for a decision to propose adjuvant therapy [25,26]. Moreover, simplified staging requirements may be achieved by incorporating ulceration status of the primary melanoma into the decision-making [27].

  • Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events

    2019, ESMO Open
    Citation Excerpt :

    They are currently tested in other cancer types, and in (neo)adjuvant settings in earlier stage cancers. Moving these effective therapies towards adjuvant and neoadjuvant approaches in stage III disease in a curative setting makes the need for biomarkers for response and severe AEs even more important.7 68 Unfortunately, there are currently no reliable biomarkers to predict occurrence of severe irAEs in response to CPI therapy.

  • A nomogram to identify high-risk melanoma patients with a negative sentinel lymph node biopsy

    2019, Journal of the American Academy of Dermatology
    Citation Excerpt :

    Melanoma patients with positive SLNBs are considered stage III patients, and despite any other characteristic, their 5-year survival will be 77%.2 In these patients, there is the discussion of whether or not to offer complete lymph node dissection4,18,19 and adjuvant treatments.5,20 However, most melanoma patients will have a negative SLNB, and it is unclear whether they need further treatments and how long they should be followed.3,8,9

View all citing articles on Scopus
View full text