2018-19 Section 7-Neoplastic and Inflammatory Diseases of the Head and Neck eBook

A.M.M. Eggermont, R. Dummer / European Journal of Cancer 86 (2017) 101 e 105

Table 1 Crucial adjuvant trials 2016 e 18 determining adjuvant landscape in melanoma. Trial Stage

RFS HR RFS at 2 years DMFS at 2 years OS at 2 years OS at 5 years at 10 years

67 e 44% 23% 52 e 44% 8%

78 e 60% 18% 62 e 53% 9% 71 e 64%

91 e 83% 8% 83 e 76% 7%

COMBI-AD Dabraf þ Tremet versus Pbo (2017) EORTC 18071 Ipi versus Pbo (2015/2016) Checkmate-238 Nivo versus Ipi 2017 EORTC 1325 Pembro versus Pbo 2018 IFN versus observation Meta- analysis

IIIA ( > 1 mm)/IIIB/C 0.47

?

65 e 54% 11%

IIIA > 1 mm/B/C 0.72

67 e 52% 65 e 51% (14%) 60 e 46%

IIIB/C IIIB/C/IV IV

0.65 0.65 0.70

?

?

IIIA ( > 1 mm)/B/C ?

?

?

?

?

II e III All melanomas Non-ulcerated Ulcerated

50 e 46% 4%

70 e 68% 2%

49 e 46% 3%

0.86

0.95 0.79

0% 7%

1% 8% at 5 years 11% at 10 years

RFS, relapse-free survival; DMFS, distant metastasis-free survival; OS, overall surviva; HR, hazard ratio; ipi, ipilimumab; Nivo, nivolumab; Dabraf, dabrafenib; tramet, trametinib; Pbo, placebo; EORTC, European Organisation for Research and Treatment of Cancer; Pembro, pembrolizumab.

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 Z 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, respec- tively. Also DMFS differences were highly impressive at these time points: at 1 year 91% versus 70%; at 2 years 77% versus 60% and at 3 years 71% versus 57%. OS differences were at 1 year 97% versus 94%; at 2 years 91% versus 83% and at 3 years 88% versus 77%. These results are very impressive and are the direct reflection of the results of this combination in stage IV melanoma [2,19] . A comparison between the various trials is made in Table 1 . It shows that the ipilimumab results across the EORTC 18071 and the Checkmate-238 trial are consistent. It also shows that DMFS data across the COMBI-AD trial and the nivolumab data in the Checkmate-238 trial are similar. It therefore seems that a choice between dabrafenib plus trametinib and nivo- lumab in BRAF-mutant patients represents a real choice, where elements such as toxicity profile and the convenience of an oral medication versus a weekly twice intravenous administration of nivolumab will be the reasonable determinants of choice.

EORTC 18991 trial [22,23] . In the EORTC adjuvant trials 18952 and 18991, patients were stratified by ul- cerated or non-ulcerated primary melanoma status, which led to interesting findings regarding the ulcerated melanoma population being the sole one to be interferon sensitive [22 e 26] . This has now been confirmed by the individual pa- tient data meta-analysis of all adjuvant IFN trials comparing IFN with observation [27] . This meta- analysis demonstrates clearly that there is no beneficial effect from adjuvant IFN therapies in patients with non- ulcerated melanomas and that all benefit is observed only in the population with ulcerated melanomas, resulting in absolute OS benefits of 8% at 5 years and 10.5% at 10 years. For the overall patient populations, dose or duration of treatment were not associated with differential benefits, as had been observed also in other meta-analyses [28,29] . The role of adjuvant IFN therapy remains important for all those countries that will have no access to nivolumab or the combination of dabrafe- nib and trametinib. However, it should be clear that IFN therapy should be restricted to patients with ul- cerated melanoma only [30] . 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 de- cisions about adjuvant therapy. This will initiate inten- sive discussions. A potential solution might be to harvest 6. Staging and the importance of CLND in SN-positive patients

5. 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

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