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

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 mel- anoma patients are upon us. ª 2017 Elsevier Ltd. All rights reserved.

1. Background

tumour load the prognosis varies significantly, and for the stage IIIA population with metastasis(es) < 0.1 mm in diameter prognosis may be indistinguishable from SN- negative patients [10 e 13] . These observations led to the decision, to be required in stage IIIA patients, that a metastasis should be > 1 mm in diameter in the EORTC 18071 trial (ipilimumab versus placebo), the EORTC 1325 trial (pembrolizumab versus placebo) and the COMBI- AD trial (D þ T versus placebo). 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 signifi- cantly better for nivolumab at 18 months with an RFS of 65% versus 53% for ipilimumab (hazard ratio [HR]: 0.65; p < 0.0001). Subgroup analyses suggested that patients with PDL1 expression > 5% fared better and derived a greater benefit and that patients with stage IIIB/IIIC also had a slightly better benefit from nivolumab than stage IV patients. Regarding the secondary end-point DMFS, nivolumab was superior to ipilimumab (HR 0.70; p Z 0.0204). The results were not linked to an under- performance of ipilimumab, as the RFS andDMFS curves are very similar to those of the EORTC 18071 trial. This is also clearly illustrated in Table 1 , which provides an overview of all recent randomised trials and the individual patient data meta-analysis of all trials comparing inter- feron (IFN) versus placebo [14] . These findings confirm that from now on, anti-PD1 agents in stage IV melanoma such as nivolumab and pembrolizumab are both superior to ipilimumab for all melanomas, regardless of the BRAF status [2,14,15] . Owing to superior efficacy and signifi- cantly less toxicity, nivolumab replaces ipilimumab in the adjuvant setting [16,17] . In terms of quality-of-life evalu- ations, neither nivolumab nor ipilimumab treatments had a significant impact on the quality of life [6,18] . 3. Nivolumab for all melanoma patients

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 situa- tion has changed dramatically. Ugurel et al. [2] published an important 2017-update of the pooled analysis regarding the currently approved active treatment regi- mens in advanced melanoma. They demonstrated that chemotherapy regimens are least effective, followed by ipilimumab and monotherapy with a BRAF inhibitor and that the most effective therapies were anti-PD1 (mono- therapy or combination therapy with ipilimumab) for all melanoma patients and BRAF þ MEK inhibitor com- binations for BRAF-mutant patients [2] . Beyond 3 years, data suggest that anti-PD1 therapies may be the most effective therapy for all melanoma patients at present. 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 five patients, evoking questions about risk-benefit dis- cussions, especially for stage IIIA patients [5 e 7] . The situation has now been changed radically in re- cord time by the spectacular results reported at the European Society for Medical Oncology (ESMO) 2017 annual meeting regarding the Checkmate-238 trial, comparing nivolumab versus ipilimumab in stage IIIB/ IIIC/IV resected patients, regardless of the BRAF status and the COMBI-AD trial, comparing dabrafenib plus trametinib treatment versus placebo in patients with stage IIIA ( > 1 mm)/B/C) BRAF-mutant mela- noma [6,7] . The stage III patient population is quite heterogeneous, with disease-specific survival rates of 78%, 59% and 40% for stage IIIA, IIIB and IIICmelanoma, respectively [8,9] . As a result, risk-benefit ratios considered acceptable per sub-stage may differ for adjuvant therapies. Even within sentinel node (SN) e positive patients, depending on 2. The 2017 new landscape

4. 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

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