A New Era of Proactive Melanoma Therapy: Hit Hard, Hit Early

L. Haas; T. Wiesner; A. C. Obenauf

Disclosures

The British Journal of Dermatology. 2018;178(4):817-820. 

In This Article

Adjuvant Therapy

With this study, Wolchok et al.[1] fortified the central therapeutic position of immunotherapy for patients with unresectable melanoma. To establish the value of targeted and immunotherapies in adjuvant settings, the two other studies in the NEJM by Weber et al. and Long et al. investigated their use in patients with completely resected melanoma.[2,3] The mechanistic rationale comes from our awareness that invasive and motile tumour cells often enter circulation long before the tumour gets diagnosed. The disseminated tumour cells are not eradicated by the surgical removal of the primary tumour or the regional lymph nodes, and may survive for years in a dormant state or as subclinical micrometastases in distant organs. After months or years of dormancy, evolution and adaption, some tumour cells may resume proliferation and form clinically detectable macrometastases.[5,16]

Adjuvant therapies aim to tackle this problem at its roots, and target disseminated cells before they establish clinically relevant metastasis, irrespectively of their anatomic location. Therapies in adjuvant settings have qualitative (less well–adapted tumour cells that have not yet acquired traits of drug resistance) and quantitative (lower number of cancer cells) advantages over therapies in metastatic settings. This logic is supported by the clinical observation that patients with a low disease burden (less than three organ sites containing metastases) and low lactate dehydrogenase levels often show more durable responses and long–term survival on targeted therapy.[9,10]

In the CheckMate 238 trial, Weber et al.[2] compared nivolumab in adjuvant settings to ipilimumab, which was approved for adjuvant therapy in 2015. In this phase III trial, more than 900 melanoma patients with complete resection in stage IIIB, IIIC and IV were randomly assigned to receive either nivolumab or high–dose ipilimumab for 12 months. At 18 months, the rate of recurrence–free survival was higher in the nivolumab vs. the ipilimumab group (66% and 53%, respectively). Median relapse–free survival had not been reached in either treatment group. In the nivolumab group, 61% of patients completed the therapy vs. 27% in the ipilimumab group, mainly because nivolumab was better tolerated (14% vs. 46% of patients experienced treatment–related grade 3 or 4 adverse events, respectively). In conclusion, the reduced toxicity and an increase in relapse–free survival clearly favours the use of nivolumab over ipilimumab in adjuvant settings.

In the COMBI–AD trial, Long et al.[3] investigated whether adjuvant treatment with RAFi (dabrafenib) and MEKi (trametinib) would improve the outcome in patients with resected stage III BRAF–mutated melanoma. In this phase III trial, 870 patients were randomly assigned to receive either dabrafenib plus trametinib or placebo for 12 months. At a median follow–up of 2·8 years, the treatment group had a 53% lower risk of relapse than the placebo group. The estimated relapse–free survival at 3 years was 58% in the treatment group vs. 39% in the placebo group. The 3–year overall survival rate was 86% in the therapy group and 77% in the placebo group. Although these results are encouraging, it should be noted that treatment–related grade 3 or 4 adverse events occurred in 41% of patients in the dabrafenib plus trametinib group. A quarter of patients stopped treatment because of adverse effects. This dropout rate is higher than in previous trials with metastatic melanoma, likely as a result of reduced willingness to tolerate side–effects in adjuvant settings. Despite the adverse events, the 53% lower risk of relapse might justify adjuvant MAPKi therapy for patients at high risk for metastasis.

The revival of adjuvant therapy becomes even more relevant in light of the Multicenter Selective Lymphadenectomy Trial I (MSLT–I) and MSLT–II. MSLT–I confirmed the prognostic value of sentinel–node biopsies, but did not show a treatment–related difference in melanoma–specific survival.[17] The recently published follow–up, MSLT–II, reported that immediate complete lymph node dissection did not increase melanoma–specific survival for patients with sentinel–node metastasis, compared with active ultrasonographic surveillance of the nodal basin.[18] Although both of these studies establish the detection of disseminated cancer cells as a biomarker for poor outcome, they show that immediate complete lymph node dissection does not achieve any therapeutic benefit. For patients with poor prognosis, adjuvant therapies might thus be a valuable treatment option.

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