Adjuvant Therapy of High-Risk (Stages IIC–IV) Malignant Melanoma in the Post Interferon-Alpha Era: A Systematic Review and Meta-Analysis

Abstract

IntroductionMultiple agents are approved in the adjuvant setting of completely resected high-risk (stages IIC–IV) malignant melanoma. Subgroups may benefit differently depending on the agent used. We performed a systematic review and meta-analysis to evaluate the efficiency and tolerability of available options in the post interferon era across following subgroups: patient age, stage, ulceration status, lymph node involvement, BRAF status.MethodsThe PubMed and Cochrane Library databases were searched without restriction in year of publication in June and September 2020. Data were extracted according to the PRISMA Guidelines from two authors independently and were pooled according to the random-effects model. The predefined primary outcome was recurrence-free survival (RFS). Post-data extraction it was noted that one trial (BRIM8) reported disease-free survival which was defined in the exact same way as RFS.ResultsFive prospective randomized placebo-controlled trials were included in the meta-analysis. The drug regimens included ipilimumab, pembrolizumab, nivolumab, nivolumab/ipilimumab, vemurafenib, and dabrafenib/trametinib. Adjuvant treatment was associated with a higher RFS than placebo (HR 0.57; 95% CI= 0.45–0.71). Nivolumab/ipilimumab in stage IV malignant melanoma was associated with the highest RFS benefit (HR 0.23; 97.5% CI= 0.12–0.45), followed by dabrafenib/trametinib in stage III BRAF-mutant melanoma (HR 0.49; 95% CI= 0.40–0.59). The presence of a BRAF mutation was associated with higher RFS rates (HR 0.30; 95% CI= 0.11–0.78) compared to the wildtype group (HR 0.60; 95% CI= 0.44–0.81). Patient age did not influence outcomes (≥65: HR 0.50; 95% CI= 0.36–0.70, <65: HR 0.58; 95% CI= 0.46–0.75). Immune checkpoint inhibitor monotherapy was associated with lower RFS in non-ulcerated melanoma. Patients with stage IIIA benefited equally from adjuvant treatment as those with stage IIIB/C. Nivolumab/ipilimumab and ipilimumab monotherapy were associated with higher toxicity.ConclusionAdjuvant therapy should not be withheld on account of advanced age or stage IIIA alone. The presence of a BRAF mutation is prognostically favorable in terms of RFS. BRAF/MEK inhibitors should be preferred in the adjuvant treatment of BRAF-mutant non-ulcerated melanoma.

Signal pathways of melanoma and targeted therapy

“… 361 – 363 Although high-dose IFN-α has been approved for the treatment of resected melanoma as adjuvant therapy, the adverse effect is considerable and then is replaced by anti-PD-1 and anti-CTLA-4 immunotherapy. 364 What should be noted is that IFN-α1b is reported to exert a better safety profile compared to IFN-α1a and is more tolerable for melanoma treatment. Prolonged usage of IFN-α1b in patients with unresectable metastatic melanoma has gained encouraging outcome.…”

Ulcerated Cutaneous Melanoma: A Review of the Clinical, Histologic, and Molecular Features Associated with a Clinically Aggressive Histologic Phenotype

“… 50 While targeted therapies for BRAF mutations have shown to increase recurrence-free survival in patients with stage III malignant melanoma, clinical benefit was consistent regardless of ulceration status. 51 …”

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma

“…The median recurrence-free survival (RFS) rate is about 80% at the first year, almost 60% after three years, and 52% at five years [ 23 , 24 ]. Such treatment demonstrated higher 3-years OS-rates than placebo (86% vs. 77% HR 0.57; 95%CI= 0.42–0.79) [ 25 ]. In fact, clinical benefit from dabrafenib/trametinib is consistent regardless of lymph node (LN) involvement or melanoma ulceration, apart from stage IIIA cases where the upper confidence interval is marginally crossed (HR 0.58; 95% CI= 0.32–1.06).…”

“…In fact, clinical benefit from dabrafenib/trametinib is consistent regardless of lymph node (LN) involvement or melanoma ulceration, apart from stage IIIA cases where the upper confidence interval is marginally crossed (HR 0.58; 95% CI= 0.32–1.06). Moreover, adjuvant therapy in non-ulcerated melanomas with macro-metastases is associated with the smallest RFS benefit and does not reach statistical significance (HR 0.73; 95%CI= 0.50–1.05) [ 25 ]. Moreover, after adjuvant therapy for stage III melanoma, the risk of relapse still remains significant, mostly in patients with initially palpable or radiographically detected nodal metastases [ 26 , 27 ].…”