Adjuvant therapy for high-risk patients with stage IIIA–IIID melanoma shows high efficacy and improves relapse-free survival. |
Adjuvant therapy with nivolumab or pembrolizumab demonstrated a significant prolongation of relapse-free survival while providing a good safety profile for patients with high-risk melanoma. |
Adjuvant therapy with BRAF/MEK inhibitors should be preferred for patients with BRAF-mutant non-ulcerated stage III melanoma. |
1 Introduction
Authors | Trial | Regimen | Patients (N) | AJCC 7th Edition stages | HR RFS | HR OS | 18-months RFS | 3-year RFS |
---|---|---|---|---|---|---|---|---|
Immunomodulatory therapy | ||||||||
Eggermont et al. [46] | EORTC 18071 | Ipilimumab 10 mg/kg vs placebo | 951 | III (> 1 mm) | 0.75 | 0.72 | – | 46.5% vs 34.8% |
Weber et al. [48] | CheckMate 238 | Nivolumab 3 mg/kg vs ipilimumab 10 mg/kg | 906 | IIIB–IIIC/IV | 0.65 | NA | 66.4% vs 52.7% | – |
Eggermont et al. [73] | KeyNote 054 | Pembrolizumab 200 mg vs placebo | 1019 | III (> 1 mm) | 0.57 | NA | 71.4% vs 53.2% | – |
Tarhini et al. [47] | ECOG 1609 | Ipilimumab 10 mg/kg vs Ipilimumab 3 mg/kg vs High-dose IFN-α 2b | 1670 | IIIB, IIIC, IV, M1a-b | 1.0 0.85 (0.66–1.09) | – 0.78 | – 59% 52% | – 53% 46% |
Targeted therapy | 2-year RFS | |||||||
Long et al. [76] | COMBI-AD | Dabrafenib/trametinib vs placebo | 870 | III (LN metastasis > 1 mm) | 0.47 | 0.57 | 67% vs 44% | 58% vs 39% |
Maio et al. [77] | BRIM8 | Vemurafenib vs placebo | 498 | IIC, IIIA, IIIB IIIC | 0.54 | NA | 72.3% vs 56.5% | - |
2 Adjuvant Immunomodulatory Therapy
2.1 Ipilimumab
2.2 Nivolumab
2.3 Pembrolizumab
2.4 Combined Checkpoint-Inhibitor Therapy
3 Adjuvant BRAF/MEK-Directed Targeted Therapy
4 Outlook and Future Concepts
4.1 Adjuvant Therapy for Patients with Stage II Melanoma
4.2 Concepts of Neoadjuvant Melanoma Therapy
Authors | Regimen | Patients (N) | AJCC 7th Edition stages | ORR | RFS | Adverse events (> grade 3 CTCAE) | Other findings |
---|---|---|---|---|---|---|---|
Huang et al. [78] | Neoadjuvant single-dose Pembro, surgery after 3 weeks, adjuvant Pembro for 12 months | 27 | Resectable stage III/IV | pCR 19%; near pCR 11% | Nearly 100% in patients with pCR or near pCR | No irAE > grade 3 reported | Mechanisms of resistance (e.g., immune suppression) |
Amaria et al. [79] [NCT02519322] | Cohort A: neoadjuvant Nivo 3 mg/kg for 4 doses, surgery, adjuvant Nivo 3 mg/kg for 24 weeks (q2w) Cohort B: IPI 3 mg/kg with Nivo 1 mg/kg for up to 3 doses, surgery adjuvant Nivo 3 mg/kg for 24 weeks (q2w) | 23 | Recectable stage III/IV | Cohort A: pCR 25% Cohort B: pCR 45% | Cohort A 56% Cohort B 81% [20 months median follow-up] | Cohort A 8% grade 3 trAE Cohort B 73% grade 3 trAE | Response to ICB was associated with an increased infiltration of TIL and clonal diversity |
Blank et al. [80] [NCT02437279] | Cohort A: surgery, adjuvant IPI 3 mg/kg with Nivo 1 mg/kg for up to 4 doses Cohort B neoadjuvant IPI 3 mg/kg + Nivo 1 mg/kg for up to 2 doses, surgery, adjuvant IPI 3 mg/kg + Nivo 1 mg/kg for up to 2 doses | 20 | Clinical stage III | Cohort B: 78% (pCR 33%, near pCR 33%) | No relapse in patients with pCR/near pCR at 25.6 months follow-up | Nearly 90% grade 3 trAE | Neoadjuvant IPI + Nivo increased infiltration of T-cell clones in TME |
Rozeman et al. [81] [NCT02977052] | Cohort A: neoadjuvant IPI 3 mg/kg + Nivo 1 mg/kg for up to 2 doses (q3w), surgery Cohort B: neoadjuvant IPI 1 mg/kg + Nivo 3 mg/kg for up to 2 doses (q3w), surgery Cohort C: vs IPI 3 mg/kg for up to 2 doses, followed by Nivo 1 mg/kg for up to 2 doses, surgery | 86 | Clinical stage III | Cohort A: 80% Cohort B: 77% Cohort C: 65% | 100% of pCR and near pCR patients on all arms at 8.3 months median follow-up | Cohort A: 40% Cohort B: 20% Cohort C: 50% | High TMB and IFN-γ signature were associated with pathological response and RFS |
Rozeman et al. [81] [NCT02977052] Experimental: PRADO extension cohort | Marker placement in ILN, neoadjuvant IPI 1 mg/kg with Nivo 3 mg/kg for up to 2 doses (q3w), ILN resection after 6 weeks Surgery and adjuvant therapy: •pCR/near pCR no CLND or adjuvant treatment, only follow-up (e.g., CT) •pPR CLND no adjuvant treatment, only follow-up •pNR will undergo CLND and start at week 12 with adjuvant treatment for 52 weeks + follow-up | 144 | III (LN metastasis >1 mm) | 71% pRR the IL, 61% MPR, TLND was omitted in 58 (97%) of the MPR patients | - | 24% | Neoadjuvant treatment induced a high pRR with tolerable toxicity |
Long et al. [82] [NCT01972347] | Neoadjuvant Dab 300 mg with Tram 2 mg daily for 12 weeks, surgery, adjuvant Dab 300 mg with Tram 2 mg daily for 40 weeks | 35 | Resectable IIIB–C | 86% at resection, 46% CR | Median 23 months | 29% | Neoadjuvant TT led to a high proportion of patients with pCR, no PD during neoadjuvant therapy |