Systemic Therapy of Metastatic Melanoma: On the Road to Cure
Abstract
:Simple Summary
Abstract
1. Introduction
2. Material and Methods
3. Immune Checkpoint Inhibitors
Trial (NCT n°) | Agents/dose (mg/kg or mg/m2) | Phase | Patients | N | Prim. EP | ORR, % | PFS Med, mts (HR [95%CI]) | OS Med, mts (HR [95%CI]) | Ref. |
---|---|---|---|---|---|---|---|---|---|
Anti-CTLA-4 directed Immunotherapy | |||||||||
MDX010-020 (NCT00094653) | Ipi 3 + gp100 vs. Ipi 3 vs. gp100 (3:1:1) | III | Unresectable Stage III/IV, pre-treated, HLA-A*0201–pos. | 676 | OS | 6 vs. 11 vs. 2 | 2.8 vs. 2.9 vs. 2.8 (0.64 [0.50–0.83]) | 10.0 vs. 10.1 vs. 6.4 (0.66 [0.51–0.87] a | [16] |
Anti-PD-1-directed Immunotherapy (Immune Checkpoint Inhibition mono, or in combination with an anti-CTLA-4 antagonist) | |||||||||
CM-066 (NCT01721772) | Niv 3 q2w + Placebo vs. Placebo + Dacarbazine 1000 q3w (1:1) | III | Metastatic, untreated, BRAF WT | 418 | OS | 40 vs. 14 | 5.1 vs. 2.2 (0.43 [0.34–0.56]) | 37.5 vs. 11.2 (0.46 [0.36–0.59]) | [24,25] |
CM-067 (NCT01844505) | Niv 1 +Ipi 3 (q3w) x4 → Niv 3; Niv 3 alone q2w, vs. Ipi 3 q3w x4 (1:1:1) | III | Unresectable Stage III/IV, untreated | 945 | PFS and OS (co-primary) | 58 vs. 44 vs. 19 | 11.5 vs. 6.9 vs. vs. 2.9 (0.42 b [0.31–0.57]) c; (0.57 b [0.43–0.76]) d | [26,27] | |
CM-511 (NCT02714218) | Niv 1 +Ipi 3 (q3w) x4 → Niv 3 vs. Niv 3 +Ipi 1 (q3w) x4 → Niv 3 (1:1) | III | Unresectable Stage III/IV, untreated | 360 | TRAE rate (grade 3–5) | TRAE: 48 vs. 34 | 8.9 vs. 9.9 (1.06 [0.79–1.42]) | NR vs. NR (1.09 [0.73–1.62]) | [28] |
CM-003 (NCT00730639) | Niv 0.1 vs. Niv 0.3 vs. Niv 1 vs. Niv 3 vs. Niv 10 (all q2w) | I | 1–5 prior systemic therapies (ocular melanoma allowed) | 107 | Safety, ORR | 35 vs. 29 vs. 31 vs. 41 vs. 20 | 3.6 vs. 1.9 vs. 9.1 vs. 9.7 vs. 3.7 | 16.2 vs. 12.5 vs. 25.3 vs. 20.3 vs. 11.7 | [29] |
KN-006 (NCT1866319) | Pem 10 q2w vs. Pem 10 q3w vs. Ipi 3 q3w (1:1:1) | III | Unresectable Stage III/IV, ≤1 prior systemic therapy, Ipi-naïve | 834 | PFS & OS (co-primary) | 34 vs. 33 vs. 12 | 8.4 vs. 3.4 (0.57 [0.48–0.67]) e | 32.7 vs. 15.9 (0.73 [0.61–0.88]) e | [30] |
KN-001 (NCT01295827) | Pem 2 q3w/Pem 10 q3w/Pem 10 q2w | IB | Advanced or metastatic, pre- or untreated | 655 | ORR | 41 (52, if untreated) | 8.3 (16.9 in the 151 untreated patients) | 23.8 (38.6 in the 151 untreated patients) | [31] |
Herpes simplex virus-1 derived Oncolytic virus | |||||||||
OPTiM (NCT00769704) | Tal (106 pfu/mL →106 pfu/mL q3w i.l.) vs. GM-CSF 125 µg/m2 (2:1) | Unresectable Stage IIIB/IV M1c, ≥1 sub-/cutaneous lesion 10 mm | 436 | DRR (16 vs. 2) | DRR: 19% vs. 1% | nr | 23.3 vs. 18.9 (0.79 [0.62–1.00]) | [32] | |
Targeted therapy (BRAF mono) 16 vs. 2 | |||||||||
BRIM-3 (NCT01006980) | Vem 960 mg td vs. DTIC (1:1) | III | Metastatic, untreated, BRAFV600E-mut. | 675 | PFS & OS (co-primary) | 48 vs. 5 | 5.3 vs. 1.6 (0.26 [0.20–0.33]) | NR vs. 7.9 (0.37 [0.26–0.55]) | [33] |
Combined BRAF+MEK blockade | |||||||||
COMBI-v (NCT01597908) | Dab 150 bd + Tra 2 od vs. Vem 960 bd (1:1) | III | Metastatic, untreated, BRAFV600E/K-mut. | 704 | OS | 64 vs. 51 | 11.4 vs. 7.3 (0.56 [0.46–0.69]) | NR vs. 17.2 (0.69 [0.53–0.69]) | [34,35] |
COMBI-d (NCT01584648) | Dab 150 bd + Tra 2 od vs. Dab 150 bd (1:1) | III | Unresectable Stage IIIC/IV, untreated, BRAFV600E/K-mut. | 423 | PFS | 69 vs. 53 | 11.0 vs. 8.8 (0.67 [0.53–0.84]) | 25.1 vs. 18.7 (0.71 [0.55–0.92]) | [35,36] |
CoBRIM (NCT01689519) | Cob 60 od d1-21 + Vem 960 bd vs. Vem 960 bd + Placebo (1:1) | III | Unresectable Stage IIIB–IV, untreated, BRAF V600-mut. | 495 | PFS | 68 vs. 45 | 9.9 vs. 6.2 (0.51 [0.39–0.68]) | 22.3 vs. 17.4 (0.70 [0.55–0.90]) | [37,38] |
COLUMBUS (NCT01909453) | Enc 450 od + Bin 45 mg bd vs. Enc 300 mg od vs. Vem 960 mg bd (1:1:1) | III | Unresectable Stage IIIB–IV, un-treated (or progressed after first-line IT), BRAFV600E/K-mut. | 577 | PFS | 63 vs.51 vs. 40 | 14.9 vs. × 9.6 vs. 7.3 (0.54 [0.41–0.71] f | 33.6 vs. 23.5 vs. 16.9 (0.61 [0.47–0.79] f | [39,40] |
NEMO (NCT01763164) | Bin 45 bd vs. Dacarbazine 1000 | III | Unresectable Stage IIIB–IV, un-treated (or progressed after first-line IT), NRASV600E/K-mut. | 402 | PFS | 15 vs. 7 | 2.8 vs. 1.5 (0.62 [0.47–0.80]) | 11.0 vs. 10.1 (1.00 [0.75–1.33]) | [41] |
Triplett therapy (ICI + BRAF/MEK-blockade) | |||||||||
IMSpire150 (NCT02908672) | Ate 840 d1,15 + Vem 720 bd + Cob 60 od d1-21 vs. Placebo + Vem 960 bd + Cob 60 od d1-21 (all: q4w) | III | Untreated, BRAF-mut. | 514 | PFS | 66 vs. 65 | 15.1 vs. 10.6 (0.78 [0.63–0.97]) | not yet reached/reported | [42] |
COMBI-I (NCT02967692) | Spa 400 mg + Dab 150 bd + Tra 2 od vs. Placebo + Dab 150 + Tra 2 (q4w) | III | Unresectable Stage IIIB–IV, untreated, BRAF V600-mut. | 532 | PFS | 16.2 vs. 12.0 (0.82 [0.66–1.03]) | NR vs. NR (0.79 [0.59–1.05]) | [43] |
3.1. Anti-PD-1 Directed Monoclonal Antibodies
Summary
3.2. Combination of Anti-PD-1 with Anti-CTLA-4 Monoclonal Antibodies
3.2.1. Dosage Regimen of the Combined Therapy
3.2.2. Summary
3.3. Resistance
3.4. Duration of Therapy
3.5. Immune-Related Adverse Events
4. T-VEC
Summary
5. Targeted Therapy
5.1. Dabrafenib + Trametinib
5.2. Cobimetinib + Vemurafenib
5.3. Encorafenib + Binimetinib
5.4. Comparative-Effectiveness of BRAF/MEK Inhibitors
5.5. Duration of Therapy
5.6. Summary
6. Sequencing and Combinations of BRAF/MEK Inhibitors and Immune Checkpoint Inhibitors
6.1. Mode of Action
6.2. First-Line BRAF/MEK Inhibitors versus Immune Checkpoint Inhibitors
6.3. Novel Sequencing Approaches for BRAF/MEK Inhibitors and Immune Checkpoint Inhibitors
6.4. Novel Combinations of BRAF/MEK Inhibitors and Immune Checkpoint Inhibitors
6.5. Combination of Targeted Therapy with ICIs in BRAF-Wildtype Melanoma
6.6. Summary
7. Novel Drugs and Combinations
7.1. Introduction
7.2. Exploration of Novel Immunotherapeutic Targets: gp100
7.3. Adoptive T Cell Transfer
7.4. Summary
8. Outlook: Treatment of Melanoma Brain Metastases (MBM)
8.1. Dabrafenib Combined with Trametinib
8.2. Nivolumab Combined with Ipilimumab
8.3. Combination of Systemic Therapy and Radiosurgery
8.4. Combination of Targeted Therapy with Immune Checkpoint Inhibitors
8.5. Intrathecal Immunotherapy
8.6. Summary
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Steininger, J.; Gellrich, F.F.; Schulz, A.; Westphal, D.; Beissert, S.; Meier, F. Systemic Therapy of Metastatic Melanoma: On the Road to Cure. Cancers 2021, 13, 1430. https://doi.org/10.3390/cancers13061430
Steininger J, Gellrich FF, Schulz A, Westphal D, Beissert S, Meier F. Systemic Therapy of Metastatic Melanoma: On the Road to Cure. Cancers. 2021; 13(6):1430. https://doi.org/10.3390/cancers13061430
Chicago/Turabian StyleSteininger, Julian, Frank Friedrich Gellrich, Alexander Schulz, Dana Westphal, Stefan Beissert, and Friedegund Meier. 2021. "Systemic Therapy of Metastatic Melanoma: On the Road to Cure" Cancers 13, no. 6: 1430. https://doi.org/10.3390/cancers13061430