Table 1 |. Summary of key clinical trials of perioperative systemic therapy for melanoma.
| Trial (phase): treatment arms | Disease stage (n) | pRR | RFS/EFSa | DMFS | OS | Refs | |||
|---|---|---|---|---|---|---|---|---|---|
| Adjuvant studies | |||||||||
| EORTC 18071 (III): ipilimumab 10 mg/kg vs placebo, every Q3W for 4 doses, then every 3 months for up to 3 years | IIIA–C (951) | NA | Median: 26.1 vs 17.1 months 1-year: 63.5% vs 56.1% 2-year: 51.5% vs 43.8% 3-year: 46.5% vs 34.8% 5-year: 40.8% vs 30.3% 7-year: 39.2% vs 30.9% HR 0.75, 95% CI 0.63–0.88; P < 0.001 |
Median: 48.3 vs 27.5 months 5-year: 48.3% vs 38.9% 7-year: 44.5% vs 36.9% HR 0.76, 95% CI 0.64–0.90; P = 0.002 |
5-year: 65.4% vs 54.4% 7-year: 60.0% vs 51.3% HR 0.73, 95% CI 0.60–0.89; P = 0.002 |
12,53,54 | |||
| COMBI-AD (III): dabrafenib 150 mg BID plus trametinib 2 mg QD vs placebo for up to 1 year | IIIA–C (BRAFV600 mutant; 870) | NA | Median: NR (mFU 60 months) vs 16.6 months 1-year: 88% vs 56% 2-year: 67% vs 44% 3-year: 59% vs 40% 4-year: 55% vs 38% 5-year: 52% vs 36% HR 0.51, 95% CI 0.42–0.61; P value NA |
Median: NR 1-year: 91% vs 70% 2-year: 77% vs 60% 3-year: 71% vs 57% 4-year: 67% vs 56% 5-year: 65% vs 54% HR 0.55, 95% CI 0.44–0.70; P value NA |
1-year: 97% vs 94% 2-year: 91% vs 83% 3-year: 86% vs 77% HR 0.57, 95% CI 0.42–0.79; P = 0.0006 |
3,55,56 | |||
| CheckMate 238 (III): nivolumab 3 mg/kg Q2W vs ipilimumab 10 mg/kg Q3W for 4 doses, then every 3 months for up to 1 year | IIIB–IV (906) | NA | Median: 52.4 vs 24.1 months 1-year: 70.5% vs 60.8% 2-year: 62.6% vs 50.2% 3-year: 58% vs 45% 4-year: 51.7% vs 41.2% HR 0.71, 95% CI 0.60–0.86; P = 0.0003 |
Median: NR (mFU 51.1 months) vs 52.9 months 1-year: 80.2% vs 73.4% 2-year: 70.5% vs 63.7% 4-year: 59.2% vs 53.3% HR 0.79, 95% CI 0.63–0.99; P value NA |
4-year: 77.9% vs 76.6% HR 0.87, 95% CI 0.66–1.14; P = 0.31 |
6,57 | |||
| KEYNOTE-054 (III): pembrolizumab 200 mg vs placebo Q3W for up to 18 doses | IIIA–C (1,019) | NA | Median: NA 1-year: 75.4% vs 60.2% 2-year: 68.3% vs 47.1% 3-year: 63.7% vs 44.1% 3.5-year: 59.8% vs 41.4% HR 0.59, 95% CI 0.49–0.70; P < 0.0001 |
Median: NA 3.5-year: 65.3% vs 49.4% HR 0.60, 95% CI 0.49–0.73; P < 0.0001 |
NA | 2,58,59 | |||
| IMMUNED (III): nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W (followed by nivolumab 3 mg/kg Q2W) vs nivolumab 3 mg/kg Q2W vs placebo for up to 1 year | IV (167) | NA | Median: NR (mFU 28.4 months) vs 12.4 vs 6.4 months 1-year: 75% vs 52% vs 32% 2-year: 70% vs 42% vs 14% HR for combination vs placebo 0.23, 97.5% CI 0.12–0.45; P < 0.0001 HR for monotherapy vs placebo 0.56, 97.5% CI 0.33–0.94; P = 0.011 |
NA | NA | 7 | |||
| CheckMate 915 (III): nivolumab 240 mg Q2W + ipilimumab 1 mg/kg Q6W vs nivolumab 480 mg Q4W for up to 1 year | IIIB–IV (1,844) | NA | Median: NR 2-year: 64.6% vs 63.2% HR 0.92, 97.295% CI 0.77–1.09; P = 0.269 |
Median: NR 2-year: 75.4% vs 77.4% HR 1.01, 95% CI 0.83–1.23 |
NA | 23 | |||
| KEYNOTE-716 (III): pembrolizumab 200 mg or placebo Q3W for up to 1 year | IIB/C (976) | NA | Median: NR 1-year: 90.5% vs 83.1% HR 0.65, 95% CI 0.46–0.92; P = 0.0066 1.5-year: 85.8% vs 77.0% HR 0.61, 95% CI 0.45–0.82; P value NA |
NA | NA | 4,5 | |||
| Neoadjuvant studies | |||||||||
| NeoCombi (II): dabrafenib 150 mg BID plus trametinib 2 mg QD as neoadjuvant therapy for 12 weeks and as adjuvant therapy for 40 weeks | IIIA–B (BRAFV600 mutant; 35) | 100% (pCR 49%) | Median: 23.3 months (30.6 months in patients with a pCR vs 18.0 months in those with a non-complete pathological response) 1-year RFS: 77.1% (82.4% vs 72.2%) 2-year RFS: 43.4% (63.3% vs 24.4%) |
Median: 30.6 months; 38.0 months in patients with a pCR vs 27.7 months in those with a non-complete pathological response (P = 0.58) | Median: NR (mFU 27 months) 1-year: 100% 2-year: 93.8% |
60 | |||
| OpACIN (Ib): nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W (2 neoadjuvant + 2 adjuvant cycles, or 4 adjuvant cycles only) | IIIB/C (20) | 78% in 9 evaluable patients (pCR 33%; pnCR 33%; pPR 11%) | Median: NR (mFU 4 years in responders) 3-year RFS: 80% (vs 60% in 10 patients in adjuvant-only group) 4-year RFS: 60% (in both groups) 3-year EFS: 80% (vs 60%) 4-year EFS: 80% (vs 60%) |
NA | 3-year: 90% (vs 70% in adjuvant-only group) 4-year: 90% (vs 70%) |
10,24 | |||
| OpACIN-neo (II): 2 cycles of nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W (group A) vs nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W (group B) vs 2 cycles of ipilimumab 3 mg/kg Q3W followed by 2 cycles of nivolumab 3 mg/kg Q2W (group C) | IIIA–C (group A 30; group B 30; group C 26) | Group A: 80% (pCR 47%; pnCR 23%; pPR 10%) Group B: 77% (pCR 57%; pnCR 7%; pPR 13%) Group C: 65% (pCR 23%; pnCR 23%; pPR 19%) |
Median: NR (mFU 2 years) 1-year RFS: 85.5% for all patients (90.0%, 82.8% and 83.3% for groups A, B and C, respectively); 96.9% for responders and 47.7% for non-responders 2-year RFS: 83.6% for all patients (90.0%, 77.6% and 83.3% for groups A, B and C, respectively); 96.9% for responders and 35.5% for non-responders 1-year EFS: 83.7% (90.0%, 80.0% and 80.8% for groups A, B and C, respectively) 2-year EFS: 81.7% (90.0%, 74.3% and 80.7% for groups A, B and C, respectively) |
NA | 1-year: 97.7% (93.3%, 100% and 100% in groups A, B and C, respectively) 2-year: 94.8% (93.3%, 95.5% and 96.2% in groups A, B and C, respectively) |
10,25 | |||
| NCT02519322 (II): nivolumab 480 mg +relatlimab 160 mg in weeks 1 and 5 (with surgery at week 9, followed by up to 10 additional adjuvant doses) | IIIA–IV (30) | 73% (pCR 59%; pnCR 7%; pPR 7%) | Median: NR (mFU 16.2 months) 1-year RFS: 93%; 100% for MPR group vs 80% for non-MPR group (P = 0.016) 1-year EFS: 90% |
NA | 1-year: 95% | 11 | |||
BID, twice daily; DMFS, distant metastasis-free survival; EFS, event-free survival; mFU, median follow-up; MPR, major pathological response; n, number of patients; NA, not available/applicable; NR, not reached; OS, overall survival; pCR, pathological complete response; pnCR, pathological near-complete response; pPR, pathological partial response; pRR, pathological response rate; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; Q6W, every 6 weeks; QD, once daily; RFS, relapse-free survival.
a
For neoadjuvant studies only; this end point captures patients with disease progression prior to surgery.