Background
Phase II randomized 3-arm open-label trial (OpACIN-neo), N=86 palpable (macroscopic) resectable stage III cutaneous melanoma. Objective: identify the optimal neoadjuvant ipilimumab + nivolumab schedule balancing pathological response and toxicity. All received 2 cycles neoadjuvant, surgery at week 6, then pathological response assessed. Enrolled 2017-2018 (Netherlands, UK).
Interventions and follow up
Arm A: Ipilimumab 1 mg/kg + nivolumab 3 mg/kg q3wk × 2 cycles → surgery week 6
Arm B: Ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk × 2 cycles → surgery week 6
Arm C: Ipilimumab 3 mg/kg + nivolumab 3 mg/kg q2wk × 2 cycles → surgery week 6
Primary endpoint: Grade ≥3 treatment-related AE rate prior to surgery
mFollow up: 36 months (Nat Med 2021 long-term analysis)
Arm B: Ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk × 2 cycles → surgery week 6
Arm C: Ipilimumab 3 mg/kg + nivolumab 3 mg/kg q2wk × 2 cycles → surgery week 6
Primary endpoint: Grade ≥3 treatment-related AE rate prior to surgery
mFollow up: 36 months (Nat Med 2021 long-term analysis)
Results
pCR (Arm A / B / C): 57% / 57% / 29%
Grade ≥3 AEs (Arm A / B / C): 20% / 20% / 64%
3-yr EFS (pCR/near-pCR vs non-responders, Nat Med 2021): 97% vs 60%
R0 resection rate: >95% across all arms
Grade ≥3 AEs (Arm A / B / C): 20% / 20% / 64%
3-yr EFS (pCR/near-pCR vs non-responders, Nat Med 2021): 97% vs 60%
R0 resection rate: >95% across all arms
Adverse events
Grade ≥3 AEs Arm A / B: 20% each (immune-mediated colitis, hepatitis, endocrinopathy)
Grade ≥3 AEs Arm C: 64%, with surgical delays in 29%
Optimal regimen: Arm B (equivalent pCR to A, higher ipi dose for activation, manageable toxicity)
Grade ≥3 AEs Arm C: 64%, with surgical delays in 29%
Optimal regimen: Arm B (equivalent pCR to A, higher ipi dose for activation, manageable toxicity)
Conclusions
Ipilimumab 3 mg/kg + nivolumab 1 mg/kg × 2 cycles (Arm B) achieved 57% pCR with acceptable toxicity (Grade ≥3 AEs 20%) and was selected as the recommended neoadjuvant dose for phase III (NADINA). Pathological response strongly predicted EFS, with near-universal EFS in pCR/near-pCR patients at 3 years.
Key Limitations
Phase II; no control arm for the key efficacy question (no adjuvant-only comparison). Small sample (N=86 total, ~28 per arm) limits precision. pCR used as a surrogate for long-term survival (validated further by NADINA and SWOG S1801). Not BRAF-stratified at dose selection. Arm B's lower nivo dose (1 mg/kg) differs from the standard metastatic dose; neoadjuvant pharmacodynamics remain under investigation.
Clinical Context
OpACIN-neo identified ipi 3 mg/kg + nivo 1 mg/kg q3wk × 2 cycles as the optimal neoadjuvant regimen for resectable stage III melanoma, directly informing NADINA (phase III). The response-adapted adjuvant paradigm (observation for pCR patients, adjuvant therapy only for non-responders) was validated in NADINA (2024). SWOG S1801 also confirmed neoadjuvant IO superiority using pembrolizumab. Neoadjuvant IO is increasingly preferred over adjuvant-only for resectable stage III melanoma; ESMO endorses neoadjuvant approaches in this setting.