Neoadjuvant immunotherapy in melanoma
Neoadjuvant ICI; pre-operative checkpoint inhibitor; S1801; NADINA; PRADO
Neoadjuvant (pre-operative) immune checkpoint inhibitor therapy in resectable stage III melanoma is one of the most significant paradigm shifts in melanoma management since the introduction of adjuvant ICI. The S1801 trial (Patel et al., NEJM 2023) demonstrated that 3 cycles of neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab significantly improves event-free survival compared with surgery followed by 18 cycles of adjuvant pembrolizumab alone. The NADINA trial (Blank et al., NEJM 2024) extended this with neoadjuvant ipilimumab + nivolumab achieving pathological complete response rates of ~ 50% and a markedly improved 12-month EFS. UK NHS England commissions a neoadjuvant pembrolizumab pathway for clinically resectable macroscopic stage IIIB–D disease, delivered through specialist MDT governance. PRADO and other trials are refining personalised therapy by pathological response.
Rationale
- Pre-operative ICI exposes a much larger tumour antigen burden to the immune system, expanding the polyclonal T-cell response and seeding immunological memory before surgery removes the antigen reservoir.
- Animal-model and translational data — pre-operative ICI generates broader and more durable anti-tumour T-cell responses than equivalent dosing after surgery.
- Clinical hypothesis tested in S1801 and NADINA — neoadjuvant ICI improves outcomes vs identical / longer adjuvant ICI.
S1801 (neoadjuvant pembrolizumab)
- Patel et al., NEJM 2023. 313 patients with resectable stage IIIB–IV melanoma randomised to:
- Neoadjuvant arm — 3 cycles of pembrolizumab → surgery → 15 cycles adjuvant pembrolizumab.
- Adjuvant arm — surgery → 18 cycles adjuvant pembrolizumab.
- Same total drug exposure; only the timing differs.
- 2-year event-free survival 72% vs 49% (HR 0.58); statistically and clinically significant.
- Surgery was not delayed or compromised by neoadjuvant therapy.
- UK adoption — basis of the NHS England neoadjuvant pembrolizumab pathway for stage IIIB–IIID melanoma.
NADINA (neoadjuvant ipi + nivo)
- Blank et al., NEJM 2024. 423 patients with resectable stage III melanoma randomised to:
- Neoadjuvant arm — 2 cycles ipilimumab + nivolumab → surgery → response-adapted adjuvant therapy.
- Standard arm — surgery → 12 cycles adjuvant nivolumab.
- 12-month EFS 83.7% vs 57.2% (HR 0.32); pathological complete response ~ 47% (major pathological response ~ 57%) in neoadjuvant arm.
- Patients with pathological complete response receive no further adjuvant therapy (tailored).
- Patients with residual viable tumour receive adjuvant nivolumab ± dabrafenib + trametinib (BRAF-mutant).
- Treatment-related Grade ≥ 3 AEs in 30% — within acceptable range for combination ICI.
- UK access — under specialist commissioning consideration; trial unit availability.
PRADO and response-adapted therapy
- PRADO trial (Reijers, Nat Med 2022) — pioneered personalised post-neoadjuvant management based on pathological response.
- Patients with major pathological response (≤ 10% viable tumour) received no further therapy (avoiding completion lymph-node dissection).
- Patients with partial response or non-response received completion lymph-node dissection ± adjuvant ICI / targeted therapy.
- 2-year RFS in major-pathological-response cohort 93%.
- Underpins the response-adapted approach in NADINA.
Current UK practice
- NHS England commissioning — neoadjuvant pembrolizumab pathway for resectable macroscopic stage IIIB–IIID melanoma.
- Regimen — pembrolizumab 200 mg IV q3w × 3 neoadjuvant doses → surgery within 3–5 weeks → resume adjuvant pembrolizumab as soon as safely possible and within 3 months, usually 15 further q3w doses or 7 q6w doses, to complete 54 weeks total treatment.
- Eligibility — macroscopic resectable stage IIIB–D, no prior immunotherapy, ECOG PS 0–1, complete surgical resection achievable within 3–5 weeks.
- MDT pathway — oncology review before surgery; refer to the melanoma MDT for neoadjuvant consideration when macroscopic stage IIIB–D disease is identified.
- Pathology — pathological response assessment in resection specimens (major pathological response = ≤ 10% viable tumour; partial response 11–50%; non-response > 50%).
- Combination ipi + nivo neoadjuvant — specialist trial / compassionate-use access; not yet routinely commissioned.
References
- Patel SP et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma (S1801). N Engl J Med; 2023;388:813–23.
- Blank CU et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma (NADINA). N Engl J Med; 2024;391:1696–708.
- Reijers ILM et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma (PRADO). Nat Med; 2022;28:1178–88.
- Long GV et al. Neoadjuvant immunotherapy in melanoma. Nat Rev Clin Oncol; 2024.
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