Pembrolizumab

Mechanism of action

PD-1 is an inhibitory receptor on activated T-cells. Tumours that express PD-L1 (or PD-L2) ligate PD-1 to suppress T-cell function — a major immune escape mechanism. Pembrolizumab binds PD-1, blocking ligation by PD-L1 / PD-L2 and restoring effector T-cell activity against tumour cells. Response correlates loosely with PD-L1 expression, mismatch-repair deficiency and tumour mutational burden.

UK skin cancer indications

Always check the current NICE / NHS England page for the indication being prescribed — commissioning criteria are refined iteratively.

Adjacent (non-skin) context: NICE recommends pembrolizumab for two mucosal head & neck squamous cell carcinoma indications: TA661 (untreated metastatic or unresectable recurrent HNSCC) and TA1145 (21 April 2026 — neoadjuvant monotherapy followed by adjuvant pembrolizumab with radiotherapy ± cisplatin for resectable locally advanced HNSCC with PD-L1 CPS ≥ 1). These are mucosal H&N indications outside the skin-oncology remit but relevant context for clinicians who manage both cutaneous and mucosal head-and-neck disease.

Neoadjuvant + adjuvant pembrolizumab for stage III melanoma (NHS England URN 2426)

From 28 April 2026, NHS England routinely commissions a neoadjuvant followed by adjuvant pembrolizumab regimen for macroscopic resectable stage IIIB–D melanoma. This is an off-label use (pembrolizumab is licensed only for adjuvant melanoma) but is NHS-funded under URN 2426. The evidence base is SWOG S1801 (Patel et al, NEJM 2023) — a phase II, open-label, randomised trial in 313 patients showing 2-year event-free survival 72% in the neoadjuvant–adjuvant arm vs 49% in the adjuvant-only arm (difference 23%; p = 0.0045), without additional grade 3/4 toxicity attributable to the neoadjuvant doses.

Eligibility

• Age ≥ 12 years.
• Histologically confirmed cutaneous, acral or mucosal melanoma.
• Macroscopic, resectable stage IIIB, IIIC or IIID — includes patients whose disease was initially I–IIIA and has now progressed to IIIB–D.
• Complete surgical resection plus therapeutic lymph node dissection planned within 3–5 weeks of the last neoadjuvant dose.
• Adjuvant pembrolizumab expected to start within 3 months of surgery.
• ECOG performance status 0 or 1.
• No previous anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 therapy.

Exclusions

• Uveal melanoma.
• Microscopic nodal disease (stage IIIB or IIIC detected on SLNB only, without macroscopic / palpable / radiologically visible nodes) — these patients remain on the adjuvant-only pathway (TA766 pembrolizumab or TA684 nivolumab).
• Previous immunotherapy for melanoma.
• Surgical resection not planned at initial diagnosis or at first detected nodal disease.
• SmPC contraindications.

Regimen (adults)

• Neoadjuvant: pembrolizumab 200 mg IV every 3 weeks × 3 doses.
• Surgery: complete resection + therapeutic lymph node dissection within 3–5 weeks of the last neoadjuvant dose.
• Adjuvant: resume pembrolizumab as soon as safely possible after surgery (and within 3 months) at 200 mg every 3 weeks × 15 doses (or 400 mg every 6 weeks × 7 doses) — 54 weeks total treatment in the NHS England URN 2426 policy, starting with 3 neoadjuvant three-weekly doses before surgery.
• Children (≥ 12 years): 2 mg/kg (max 200 mg) IV every 3 weeks for the neoadjuvant phase; resume adjuvant after surgery to complete approximately 1 year of total treatment.
• Stop for completion of the protocol, distant disease progression, unacceptable toxicity, or patient withdrawal.

Governance

Initiate and supervise within a specialised centre under MDT supervision, by an oncologist trained and accredited in SACT with melanoma / immunotherapy experience. Baseline FBC, U&E, LFT, TFT, blood glucose and ECG. Formal medical review by the start of the third (3-weekly) neoadjuvant cycle. Register all patients via prior approval software.

Dosing

• Standard: 200 mg IV every 3 weeks, OR 400 mg IV every 6 weeks.
• Infusion over 30 minutes.
• Adjuvant melanoma: 12 months (or until recurrence / unacceptable toxicity).
• Metastatic: until progression or unacceptable toxicity (typically up to 2 years in responders).

Immune-related adverse events (irAEs)

The trade-off for ICI efficacy is autoimmune toxicity. irAEs can affect any organ, develop at any time during or after therapy, and may persist permanently.

Management principles

• Grade 1: continue, monitor.
• Grade 2: hold ICI; consider corticosteroids.
• Grade 3–4: stop ICI; high-dose corticosteroids; specialist input; second-line immunosuppressants if refractory.
• Most irAEs (except endocrinopathies) resolve with corticosteroids and ICI cessation.
• Endocrinopathies usually require lifelong replacement.
• Discuss rechallenge after grade 2–3 irAE; never re-challenge after life-threatening irAE.

Practical considerations

• Baseline: full blood count, U&E, LFT, TFT, glucose, cortisol, CK; pregnancy test if applicable.
• Ongoing: check FBC, U&E, LFT, TFT before each cycle; symptom-directed broader work-up.
• Solid organ transplant recipients: significant organ-specific graft-rejection risk — kidney ~40–50%, liver ~30%, heart less well characterised but substantial. Use only with multidisciplinary transplant-team consensus and an explicit pre-treatment discussion of allograft loss as a likely outcome.
• Autoimmune disease: relative contraindication; case-by-case decision based on severity and reversibility of the autoimmune disease.
• Pregnancy: avoid; counsel on contraception during and 4 months after.
• Patient should carry an alert card identifying ICI therapy.