Education and decision-support only — not a medical device or personalised advice. Always discuss your specific situation with your specialist team.

If your oncologist has mentioned immunotherapy, you have probably heard terms like "checkpoint inhibitor", "anti-PD-1", or "CTLA-4 blockade". This article explains what these terms mean in plain language, how these drugs help the immune system fight melanoma, what to expect during treatment, and what questions to ask your specialist.

What are immune checkpoints?

Your immune system has cells called T cells that patrol the body looking for abnormal or foreign cells to destroy. To prevent T cells from attacking healthy tissue, the immune system uses "checkpoint" proteins — molecular switches that tell T cells when to slow down or stop.

Cancer cells are clever. They can hijack these checkpoint switches to hide from T cells. The three checkpoints most important in melanoma treatment are:

  • PD-1 / PD-L1 — a brake on T cell activity. Many melanoma cells express PD-L1 (a protein that binds to PD-1 on T cells), effectively telling T cells "do not attack me."
  • CTLA-4 — a second brake that reduces T cell activation early in the immune response. Like PD-1, tumours can exploit it to evade the immune system.
  • LAG-3 — a third, more recently identified checkpoint. It works alongside PD-1 to suppress T cell function, particularly in tumours that have become resistant to PD-1 blockade.

How do checkpoint inhibitor drugs work?

Checkpoint inhibitor drugs are antibodies (proteins) that block these checkpoint switches, freeing T cells to recognise and attack melanoma cells.

DrugTargetCommon brand nameApproval
PembrolizumabPD-1KeytrudaFDA 2014
NivolumabPD-1OpdivoFDA 2014
IpilimumabCTLA-4YervoyFDA 2011
Nivolumab + relatlimabPD-1 + LAG-3OpdualagFDA 2022

The landmark clinical trials that established these drugs are among the most important in oncology history:

  • Ipilimumab (anti-CTLA-4): the first drug ever to show an overall survival benefit in metastatic melanoma. In the pivotal Phase III trial, 20.8% of patients were alive at 3 years versus 12.2% with the previous standard of care. PMID 20525992A (Grade A, Tier 1)

  • Pembrolizumab (anti-PD-1) vs ipilimumab: pembrolizumab produced a 6-month progression-free survival rate of 47.3% versus 26.5% for ipilimumab, and with fewer severe side effects. This established anti-PD-1 as the preferred single-agent first-line immunotherapy. PMID 25891174 (Grade A, Tier 1)

  • Nivolumab + ipilimumab combination: combining anti-PD-1 and anti-CTLA-4 produced a 5-year overall survival rate of 52% in advanced melanoma — an unprecedented result. The combination causes more side effects than single-agent therapy but is highly effective for patients who can tolerate it. PMID 26027431A (Grade A, Tier 1)

  • Nivolumab + relatlimab (anti-PD-1 + anti-LAG-3): blocking a third checkpoint (LAG-3) alongside PD-1 improved progression-free survival compared to nivolumab alone (median 10.1 vs 4.6 months) in first-line advanced melanoma, with a more manageable side-effect profile than nivolumab + ipilimumab. PMID 34986285A (Grade A, Tier 1)

Who might receive checkpoint inhibitors?

Checkpoint inhibitors are primarily used in Stage III (unresectable) and Stage IV (metastatic) melanoma, and as adjuvant therapy (to reduce recurrence risk) in resected Stage IIB–III disease. Your oncologist will consider:

  • BRAF mutation status: if your tumour has a BRAF V600 mutation, BRAF + MEK targeted therapy is an alternative first-line option. Your oncologist will discuss the pros and cons of starting with immunotherapy versus targeted therapy.
  • Overall health and organ function: checkpoint inhibitors activate the immune system, which can affect any organ. Patients with certain autoimmune conditions or organ transplants may not be suitable candidates.
  • Goals of care: some patients prefer the depth of response seen with combination immunotherapy (nivolumab + ipilimumab) despite higher side-effect risk; others prefer the better tolerability of single-agent therapy.

What are the side effects?

Because checkpoint inhibitors activate the immune system, they can cause inflammation in healthy tissues — called immune-related adverse events (irAEs). These can affect almost any organ:

  • Skin: rash, itching (very common, usually manageable)
  • Bowel: diarrhoea, colitis (can be severe; report promptly)
  • Liver: elevated liver enzymes, hepatitis
  • Lungs: pneumonitis (inflammation; can be serious)
  • Endocrine glands: thyroid dysfunction, adrenal insufficiency, type 1 diabetes (often permanent; treated with replacement hormones)
  • Joints: inflammatory arthritis

Most irAEs respond to corticosteroids if caught early. Report any new symptom promptly — do not wait until your next clinic appointment.

Combination therapy (nivolumab + ipilimumab, or nivolumab + relatlimab) causes more irAEs than single-agent therapy, and they can be more severe. Your team will monitor you closely with regular blood tests.

Questions to ask your oncologist

Bring this list to your next appointment:

  1. Which checkpoint inhibitor(s) are you recommending, and why? Is it single-agent or combination? How does my BRAF status influence this choice?
  2. What are the most common side effects I should watch for? Which symptoms should make me call you straight away?
  3. How often will I have treatment? Pembrolizumab and nivolumab are typically given every 3–6 weeks by infusion.
  4. How will you know if it is working? What scans or blood tests will you use, and when?
  5. What happens if the treatment stops working? What are the next options?
  6. Are there clinical trials I might be eligible for? See our clinical trial finder for current UK/EU trials.
  7. Will I need to stop other medications? Some drugs can interact with checkpoint inhibitors.

Further reading on this platform

References

[1] Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723. PMID 20525992A (Grade A, Tier 1)

[2] Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–2532. PMID 25891174 (Grade A, Tier 1)

[3] Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. PMID 26027431A (Grade A, Tier 1)

[4] Tawbi HA, Schadendorf D, Lipson EJ et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24–34. PMID 34986285A (Grade A, Tier 1)