Teaching pack: Melanoma

Melanoma arises from pigment cells and is the deadliest skin cancer, though most cases are cured by excision when found early. Risk is driven by ultraviolet exposure and fair skin; the tumour carries the highest mutation burden of any common cancer, which is why it became the proving ground for immunotherapy. About half of cutaneous melanomas carry BRAF V600 mutations, a quarter NRAS, and acral and mucosal subtypes carry KIT alterations; uveal melanoma is a distinct disease driven by GNAQ/GNA11 and BAP1.

The treatment revolution began in 2011 with ipilimumab and vemurafenib and accelerated with PD-1 blockade (2014). Nivolumab-ipilimumab now delivers ~50% melanoma-specific survival at ten years in advanced disease (CheckMate 067), pembrolizumab 34% overall survival at ten years (KEYNOTE-006), and nivolumab-relatlimab offers a gentler doublet. For BRAF-mutant disease, DREAMseq settled that immunotherapy should come first. In resectable stage III disease, NADINA and SWOG S1801 moved immunotherapy to before surgery with response-adapted follow-on treatment, and adjuvant PD-1 or BRAF/MEK covers stage IIB-III. After immunotherapy fails, lifileucel TIL therapy (2024) and the oncolytic virus RP1 with nivolumab (2026) are approved; tebentafusp is the first survival-extending drug in metastatic uveal melanoma. Intismeran autogene plus pembrolizumab became the first personalised mRNA vaccine to pass a phase 3 in August 2026.

• 10-year survival ~50% with IO doublet.
• First cell therapy for a solid tumour.
• First positive phase 3 personalised vaccine.
• About half of patients with advanced melanoma treated with nivolumab-ipilimumab are alive at ten years, and a third of those on pembrolizumab; durable remissions persist off treatment.
• Neoadjuvant immunotherapy with response-adapted follow-on treatment (NADINA, SWOG S1801) is the new standard for resectable stage III disease and lets most patients skip a year of adjuvant therapy.
• Sequencing is settled for BRAF-mutant disease: immunotherapy first, targeted therapy in reserve.

1. 1975Dacarbazine: ~10% response, standard for 35 years
2. 1992High-dose interleukin-2 produces rare durable cures
3. 2002BRAF V600E mutations discovered in ~50% of melanomas
4. 2010Ipilimumab is the first drug to extend survival in metastatic melanoma
5. 2011Ipilimumab and vemurafenib approved
6. 2011Ipilimumab and vemurafenib approved
7. 2014PD-1 inhibitors approved
8. 2014Pembrolizumab and nivolumab approved; first BRAF/MEK combination (dabrafenib-trametinib)
9. 2015T-VEC: first oncolytic virus
10. 2015CheckMate 067 combination and KEYNOTE-006; T-VEC first oncolytic virus; cobimetinib

• Intismeran autogene (product)
• Vusolimogene oderparepvec (product)
• Lifileucel (product)
• Tebentafusp (product)
• INTerpath-001 (V940-001) (trial)
• Brenetafusp (product)
• PRISM-MEL-301 (trial)
• PRAME (target)
• Fianlimab (product)
• ctDNA-guided adjuvant therapy in stage II-III melanoma (idea)
• TCR therapeutics for non-HLA-A*02 patients (idea)
• MRD / molecular residual disease testing (technology)

• KEYNOTE-006 (phase 3, n=834): Overall survival at 10 years: 34% vs 23.6%
• IMCgp100-202 (phase 3, n=378): Overall survival: 21.7 months vs 16 months, HR 0.51
• DREAMseq (ECOG-ACRIN EA6134) (phase 3, n=265): Overall survival at 2 years: 71.8% vs 51.5%
• CheckMate 067 (phase 3, n=945): Progression-free survival (co-primary): 11.5 months vs 6.9 months vs 2.9 months, HR 0.42
• INTerpath-001 (V940-001) (phase 3, n=1,137): Recurrence-free survival: Met; hazard ratio and medians not yet disclosed (topline 19 August 2026).
• COLUMBUS (phase 3, n=577): Progression-free survival: 14.9 months vs 7.3 months, HR 0.54

• Primary IO resistance in ~40%.
• Uveal and mucosal subtypes.
• Brain metastases.
• Primary resistance: about 40% of advanced patients never respond to PD-1-based therapy, and predictive biomarkers (PD-L1, TMB, interferon signatures) remain too weak to guide choices.
• After PD-1 failure, response rates for approved options are ~30% at best; most patients still die of melanoma.
• LAG-3 blockade is not a class effect: it failed as adjuvant therapy and with cemiplimab, so the biology of when it helps is unresolved.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
3. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).
4. Why is pancreatic cancer so hard to treat with immunotherapy?
   Answer

   It is immunologically cold: dense desmoplastic stroma blocks drug and T-cell entry, low mutational burden gives few neoantigens, and an immunosuppressive myeloid microenvironment. Vaccines (autogene cevumeran) and RAS inhibitors that may increase antigen presentation are the main hopes.
5. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
6. What was the first personalised cancer vaccine to win a phase 3 trial?
   Answer

   Intismeran autogene (V940/mRNA-4157, Moderna/Merck) with pembrolizumab in resected stage IIB-IV melanoma: INTerpath-001 met recurrence-free and distant-metastasis-free survival, announced 19 August 2026.

• Wikipedia: https://en.wikipedia.org/wiki/Melanoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492