Skin Cancer and Melanoma: The Immunotherapy and Targeted-Therapy Success Story
A generation ago, metastatic melanoma was a death sentence measured in months. Today the same diagnosis can mean years of life — because we learned to do one of two things: switch off a single mutated signal, or take the brakes off the patient's own immune system. This is the story of how skin cancer became oncology's brightest proof that understanding a tumour's biology changes everything.
A 44-year-old woman sits in the oncology clinic, scrolling through photos of her daughter's graduation — one she was told, four years ago, she would almost certainly not live to see. Her melanoma had spread to her lungs and liver. A generation earlier, that meant months. Instead she was given a drug that silenced a single mutated signal inside her tumour cells, and later a second that unleashed her own immune system against them. Same disease, two different keys — and both were barely imaginable two decades ago. She is here today for a routine scan.
First, the common cancers we worry about least
Not all skin cancer is melanoma — and most of it is far less dangerous. The two non-melanoma skin cancers are the most common cancers in humans. Basal cell carcinoma (BCC) is the commonest of all; it grows locally, can be locally destructive, but almost never metastasises. Squamous cell carcinoma (SCC) is next; it too is usually curable but has a higher (still small) risk of spread. For both, the answer is overwhelmingly simple: surgery. Cut it out with clear margins and the patient is usually cured. The drug story only begins for the rare advanced cases that surgery and radiation can't reach.
For advanced or metastatic BCC, a hedgehog-pathway inhibitor (vismodegib) blocks the abnormal Hedgehog signalling that drives these tumours. For advanced SCC that can't be cured surgically, the anti-PD-1 checkpoint inhibitor cemiplimab has become a mainstay — a preview of the immunotherapy theme that dominates melanoma. Two rare cancers, two elegant biology-based drugs.
- Non-melanoma skin cancers (BCC, SCC) are the most common human cancers but rarely lethal.
- Surgery cures the overwhelming majority of BCC and SCC.
- Advanced BCC → hedgehog-pathway inhibitor (vismodegib).
- Advanced SCC → anti-PD-1 checkpoint inhibitor (cemiplimab).
- The high-stakes drama — and the therapeutic revolution — is in melanoma.
Melanoma: from untreatable to the flagship of two revolutions
Melanoma arises from melanocytes, the pigment cells. Caught early as a thin lesion, it is cured by simple excision. The terror was always the metastatic stage: once it spread, old chemotherapy barely touched it, and median survival was measured in months. Then, within a few short years around 2011, two entirely different approaches transformed the disease at once. Understanding them means understanding two questions we now ask of every advanced melanoma: what mutation drives it, and can we recruit the immune system against it?
Revolution one — targeted therapy for BRAF-mutant melanoma
About half of melanomas carry a single, targetable typo. Roughly half of all melanomas harbour a BRAF-V600 mutation — a change in the BRAF gene that jams the MAPK growth-signalling pathway permanently "on," telling the cell to divide endlessly. Because the tumour leans so heavily on this one broken switch, blocking it produces dramatic, rapid shrinkage. A BRAF inhibitor (dabrafenib or vemurafenib) does exactly this. The catch: given alone, resistance emerges within months as the pathway reactivates by another route.
The solution is to block the pathway at two points at once. Adding a MEK inhibitor (trametinib or cobimetinib) — MEK is the very next relay downstream of BRAF — closes the escape route, delays resistance, and, paradoxically, reduces certain skin side effects seen with a BRAF inhibitor alone. So the modern standard is always a pair: dabrafenib + trametinib, or vemurafenib + cobimetinib. These are kinase inhibitors, and their behaviour, dosing and resistance biology belong to that broader family — covered in the Kinase-inhibitors chapter.
Why never a BRAF inhibitor alone? In cells that DON'T carry the BRAF-V600 mutation, a BRAF inhibitor can paradoxically ACTIVATE the pathway and even trigger new squamous skin lesions. Adding the MEK inhibitor suppresses this paradox. So the pairing isn't just about delaying resistance — it's also about safety and about never using these drugs in BRAF-wild-type tumours.
- ~50% of melanomas carry a BRAF-V600 mutation driving the MAPK pathway.
- BRAF inhibitors (dabrafenib, vemurafenib) give rapid but resistance-prone responses.
- Always pair with a MEK inhibitor (trametinib, cobimetinib) to delay resistance.
- Targeted therapy is only for BRAF-mutant tumours — test first.
- Strength: fast tumour control. Weakness: responses eventually wane.
Revolution two — immunotherapy that works for everyone
The second revolution ignores the BRAF question entirely: it works regardless of mutation status. Melanoma is highly "immunogenic" — the immune system can recognise it, but the tumour hides by exploiting the normal brakes (checkpoints) that keep T-cells from attacking healthy tissue. Checkpoint inhibitors release those brakes. Anti-PD-1 antibodies (nivolumab, pembrolizumab) are the backbone; adding an anti-CTLA-4 antibody (ipilimumab) presses a second brake for deeper, though more toxic, responses.
The prize is durability. What makes immunotherapy different from targeted therapy is the shape of its success. Targeted drugs shrink tumours fast but responses fade; checkpoint inhibitors are slower to act but, in a meaningful minority of patients, produce durable, sometimes years-long remissions — the immune system keeps working after the drug stops. They are used both in advanced/metastatic disease and, crucially, as adjuvant therapy after surgery for high-risk melanoma, to hunt down micro-metastases and prevent recurrence. The mechanism and the class as a whole live in the Checkpoint-inhibitors chapter.
Because checkpoint inhibitors unleash the immune system broadly, T-cells may also attack healthy organs — immune-related adverse events (irAEs): colitis, hepatitis, dermatitis, thyroiditis, pneumonitis, hypophysitis. These are NOT chemotherapy toxicity and are NOT managed like it. Mild ones may be watched; moderate-to-severe ones are treated by suppressing the over-active immune response with corticosteroids (and sometimes stronger immunosuppression), while pausing or stopping the drug. Recognising an irAE early is a core skill of modern oncology.
- Immunotherapy works regardless of BRAF status.
- Anti-PD-1 (nivolumab, pembrolizumab) ± anti-CTLA-4 (ipilimumab) release T-cell brakes.
- Slower to act than targeted therapy but responses can be durable.
- Used in advanced disease AND as adjuvant therapy after surgery.
- Immune-related adverse events (irAEs) are treated with steroids, not chemo protocols.
The decision at the bedside: which key, and when
So how does the oncologist choose? The first step is always to test the tumour for a BRAF mutation — this single result decides whether targeted therapy is even an option. If BRAF is wild-type, immunotherapy is the path. If BRAF is mutant, both doors are open, and immunotherapy is often chosen first for its durability. Targeted therapy is favoured when rapid control is needed — a heavy tumour burden or a symptomatic patient who can't wait weeks for the slower immune response — or when immunotherapy has failed or can't be used. BRAF testing itself belongs to the wider practice of matching drugs to mutations, covered in the Precision-oncology chapter.
Prevention still beats every drug. Most melanomas are linked to ultraviolet exposure, and early detection changes the whole prognosis. Teach the ABCDE of a suspicious mole: Asymmetry, irregular Border, varied Colour, Diameter over ~6 mm, and Evolving (changing over time). A thin melanoma caught early is cured by a scalpel; a thick one that has spread is the one that needs this entire chapter.
- Not testing BRAF status in advanced melanoma — you miss the entire option of targeted therapy.
- Using a BRAF inhibitor ALONE without a MEK inhibitor — faster resistance and paradoxical tumour growth.
- Managing immune-related adverse events like chemotherapy toxicity — irAEs need steroids/immunosuppression, not dose reductions alone.
- Giving targeted therapy to a BRAF-wild-type tumour — it doesn't work and can be harmful.
A patient with metastatic melanoma is found to have a BRAF-V600 mutation. Which principle is correct?
- Non-melanoma skin cancers (BCC, SCC) are common but surgery-cured; advanced cases → vismodegib (BCC) or cemiplimab (SCC).
- Metastatic melanoma went from months of survival to years via two revolutions.
- Targeted therapy: BRAF inhibitor + MEK inhibitor for BRAF-V600-mutant tumours — fast but resistance emerges.
- Immunotherapy: anti-PD-1 ± anti-CTLA-4 — works regardless of BRAF, durable responses, watch for irAEs.
- Always test BRAF first; immunotherapy is often first-line, targeted therapy when speed is needed.
- NCCN Clinical Practice Guidelines in Oncology — Melanoma: Cutaneous.
- NCCN Clinical Practice Guidelines in Oncology — Basal Cell & Squamous Cell Skin Cancers.
- Michielin O, et al. ESMO Clinical Practice Guidelines — Cutaneous melanoma: diagnosis, treatment and follow-up.
- DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology — Melanoma & BRAF/MEK and checkpoint-inhibitor therapy.
- Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics — Targeted therapy & immune checkpoint blockade.
