Malignant Melanoma (Skin Cancer) Symptoms, Stages and Treatment
In this article
What Is Malignant Melanoma?
Malignant melanoma is a malignant cancer arising from pigment-producing cells (melanocytes) in the skin (and much more rarely in the eye or mucosal surfaces). Although it is much less common among skin cancers than basal cell and squamous cell carcinomas, it accounts for the great majority of skin cancer deaths because it tends to spread (metastasize) much faster if not detected early. Melanoma is also at the center of one of modern oncology's most striking success stories: before 2011, treatment options for advanced melanoma were extremely limited, but immunotherapy and targeted treatments developed over the past 15 years have markedly increased 5-year survival even in distant metastatic disease. In this guide, we discuss malignant melanoma's causes, symptoms, diagnostic and staging methods, current treatment options, the field's FDA approval timeline, and the diagnostic and treatment process in Turkey comprehensively and based on current literature.
Melanocytes are cells found in the skin, the eye's vascular layer (choroid), and certain mucosal surfaces (nasal, oral, and genital mucosa); they produce melanin pigment to protect the skin from the sun's harmful ultraviolet (UV) rays. The great majority of melanomas (over 90%) develop in the skin (cutaneous melanoma); subtypes developing within the eye (uveal/ocular melanoma) and on mucosal surfaces are much rarer, have different biology, and are discussed separately in this guide.
How Common Is Malignant Melanoma? (Current Statistics)
According to the report published by IARC on 8 July 2026 in CA: A Cancer Journal for Clinicians containing estimates for 2024, GLOBOCAN 2024 approximately 337.969 new cutaneous melanoma cases occur worldwide each year (1,6% of all cancers, the 17th most common cancer), and approximately 58.398 people die from melanoma (ranking 22nd). Melanoma is relatively evenly distributed between men and women (180.515 male cases, 157.454 female cases). Incidence varies strikingly between countries; the world's highest rates are in Australia/New Zealand (46,6 per 100.000 men and 31,4 per 100.000 women), where a fair-skinned population experiences intense sun exposure.
According to the Türkiye country fact sheet published by IARC in July 2026 as part of the same GLOBOCAN 2024 publication cycle, approximately 1.716 new melanoma cases are reported (0,73% of all cancers), and approximately 664 people die from melanoma. In Turkey, melanoma is much less common than in countries such as Australia with high sun exposure/fair-skinned populations (ranking 22nd in incidence); this is consistent with the relative protective effect of the darker skin types in our country (predominantly Fitzpatrick types III-IV). However, rarity does not make the disease unimportant; early diagnosis is also the most critical factor directly determining survival in this cancer.
According to the American Cancer Society's "Cancer Statistics, 2026" report, published on 13 January 2026, the estimated number of new invasive melanoma cases in the US for 2026 is approximately 112.000 (65.400 men, 46.600 women), with approximately 122.680 additional "in situ" (not yet invasive, earliest-stage) melanoma cases reported separately. The estimated number of deaths is 8.510 (5.500 men, 3.010 women). The overall 5-year relative survival rate, based on the SEER database and the cohort of patients diagnosed between 2015-2021, is a high %95 (almost 100% for localized disease, 76% for regional spread); however, the most striking finding concerns distant metastatic disease , in which, according to the report itself, 5-year survival has risen from the middle of the 1990s figure of %16 to %35 today — an almost twofold increase. This marked improvement is a direct result of the immunotherapy and targeted treatment revolution discussed in detail below.
Risk Factors
Exposure to ultraviolet rays from sunlight or artificial sources (tanning beds) is melanoma's most important modifiable risk factor. In particular, intense/intermittent sun exposure during childhood and adolescence that causes skin blistering (sunburn) is more strongly associated with risk than continuous low-level exposure. The WHO's IARC has classified tanning beds/solarium devices, particularly because first use before age 35 markedly increases risk, as carcinogenic to humans (Group 1) .
- Fair skin, light eye/hair color (Fitzpatrick types I-II): Risk is markedly increased in fair-skinned people who burn easily and tan poorly.
- Many moles (nevi) or atypical/dysplastic nevi: Risk is increased in people with many moles (particularly more than 50), irregular-looking moles, or a diagnosis of dysplastic nevus syndrome.
- A personal or family history of melanoma: A previous melanoma or a first-degree relative with melanoma markedly increases risk; some familial cases are associated with an inherited mutation in the CDKN2A gene.
- Immune suppression: Risk is increased in people receiving immunosuppressive treatment after organ transplantation or with conditions that weaken immunity, such as HIV.
- Older age: Risk increases with age, but melanoma is also one of the relatively common cancers in young adults.
The ABCDE Rule and Skin Self-Examination
Developed by the American Academy of Dermatology and still widely used, this simple rule helps identify which moles should be assessed by a specialist:
- A — Asymmetry: One half of the mole does not resemble the other
- B — Border: Irregular, notched, or blurred borders
- C — Color: Multiple color shades (brown, black, red, white, blue) within a single mole
- D — Diameter: Diameter greater than 6 mm (the size of a pencil eraser)
- E — Evolving: A marked change over time in size, shape, color, or height, or new itching/bleeding
Alongside these criteria, a simple principle called the "ugly duckling" sign is also valuable clinically: while most moles on a person's body follow a similar pattern, a single "different-looking" mole that does not fit this general pattern should be carefully assessed regardless of size. Any new or changing skin lesion should be assessed by a dermatologist even if it does not fully meet the criteria above.
Melanoma Subtypes
The most common subtype; it generally first appears as an irregular-bordered, multicolored lesion growing slowly horizontally. This horizontal growth phase allows relatively more time for early detection.
This subtype grows rapidly vertically (deeper into the skin) from the outset, without a horizontal growth phase; it is therefore generally diagnosed at a greater Breslow depth and with a worse prognosis. It usually appears as a dark, dome-shaped nodule; some cases may lack pigment (amelanotic), which can delay diagnosis.
Generally develops at an older age in chronically sun-damaged skin (such as the face or neck); it begins as a slow-growing, irregularly bordered brownish patch (lentigo maligna, the in-situ stage) and may become invasive over years.
Develops in hairless (acral) areas such as the palms, soles, fingertips, and nail beds. Its association with sun exposure is weak; it therefore accounts for a relatively larger proportion of melanomas in darker-skinned individuals (in populations in Africa, Asia, and countries such as Turkey) — although rare in the general population, it may be the most common subtype in darker-skinned patients. Because it is generally noticed late in less visible areas such as beneath the nails, diagnosis is often at a more advanced stage.
These two subtypes account for a small proportion of all melanomas, are biologically markedly different from cutaneous (skin) melanoma, and are not associated with UV exposure. Mucosal melanoma develops in nasal/sinus, oral, esophageal, or genital/anal mucosa; it is generally diagnosed late and has a worse prognosis than cutaneous melanoma. Uveal (intraocular) melanoma arises from the eye's vascular layer (choroid, ciliary body, iris); unlike cutaneous melanoma, it is often associated with GNAQ or GNA11 gene mutations, almost never has BRAF mutations, and characteristically tends to spread to the liver when it metastasizes. Because of this different biology, systemic treatment for uveal melanoma also differs from that for cutaneous melanoma (discussed separately below in the tebentafusp section).
How Is the Diagnosis Made?
- Dermoscopy: Examination by a dermatologist with a specialized magnifying device (dermatoscope) reveals structural features invisible to the naked eye and helps distinguish suspicious lesions.
- Biopsy: A tissue sample is taken from a suspicious lesion for definitive diagnosis. When possible, a full-thickness excisional biopsy (complete removal of the lesion with a narrow margin of healthy tissue) is preferred; this is important for the pathologist to measure Breslow depth accurately (described below). Avoiding superficial "shave" biopsy whenever possible is recommended because it risks underestimating tumor depth.
- Key elements of the pathology report: After diagnosis, the pathology report must specify Breslow depth (tumor depth in millimeters — the single most important prognostic factor), ulceration (breakdown of skin integrity over the tumor — a poor prognostic finding), and mitotic rate (the rate of cell division); these three elements form the basis of staging.
Molecular and Genetic Tests
Approximately half of cutaneous melanomas carry a BRAF mutation, most commonly BRAF V600E (more rarely V600K); its presence is required to use the BRAF/MEK inhibitor combinations discussed in detail below. Guidelines recommend BRAF mutation testing in every patient with advanced/metastatic disease.
NRAS mutations occur in approximately 15-20% of cases; there is currently no directly approved targeted treatment for them. KIT mutations are relatively more common in chronically sun-damaged skin, acral, and mucosal melanomas; responses to KIT inhibitors (such as imatinib) have been reported in some cases, but this is not a routinely approved indication. NF1 mutations also occur in some BRAF/NRAS wild-type (mutation-free) tumors. Tumors with no detected BRAF, NRAS, or NF1 mutations are called "triple wild-type."
Staging: the TNM System (AJCC 8th Edition)
Melanoma staging is based on the TNM system, combining the T category describing the primary tumor, the N category describing regional lymph node/subcutaneous spread, and the M category describing distant metastasis. Each category is presented separately below, followed by their combinations into the general groups from Stage 0 to Stage IV.
T Category: Breslow Depth and Ulceration
| T Category | Definition |
|---|---|
| Tis | Melanoma in situ (not yet invasive) |
| T1a | <0,8 mm, no ulceration |
| T1b | <0,8 mm, ulceration present; or 0,8-1,0 mm (with or without ulceration) |
| T2a / T2b | >1,0-2,0 mm, ulceration absent / present |
| T3a / T3b | >2,0-4,0 mm, ulceration absent / present |
| T4a / T4b | >4,0 mm, ulceration absent / present |
In patients without clinically detected lymph node involvement, occult (microscopic) nodal spread can be assessed by sentinel lymph node biopsy (SLNB) . In general, SLNB is recommended for tumors with Breslow depth ≥1,0 mm and for thin tumors of 0,8-1,0 mm with additional risk factors such as ulceration or a high mitotic rate; it is generally unnecessary for very thin, nonulcerated tumors <0,8 mm. If SLNB is positive, based on the MSLT-2 and DeCOG-SLT results, routine completion (radical) lymph node dissection is no longer performed for micrometastatic disease; instead, close imaging surveillance with ultrasonography is preferred — these trials showed that completion dissection did not improve melanoma-specific survival and only added surgical morbidity, such as lymphedema.
N Category: Regional Spread
The N category considers not only the number of involved lymph nodes but whether involvement is clinically detected (apparent on examination/imaging or found only by SLNB) and whether associated skin/subcutaneous metastases called "in-transit," satellite, or microsatellite metastases are present:
| N Category | Definition |
|---|---|
| N0 | No regional lymph node involvement or in-transit/satellite/microsatellite metastases |
| N1a | 1 clinically occult lymph node (detected only by SLNB) |
| N1b | 1 clinically detected lymph node (apparent on examination/imaging) |
| N1c | No lymph node involvement, but in-transit/satellite/microsatellite metastases present |
| N2a | 2-3 clinically occult lymph nodes |
| N2b | 2-3 lymph nodes, at least one clinically detected |
| N2c | 1 lymph node (occult or detected) + in-transit/satellite/microsatellite metastases |
| N3a | ≥4 clinically occult lymph nodes |
| N3b | ≥4 lymph nodes (at least one clinically detected) or matted lymph nodes |
| N3c | ≥2 lymph nodes (occult or detected) and/or matted lymph nodes + in-transit/satellite/microsatellite metastases |
M Category: Distant Metastasis and LDH
Four subgroups are defined for disease with distant metastases (Stage IV), according to metastatic location; each is additionally reported with a suffix indicating whether serum lactate dehydrogenase (LDH) is normal (0) or elevated (1) — elevated LDH indicates a worse prognosis in every M subgroup (in AJCC 7th edition, elevated LDH automatically upgraded a patient to M1c; this rule was removed in the 8th edition, and LDH is now reported as a separate suffix):
| M Category | Definition |
|---|---|
| M1a | Distant skin, soft tissue (including muscle), and/or nonregional lymph node metastases |
| M1b | Lung metastases (with or without M1a sites) |
| M1c | Visceral organ metastases outside the central nervous system (with or without M1a/M1b sites) |
| M1d | Central nervous system (brain) metastases (with or without other sites) |
General Stage Groups (Stage 0 - IV)
Because many combinations of T, N, and M categories are possible (particularly Stage III subgroups), the table below summarizes the general logic; a patient's precise stage is determined by the oncologist using the pathology report's T/N/M values:
| Stage | General Definition (T / N / M) |
|---|---|
| Stage 0 | Tis, N0, M0 |
| Stage IA | T1a, N0, M0 |
| Stage IB | T1b or T2a, N0, M0 |
| Stage IIA | T2b or T3a, N0, M0 |
| Stage IIB | T3b or T4a, N0, M0 |
| Stage IIC | T4b, N0, M0 |
| Stage IIIA | Thin/intermediate-thickness tumor (T1a-T2a) + low-burden, clinically occult nodal involvement (N1a-N2a), M0 |
| Stage IIIB | T0-T3a + clinically detected lymph nodes or in-transit/satellite involvement (N1b/N1c/N2b), M0 |
| Stage IIIC | Thicker tumor (T3b-T4b) + variable N involvement, or thinner tumor + high-burden N involvement (N2c-N3c), M0 |
| Stage IIID | T4b + highest nodal burden (N3a-N3c), M0 |
| Stage IV | Any T, any N, M1 (reported with an a/b/c/d subgroup according to location and an LDH (0)/(1) suffix) |
Clinical staging (indicated by a "c" before the stage) is based on biopsy and imaging results and generally does not include SLNB results; it guides initial treatment planning. Pathological staging (indicated by a "p" before the stage) is based on definitive pathology obtained after SLNB and/or lymph node dissection and is generally considered more precise; adjuvant decisions are largely based on pathological staging.
Treatment of Localized Disease: Surgery
The main curative treatment for melanoma is removal of the tumor with a margin of healthy tissue, called wide local excision. The surgical margin width is determined by the tumor's Breslow depth:
| Breslow Depth | Recommended Surgical Margin |
|---|---|
| In situ (not yet invasive) | 0,5-1,0 cm |
| ≤1,0 mm | 1,0 cm |
| 1,01-2,0 mm | 1-2 cm |
| 2,01-4,0 mm | 2,0 cm |
| >4,0 mm | 2,0 cm |
Postoperative (Adjuvant) and Preoperative (Neoadjuvant) Systemic Treatment
Adjuvant anti-PD-1 treatment is a standard option to reduce recurrence risk in resected Stage III patients (and selected Stage IIB/IIC and oligometastatic Stage IV patients). Nivolumab was approved based on CheckMate 238 first in Stage III/IV (2017), then expanded to Stage IIB/IIC with CheckMate 76K (2023). Pembrolizumab was similarly approved based on KEYNOTE-054 (Stage III, 2019), then expanded to Stage IIB/IIC with KEYNOTE-716 (2021) — adjuvant immunotherapy, previously limited to patients with advanced nodal involvement, has therefore now been expanded to patients with thick tumors but no nodal involvement (Stage IIB/IIC).
In resected Stage III patients positive for a BRAF V600 mutation, adjuvant dabrafenib+trametinib is also an approved option based on COMBI-AD; at 5-year follow-up, disease-free survival was markedly superior to placebo. Adjuvant treatment selection in BRAF-mutant patients (immunotherapy or targeted therapy) is individualized according to risk profile and preference.
Immunotherapy, long reserved for after surgery (adjuvant treatment), can also be beneficial when given before surgery, as shown by SWOG S1801: in resectable Stage III/IV melanoma, several preoperative doses plus postoperative pembrolizumab (neoadjuvant+adjuvant) markedly improved event-free survival compared with postoperative pembrolizumab alone (the standard adjuvant approach) — despite the same drug dose and total treatment duration, changing only the timing made a significant difference. This supports the hypothesis that activating immunity while the tumor remains in the body as an "antigen reservoir" may produce a stronger immune response than activation after removal and marks an important conceptual change in treatment sequencing.
Systemic Treatment of Metastatic (Advanced) Melanoma
Treatment for patients with distant metastases follows the generally accepted cancer treatment concept of line of therapy : first, the regimen expected to be most effective is selected; when disease progresses, a previously unused treatment class is chosen (second line), followed by third-line and later options once that is exhausted. Selection depends on BRAF mutation status, tumor burden/symptoms, central nervous system involvement, and previous treatments.
First-Line Treatment
As a general principle, regardless of BRAF status, immunotherapy is the preferred initial approach in most patients because responses are more durable; in BRAF-mutant patients, targeted treatment is considered an alternative, particularly with high tumor burden/symptomatic disease requiring a rapid response.
Immunotherapy-Based Approaches
Targeting two different checkpoints simultaneously (PD-1 and CTLA-4), this combination generally provides the highest response rate and longest survival among the tested regimens. According to the 10-year follow-up published in 2024, the overall response rate was approximately 58%, median progression-free survival 11,5 months, median overall survival 71,9 months (approximately 6 years), and 10-year overall survival approximately 43%. However, immune-related side effects (discussed below) may be markedly more frequent and severe than with single agents; selection is therefore balanced against the patient's overall health and ability to tolerate toxicity.
Combining nivolumab with relatlimab, which targets a different immune checkpoint called LAG-3, significantly improved progression-free survival compared with nivolumab alone (median PFS 10,2 months versus 4,6 months at 3-year follow-up); overall survival showed a favorable trend in this comparison but, as of the latest reports, data were not fully mature. It generally offers a better-tolerated profile than nivolumab+ipilimumab, providing an alternative form of dual checkpoint blockade for some patients.
Less toxic than combinations, pembrolizumab alone (KEYNOTE-006) or nivolumab may be preferred, particularly with lower tumor burden or when combination toxicity is unlikely to be tolerated. In the 10-year KEYNOTE-006 follow-up, pembrolizumab's overall response rate was approximately 42%, median PFS 8,4 months, median overall survival 32,7 months, and 10-year overall survival approximately 34%; in CheckMate 067's nivolumab-alone arm, the reported overall response rate was approximately 45%, median overall survival 36,9 months, and 10-year overall survival approximately 37%.
Targeted Treatment in BRAF-Mutant Disease
Three different BRAF inhibitor + MEK inhibitor combinations are approved for BRAF V600 mutation-positive patients: dabrafenib+trametinib (in the pooled 5-year COMBI-d/COMBI-v analysis: overall response rate approximately 68%, median PFS 11,1 months, median overall survival 25,9 months, 5-year overall survival 34%), vemurafenib+cobimetinib (in the 5-year coBRIM follow-up: overall response rate approximately 70%, median PFS 12,6 months, median overall survival 22,5 months, 5-year overall survival approximately 31%), and encorafenib+binimetinib (in the 5-year COLUMBUS follow-up: overall response rate 63%, median PFS 14,9 months, median overall survival 33,6 months, 5-year overall survival approximately 35% — in the same trial, median overall survival was 23,5 months with encorafenib alone and 16,9 months with vemurafenib alone). No trial directly compares these three combinations, but COLUMBUS reported relatively longer median overall survival than the other two, making encorafenib+binimetinib the preferred BRAF+MEK combination for many clinicians (see the comparison table and warning box on the limitations of indirect comparisons below). A clear advantage of targeted treatments is that they generally produce responses faster than immunotherapy — potentially valuable in symptomatic/high-burden disease requiring rapid tumor shrinkage.
This triple regimen, intended to combine immunotherapy and targeted treatment in BRAF-mutant patients, received FDA approval on 30 July 2020; in IMspire150's second interim analysis, it improved median progression-free survival compared with dual targeted treatment (placebo+vemurafenib+cobimetinib): 15,1 months versus 10,6 months. Overall survival data were still maturing when this article was prepared, with no statistically established significant difference reported. Because toxicity can be higher and it has not become a routinely preferred approach for all patients, use has remained limited to selected patients.
Comparative Efficacy Data: How Do the Regimens Compare?
The table below summarizes side by side the outcomes reported in the individual trials of the first-line regimens discussed above:
| Regimen (Trial, Follow-up) | Response Rate (ORR) | Median PFS | Median / Long-Term OS |
|---|---|---|---|
| Nivolumab + Ipilimumab (CheckMate 067, 10 years) | ~%58 | 11,5 months | 71,9 months (10-year OS ~43%) |
| Nivolumab alone (CheckMate 067, 10 years) | ~%45 | 6,9 months | 36,9 months (10-year OS ~37%) |
| Ipilimumab alone (CheckMate 067, 10 years) | ~%19 | 2,9 months | 19,9 months (10-year OS ~19%) |
| Pembrolizumab (KEYNOTE-006, 10 years) | ~%42 | 8,4 months | 32,7 months (10-year OS ~34%) |
| Nivolumab + Relatlimab (RELATIVITY-047, 3 years) | not reported* | 10,2 months | data still maturing |
| Dabrafenib + Trametinib (COMBI-d/v, 5 years) | ~%68 | 11,1 months | 25,9 months (5-year OS ~34%) |
| Vemurafenib + Cobimetinib (coBRIM, 5 years) | ~%70 | 12,6 months | 22,5 months (5-year OS ~31%) |
| Encorafenib + Binimetinib (COLUMBUS, 5 years) | ~%63 | 14,9 months | 33,6 months (5-year OS ~35%) |
| Atezolizumab + Vem. + Cobi. (IMspire150, 2nd interim analysis) | not reported* | 15,1 months | data still maturing |
*For some trials, detailed ORR data were not clearly reported in publicly available sources when this article was prepared. All values are rounded from published articles and should be treated as approximate.
The table presents outcomes from regimens tested in their own separate randomized trials side by side — however, the great majority of these regimens have not been directly compared head to head. Differences must therefore be interpreted carefully: trials were conducted in different years (supportive care and later-line options changed over time), patient populations differed (some trials included only BRAF-mutant patients while others were mixed), and the "proportional hazards" assumption often used statistically is generally not valid in immunotherapy trials because survival curves separate late/plateau — weakening direct comparability of medians. Published network meta-analyses and matching-adjusted indirect comparisons (MAIC — for example, Amdahl et al. 2016; An and Liu 2019; a European meta-analysis from 2023) have attempted statistical comparisons; however, one analysis (An and Liu, 2019) reported statistically significant inconsistency in indirect PFS comparisons (heterogeneity, I²=62,9%) — rankings from indirect methods can themselves vary between analyses. Thus, this table offers general guidance, but there is no single correct answer to "which regimen is definitively better"; choice is individualized according to BRAF status, tumor burden, urgency, and tolerance of toxicity.
Second-Line Treatment
When disease progresses during or after first-line treatment, selection depends largely on which treatment class was used previously .
After progression on anti-PD-1 alone (nivolumab or pembrolizumab), ipilimumab can be added as a single agent. However, according to Pires da Silva and colleagues' Lancet Oncology multicenter retrospective analysis published in 2021, the response rate with this second-line ipilimumab monotherapy (13%) was markedly lower than in patients treated with nivolumab+ipilimumab from the outset (31%). This emphasizes why choosing the combination in the first line, if possible, is important; nevertheless, adding ipilimumab after progression remains a reasonable second-line option in patients initially given anti-PD-1 alone.
BRAF V600 mutation-positive patients who received first-line immunotherapy can start one of the three approved BRAF+MEK inhibitor combinations described above in the second line. Conversely, patients starting with a BRAF+MEK inhibitor are preferably switched to immunotherapy (single agent or combination) on progression. The general principle is that both treatment classes can be used sequentially at different lines during the course of BRAF-mutant disease.
Based on a genetically modified herpes simplex virus, talimogene laherparepvec (T-VEC) is injected directly into skin, subcutaneous, or lymph node metastases, both directly killing tumor cells and stimulating immunity. Approved in 2015, it was the first oncolytic virus treatment approved in the US. Its use is chiefly determined by the disease's anatomical distribution pattern: it is considered mainly in patients with a limited number of skin/subcutaneous/lymph node metastases that cannot be completely surgically removed and without widespread visceral (internal organ) metastases, generally in the second line or later; its role in widespread visceral disease is limited.
Third-Line and Later Treatment
Options narrow for patients whose disease has progressed after both anti-PD-1 and, if BRAF-mutant, a BRAF/MEK inhibitor; cellular immunotherapy and other novel approaches become prominent at this point.
Lifileucel, approved by the FDA on 16 February 2024, is a personalized cellular immunotherapy based on returning immune cells obtained from the patient's own tumor and expanded in large numbers in a laboratory (tumor-infiltrating lymphocytes, TILs) to the patient — it is the first TIL cellular therapy approved for a solid tumor. FDA approval was granted for use in patients with advanced disease who had previously received anti-PD-1 therapy (and a BRAF/MEK inhibitor if BRAF-mutant), in the third line and beyond . According to the pooled 5-year follow-up data from the C-144-01 study, the overall response rate was 31,4%, the median duration of response was 36,5 months, and median overall survival was 13,9 months; the 5-year overall survival rate was reported as 19,7% — reflecting a remarkably durable response in this heavily pretreated patient population. The treatment process is complex: tissue is first surgically collected from the patient's tumor, the cells are expanded in a laboratory over several weeks, the patient receives lymphodepleting chemotherapy (temporarily suppressing the immune system) during this process, the expanded cells are then administered to the patient, followed by interleukin-2 (IL-2) support — therefore, it can only be administered at experienced centers able to manage this process.
Tebentafusp, approved on 25 January 2022, is the first bispecific T-cell engager therapy approved for a solid tumor (binding the gp100 protein on the tumor cell at one end and a T cell at the other). It is used only in patients with HLA-A*02:01-positive, unresectable or metastatic uveal (intraocular) melanoma — it is not effective in cutaneous melanoma because the molecular structure it targets is specific to the biology of uveal melanoma. Unlike cutaneous melanoma, the effectiveness of standard combination immunotherapy in uveal melanoma is limited, so tebentafusp may also be considered early in eligible patients regardless of treatment-line order. This is an important practical example of how different uveal melanoma is from cutaneous melanoma, as discussed in the section "Melanoma Subtypes" above.
On 6 August 2026 — very close to the week this guide was prepared — the FDA, based on the IGNYTE study, granted accelerated approval for patients with unresectable advanced cutaneous melanoma whose disease had progressed during previous treatment with a PD-1 inhibitor to the combination of vusolimogene oderparepvec (Tudriqev) + nivolumab (overall response rate 24,2%, median duration of response 14,1 months). This is the second oncolytic-virus-based melanoma treatment approved after T-VEC and is the field's most recent development as of the date this guide was written; it is an option considered in the third line and beyond for patients progressing after anti-PD-1 therapy.
Before the development of immunotherapy and targeted therapies, conventional chemotherapy agents such as dacarbazine were standard treatment for melanoma; today, because of low response rates and the availability of much more effective options, chemotherapy is considered beyond the third line only in selected patients in whom the options above have been exhausted or are unsuitable. In some patients who responded for a long time to their initial immunotherapy and then progressed, or whose disease recurred long after completing treatment, small studies have reported that "retreatment" — restarting a checkpoint inhibitor that previously produced a response — can achieve a response in some patients; however, there is no large-scale randomized study on this topic, and the decision is entirely individualized.
Management of Brain Metastases
Melanoma is one of the cancers with a high propensity to metastasize to the brain (this is separately defined as subcategory M1d in the AJCC 8th edition). The CheckMate 204 study showed that the nivolumab+ipilimumab combination can also produce meaningful intracranial response rates in patients with active, asymptomatic brain metastases; this finding demonstrated that systemic immunotherapy may play an important role in selected patients with brain metastases (beyond merely being an addition to local treatments such as radiosurgery).
Treatment Side Effects and Their Management
Immunotherapy Drugs
Checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, relatlimab) can cause "immune-related adverse events" (irAEs) due to excessive immune-system activation: colitis, hepatitis, pneumonitis, endocrine disorders (thyroiditis, hypophysitis, adrenal insufficiency), and skin reactions. Combinations containing ipilimumab carry a significantly higher risk of more frequent and severe irAEs than single agents; management is based on grading (monitoring for mild side effects and corticosteroid treatment for moderate-to-severe side effects).
BRAF and MEK Inhibitors
Dabrafenib is particularly associated with pronounced fever (pyrexia) occurring frequently and sometimes requiring treatment interruption. Vemurafenib is associated with sensitivity to sunlight (photosensitivity) and skin rash; when BRAF inhibitors are used alone (without adding a MEK inhibitor), they paradoxically carry a risk of developing new cutaneous squamous cell carcinomas/keratoacanthomas — adding a MEK inhibitor reduces this risk. MEK inhibitors (trametinib, cobimetinib, binimetinib) can cause reduced cardiac function (decreased ejection fraction — requiring regular echocardiographic monitoring), eye problems (retinal vein occlusion, uveitis), and skin rash.
Specific Considerations for T-VEC and Lifileucel
Because T-VEC is based on a live (attenuated) virus, it requires special precautions after administration, such as avoiding close contact with severely immunocompromised people or pregnant women, in addition to local reactions such as pain/swelling at the injection site. The lymphodepleting chemotherapy administered before lifileucel causes severe bone marrow suppression, and the subsequent IL-2 carries a risk of serious side effects (capillary leak syndrome, hypotension), so treatment can only be administered at experienced centers able to provide intensive care support.
FDA Approval Timeline: A Revolution in Systemic Melanoma Treatment
Malignant melanoma is one of the fields in modern oncology where the immunotherapy and targeted-therapy revolution began and advanced most rapidly. The chronological timeline below summarizes the principal systemic treatments approved by the FDA from the 1970s to the present:
Dacarbazine
The first systemic chemotherapy drug approved for metastatic melanoma; it remained standard treatment for approximately 35 years, but response rates and survival benefits were limited.
High-Dose Interleukin-2 (IL-2)
This treatment, which directly stimulates the immune system, could produce durable complete responses in selected patients; however, because of its severe toxicity, it could only be administered at centers with intensive care support and was gradually replaced by safer immunotherapies.
Ipilimumab The First Checkpoint Inhibitor
Ipilimumab, which targets CTLA-4, is the first checkpoint inhibitor approved across all cancer types — it is regarded as the effective starting point of the immunotherapy era.
Vemurafenib
The first approved drug targeting the BRAF V600E mutation; it initiated the targeted-therapy era in melanoma.
Dabrafenib and Trametinib (Single-Agent Approvals)
The second BRAF inhibitor (dabrafenib) and the first MEK inhibitor (trametinib) were approved separately as single agents on the same day.
Dabrafenib + Trametinib Combination
Combined use of two targeted drugs was approved; this was an important step in delaying resistance to BRAF inhibitors and improving the side-effect profile (reducing paradoxical skin cancers).
Pembrolizumab The First Anti-PD-1
The first approved drug targeting the PD-1 checkpoint (KEYNOTE-001 study) heralded a new era in melanoma treatment.
Nivolumab
The second anti-PD-1 drug (CheckMate-037 study) was approved; together with pembrolizumab, it became one of the two pioneering members of the anti-PD-1 class.
Nivolumab + Ipilimumab Combination
Approved on the basis of the CheckMate-069 study (initially restricted to BRAF wild-type patients, then expanded to all patients in January 2016), this combination enabled dual checkpoint blockade.
Talimogene Laherparepvec / T-VEC The First Oncolytic Virus
T-VEC, approved on the basis of the OPTiM study, became the first oncolytic virus therapy approved in the United States.
Vemurafenib + Cobimetinib Combination
Based on the coBRIM study, the third BRAF+MEK inhibitor combination pair was established.
Adjuvant Nivolumab (Stage III/IV)
Based on the CheckMate-238 study, an anti-PD-1 drug was approved for the first time as adjuvant treatment to reduce the risk of recurrence after surgery.
Encorafenib + Binimetinib Combination
This combination, approved on the basis of the COLUMBUS study, reported relatively the longest overall survival compared with the other BRAF+MEK combinations in the final analysis.
Adjuvant Pembrolizumab (Stage III)
Based on the KEYNOTE-054 study, a second anti-PD-1 drug gained an adjuvant indication alongside nivolumab.
Atezolizumab + Vemurafenib + Cobimetinib (Triple Combination)
Based on the IMspire150 study, the first triple regimen combining immunotherapy with dual targeted therapy was approved for BRAF-mutant patients.
Adjuvant Pembrolizumab Expanded to Stage IIB/IIC
Based on the KEYNOTE-716 study, adjuvant immunotherapy was now expanded to patients without lymph node involvement but with thick tumors (Stage IIB/IIC).
Tebentafusp The First Bispecific T-Cell Engager
The first bispecific T-cell engager therapy approved for a solid tumor; it is used only in HLA-A*02:01-positive patients with uveal melanoma.
Nivolumab + Relatlimab The First LAG-3 Inhibitor
Based on the RELATIVITY-047 study, the first class of drugs targeting the LAG-3 checkpoint was approved.
Adjuvant Nivolumab Expanded to Stage IIB/IIC
Based on the CheckMate 76K study, nivolumab was also expanded to Stage IIB/IIC, following pembrolizumab.
Lifileucel The First TIL Cellular Therapy
Based on the C-144-01 study, it became the first tumor-infiltrating lymphocyte (TIL) cellular therapy approved for a solid tumor.
Vusolimogene Oderparepvec + Nivolumab The Most Recent Approval
Based on the IGNYTE study, it received accelerated approval for patients whose disease progressed after PD-1 therapy; it is the second oncolytic-virus-based melanoma treatment approved after T-VEC. It is the field's newest development as of the date this guide was written.
This timeline covers only systemic (drug-based) treatments; it does not include advances in surgical or radiotherapy techniques. Dates reflect the relevant drug's initial FDA approval (accelerated approval in some cases); some drugs received additional indication expansions in subsequent years.
Diagnosis, Licensing, and Reimbursement Status in Türkiye
In Türkiye, malignant melanoma is diagnosed and treated in dermatology, general surgery, and oncology centers at university hospitals and training and research hospitals, in line with international guidelines. For drugs to be used in Türkiye, a TİTCK license is required first; for coverage by SGK, a separate reimbursement decision under SUT is also required.
Standard chemotherapy (dacarbazine), nivolumab (as a single agent in early/advanced/metastatic disease, as adjuvant treatment in resected Stage III-IV, and in first-line combination with ipilimumab — with ipilimumab limited to a maximum of 4 doses), and the dabrafenib+trametinib combination (in BRAF V600 mutation-positive patients with ECOG 0-1 who have not previously received a RAF-pathway inhibitor) are licensed in Türkiye and covered by SGK under specified conditions. Pembrolizumab is also reported to be licensed for melanoma, which is one of the limited number of indications covered by SGK.
According to our sources, current SGK reimbursement coverage in Türkiye could not be clearly verified for pembrolizumab adjuvant use in Stage IIB/IIC (a relatively recent expansion approved by the FDA in 2021), or for vemurafenib, cobimetinib, and the encorafenib+binimetinib combination — although these drugs are licensed in Türkiye, our sources do not explicitly confirm the conditions under which SGK covers them.
According to our sources, nivolumab+relatlimab (Opdualag), talimogene laherparepvec (T-VEC), lifileucel (Amtagvi), tebentafusp (Kimmtrak) and high-dose interleukin-2 appear not to have a TİTCK license in Türkiye or not to be in routine clinical use. The newest approval of 2026, the vusolimogene oderparepvec+nivolumab combination, is also thought not to be available in Türkiye yet because its approval is so recent.
Drug authorization and reimbursement status can change frequently with SUT updates. The information in this section is a general summary compiled as of the article's update date (August 2026); always confirm definitive and current information about your individual treatment and reimbursement situation with your treating physician and SGK's current SUT text.
Frequently Asked Questions
- Does every mole mean melanoma?
- No. Most people have many harmless, benign moles on their bodies. A mole meeting the ABCDE criteria or changing over time must be assessed by a dermatologist; however, this does not mean that the mole is definitely melanoma.
- Does melanoma occur only in people with high sun exposure?
- No. Although sun/UV exposure is the most important risk factor, some subtypes, such as acral lentiginous melanoma, are not related to sunlight and may develop in areas not exposed to the sun, such as the palms and soles. Suspicious skin changes therefore need assessment even in people with little sun exposure.
- If the sentinel lymph node is positive, are all lymph nodes necessarily removed?
- No, no longer routinely. In cases of micrometastatic lymph node involvement (detected by sentinel biopsy but not apparent on imaging), current guidelines recommend close imaging surveillance rather than completion lymph node dissection; this approach is supported by research.
- Which is better: immunotherapy or targeted therapy?
- There is no single correct answer. Immunotherapy is the only option for patients without a BRAF mutation; in BRAF-mutant patients, the oncologist individualizes the choice according to factors such as the urgency of the disease (targeted therapy may be preferred when a rapid response is needed), overall health, and immunotherapy's tendency to produce more durable responses.
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