- What every physician needs to know:
- Are you sure your patient has melanoma? What should you expect to find?
- Beware of other conditions that can mimic melanoma:
- Which individuals are most at risk for developing melanoma:
- What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
- What therapies should you initiate immediately i.e., emergently?
- What should the initial definitive therapy for melanoma be?
- What should you tell the patient and the family about prognosis?
What if scenarios in the treatment of melanoma.
Follow-up surveillance and therapy/management of recurrences.
- Stage IA, IB, IIA
- Stage IIB, IIC, IIIA
- Stage IIIB, IIIC
- Stage IV (previously resected)
- Treatment of isolated metastatic disease
- Systemic treatment - treatment of disseminated disease
- Anti-PD1/anti-PDL1 inhibitors (Pembrolizumab (MK-3475), Nivolumab, and MPDL3280A)
- Evidence for systemic therapy
- Ipilimumab mechanism of anti-tumor effects
- Anti-PD1/anti-PDL1 inhibitors (Pembrolizumab (MK-3475), Nivolumab, and MPDL3280A)
What other clinical manifestations may help me to diagnose melanoma?
What's the evidence?
What every physician needs to know:
Melanoma: an introduction and its initial evaluation
Melanoma (ICD code 172.9) occurs in over 764,000 individuals in the US annually, with over 9700 deaths. If diagnosed early, melanoma is easily cured. The AJCC staging provides valuable information on prognosis. In early stage T1a, stage IA the cure rate is well over 90%. In contrast, those patients with deep (>4mm) ulcerated T4b primary lesions have a survival of under 50% at 5 and 10 years.
The recognition of a melanoma early in its course is therefore of great importance and can markedly impact upon the patient's survival. While the ABCD (asymmetry, border, color, diameter) of melanoma is well known, the E for evolution is not as appreciated as it should be. New or changing lesions can look very benign, but harbor deep invading melanoma.
Location: biology - therapy
The histology and location of melanomas have recently become linked to its biology. (
Lesions on the torso or other body areas where sun exposure is only intermittent associated with intense burns as a child or young adult are now recognized to display mutations in the BRAF gene at V600 in over 50% of cases. The importance is the fact that BRAF V600 mutations are a target for new therapy.
In contrast, lesions found on the hands (primarily palms) or feet (primarily soles) are acral by definition. In these cases mutations in the BRAF gene at V600 are observed in only 15-20% of cases while mutations of CKIT are reported in 15-20% of cases, which also impacts therapeutic options.
Melanoma originating in the head and neck region and occasionally on the extremities where there is chronic solar damage display a different genetic make-up. These lesions demonstrate BRAF V600 mutations in only about 10-20% of the time, while CKIT mutations may be seen in up to 5%.
Melanoma can originate from mucosal surfaces such as the rectum/anus, sinuses, oral cavity, vaginal/vulvar surfaces. These lesions originating from mucosal surfaces have always been viewed as extremely aggressive. Recent studies have demonstrated only very rare BRAF mutations and about 20% with CKIT mutations.
Melanomas can also originate from the uveal tract of the eye. These melanomas primarily originate from the choroid and demonstrate mutations in the G-binding proteins GNAQ and GNA11, in the majority of these cases. BRAF and CKIT mutations are extremely rare if they occur at all in the uveal tract melanomas. About 15-20% of melanomas of the cutaneous surfaces express mutations in the NRAS protein. These predominantly occur at codon 61 and less frequently at codon 12 and 13. These are activating mutations that are generally mutually exclusive of BRAF V600 mutations.
Later the significance of these genetic alterations in melanoma will be discussed in the context of treatment.
Are you sure your patient has melanoma? What should you expect to find?
Disease manifestations of melanoma
Primary melanoma can originate from any body surface including skin, mucosa including vaginal, anal, and oral/gastrointestinal tract, and even the uveal tract of the eye.
In addition, a relatively large number of melanomas are diagnosed at sites of metastases without an obvious primary site. Those cases with unknown primaries can present as an involved single lymph node basin, isolated skin or soft tissue mass, or even an isolated lesion in a major organ (lung and brain) mimicking a primary brain tumor or lung cancer.
In some cases, skin metastases are very difficult to discern from primary lesions.
Interestingly, patients presenting with an isolated lymph node site and no primary lesion appear to have a better prognosis than those with a known primary lesion.
On the other hand many times disseminated disease is the first presentation of melanoma without a known primary lesion.
Frequently, melanoma can present as a changing lesion at the primary site which may bleed, be pruritic, fail to heal, or have discharge.
Lesions of the acral surfaces and other mucosal surfaces may be especially difficult to diagnose unless there is a high index of suspicion.
Lesions may occur in subungual sites and appear as traumatic hematomas under the nail.
Anorectal melanomas frequently masquerade as benign thrombosed hemorrhoids.
Distant metastases can involve a great diversity organs. This includes frequent skin, lymph node, and soft tissue involvement in nearly 40% of patients.
Small bowel is a metastatic site where melanoma is the most frequent metastatic tumor. Small bowel obstruction or a slow gastrointestinal bleed and anemia are two common scenarios with small bowel metastases.
Brain is a site which appears especially vulnerable. Most, if not all patients, with disseminated disease will develop brain metastases in the setting of uncontrolled metastatic disease.
In the past, bone involvement had been considered to be infrequent. More recently, with widespread use of PET scanning, it has been recognized more frequently. It typically features bone marrow involvement as opposed to lytic or sclerotic cortical lesions.
Additionally, on occasion, primary melanomas originating in the extremities can disseminate in the affected limb below the draining lymph nodes for long periods of time. This in-transit disease is most prevalent in the leg, but can also be observed in the upper extremities or in the head and neck region. These lesions are a result of disease trapped in lymphatics where it can become confluent and a significant local or regional problem. The lower extremity lesions can occasionally be treated through isolation of the limb and perfusion of the extremity with chemotherapy (melphalan), while heating the leg. This limits systemic exposure to the high doses of chemotherapy administered to the leg. While local control can be achieved, patients will frequently die of systemic disease. However, isolated limb disease can still be a prolonged symptomatic problem.
Beware of other conditions that can mimic melanoma:
Diseases that may mimic melanoma
This is frequently an issue when patients present with a mass or disseminated disease without a history of an underlying malignancy. Melanoma is frequently poorly differentiated and a consideration whenever there is a malignancy of unknown primary. The melanoma cells demonstrate large nucleoli and occasionally evidence of pigment which makes the diagnosis easier if melanin is present.
Most helpful are special immunohistochemical stains, including the following:
These are by no means uniformly positive, but usually one of them demonstrates expression and directs the diagnosis in the direction of melanoma. Therefore melanoma is a consideration, when cases may present similar to breast cancer (axillary lymph node enlargement), lymphoma (with diffuse lymphadenopathy and B symptoms), or even as a primary brain tumor (glioblastoma multiforme).
At times, primary lesions can appear very unimpressive with none of the commonly described characteristics (ABCD). Frequently nodular melanoma is described to look like a “blood blister.” Other lesions may be new or changed but still have well defined borders, no color variation, and even small size (diameters less than 5mm). Some may be flesh colored without any pigmentation (amelanotic).
Histologically the differentiation between an invasive melanoma (Clark level II and III) that does not grow vertically and a melanoma-in-situ or dysplastic nevus can be difficult. Many times these may be treated as early stage melanoma with appropriate margins (1 cm or less). The lesion which can be most difficult to discern from melanoma is the Spitz nevus which occurs in children and young adults.
By gross and microscopic appearance, both lesions have many classic features of malignancy. The melanoma cells usually exhibit great variation, increase size under the microscope great atypia and “invasion into connective tissue.” Most frequently, a diagnostic problem is confronted in young adults. Mutational analysis has been used to help differentiate benign from malignant. In the end, many patients undergo wide excision and sentinel lymph node mapping both as a diagnostic and therapeutic procedure.
Which individuals are most at risk for developing melanoma:
Both acute intense ultraviolet radiation in the form of UVA and chronic sun exposure in the form of UVB have been associated with risk of melanoma.
Intense sun exposure with one or more severe burns at a younger age.
Chronic sun exposure over many years - generally older males.
Exposure to tanning booths among younger adults or teenagers.
Clinical setting associated with significant host immune suppression - especially with Cyclosprin A or tacrolimus.
Bone marrow transplantation - organ allograft.
Patient's own history of melanoma.
Family history of melanoma, especially those with 3 or more first degree relatives.
Dysplastic nevi syndrome.
Skin color, red hair, freckles, easy burnability - association with MC1R polymorphism.
Prevalence is gradually increasing in older males but for many years ratio had been 1:1 males versus females.
Median age now 57 years but frequency higher in females in their 20s and males over 50 years of age.
Most prevalent in Caucasians especially with light skin and easy burnability - Australian, Scandinavian, North American.
Rare in more pigmented races/ethnicities - African, African-American, Hispanic, Asian. Primarily acral and mucosal in these populations.
What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
Primary lesion biopsy
The manner in which the cutaneous lesion is first biopsied in order to make a diagnosis is of great importance. Either an excisional biopsy or a punch biopsy through the depth of the deepest part of the lesion is greatly preferred over a shave biopsy. This will allow a much better appreciation for the initial stage of the primary.
The Breslow depth, Clark level, presence of ulceration, and number of mitoses (>1/mm2) are all used to stage primary lesions and to decide on further staging. Physicians need to know that it is rare that a patient with a primary melanoma needs systemic staging such as, positron emission tomography (PET) scans, computed tomography (CT) scans, or brain imaging.
Systemic staging is generally indicated only for very deep primary lesions (T4) with ulceration (T4b) or those with documented involved lymph nodes. At present there is even some debate whether systemic staging is required for microscopic lymph node involvement and early primary lesions (less than 2mm in depth).
Patients who undergo sentinel lymph node mapping based on the stage and depth of their primary have their lymph nodes carefully analyzed by the pathologist for even a minute collection of melanoma cells. This involves thin sectioning and staining with standard H&E as well as immunohistochemical staining for melanoma markers.
Sentinel lymph node involvement can be categorized according to tumor burden: diameters less than 0.1mm; 0.1-1.0mm; or greater than 1.0mm. These differences in tumor burden correlate with both tumor involvement in the non-sentinel nodes from the completion lymph node dissection (CLND) and patient outcome/survival.
Due to the challenges of accessing archival tissue, it is reasonable to perform further molecular analysis at the time of diagnosis in cases that have a sizeable risk of recurrence requiring systemic therapy (Stage IIIA-C, IIB, IIC, and possibly earlier). These include:
BRAF: with BRAF and MEK inhibitors now available, knowledge of the presence of the BRAF V600 mutation is potentially critical. The combination of Trametinib (MEK inhibitor) and Dabrafenib (BRAF inhibitor) has become the standard of care for BRAF V600 mutant melanoma based on several phase III trials (see below). Adjuvant studies are underway and metastatic studies demonstrate a strong survival advantage over standard chemotherapy. This mutation will be found in approximately 50% of cutaneous melanomas originating from the torso or other body areas with intermittent sun exposure. Although less frequently, it is also seen in melanomas from chronic sun damage sites, and acral sites as well.
CKIT: CKIT mutations are observed in acral and mucosal melanomas primarily but also in regions with chronic sun damage (5-10%) and less frequently on intermittent sun exposed skin. KIT inhibitors have proven to be active in these melanomas when disseminated.
Other genetic alterations are likely to gain in importance over the next few years. Already studies are directed at NRAS mutated melanoma. Clinical activity has been observed with MEK inhibitors and now larger phase III trials are examining the true benefit of these agents in NRAS mutant melanoma. The ability to use next generation sequencing especially with a targeted capture approach has allowed one to explore for mutations in the entire sequence of hundreds of different cancer related genes.
Genetic mutation analysis may be delayed until treatment is indicated, but in those cases, tissue may not be available.
What therapies should you initiate immediately i.e., emergently?
Emergency scenarios associated with melanoma
It is rare that a primary melanoma is associated with a clinical emergency, but it is critical that it is recognized as early as possible by the patient and physician as suspicious and a biopsy performed. Other situations where emergent surgery or radiation may be indicated include:
Surgery for large, painful and ulcerated lymph node metastases which are impinging on vessels or nerves.
Surgery for brain metastases that are isolated and symptomatic (or asymptomatic) when the extracranial disease is limited or controlled.
Surgery for small bowel metastases which are causing blood loss and anemia or bowel obstruction.
Radiation therapy in patients with controlled or limited systemic disease. Stereotactic radiation therapy for limited number of brain metastases (<5 lesions) whole brain radiation therapy (WBRT) may follow in some cases.
WBRT for multiple brain metastases in patients with poorly controlled systemic disease or poor performance status.
Other clinical emergencies associated with disseminated cancer seen with melanoma:
Spinal cord compression - radiation therapy or surgical debulking and then radiation therapy.
Pathologic bone fracture of long bone (weight bearing) - surgery and radiation therapy.
What should the initial definitive therapy for melanoma be?
Approach to Primary lesions
1. Adequate whole thickness punch biopsy or incisional biopsy.
2. If primary is narrow (<1 mm) and it is greater than 0.75 mm, displays Clark level IV (into the reticular dermis), ulceration, or excess mitoses (>1/mm2) then a sentinel lymphatic staging is suggested. Lesions greater than 1mm are generally mapped at the time of the wide excision.
3. Initially any laboratory testing or CT or PET scanning is not recommended.
4. A wide local excision recommended (when feasible) -
melanoma in situ- excision with clear borders
melanoma primary T1a/b: 1 cm margin
melanoma primary T2a/b: 1-2 cm margin
melanoma primary T3a-T4b: 2 cm margin
5. At time of sentinel lymph node staging - chest x-ray and LDH.
6. If deep primary lesion greater than 4 mm or positive lymph nodes (stage N1a-N3) - full body staging (PET preferred or CT of chest/abdomen/pelvis) and brain MRI or CT scan.
7. For patients with palpable lymph nodes, it may be reasonable to perform lymphatic mapping to determine if there are additional draining lymph node basins. In addition, some palpable lymph nodes may turn out to be benign or reactive. Nevertheless, if gross lymph nodes are found then a complete lymph node dissection should be performed. Optimally, this entails removal and analysis of greater than 15 lymph nodes from the head and neck, greater than 10 lymph nodes from the axilla, or greater than 5 lymph nodes from the groin.
Upon completion of primary and regional staging, the AJCC staging criteria provide the patient and physician with an excellent understanding of their prognosis effecting their need or acceptance of adjuvant therapy with IFN, their eligibility for clinical trials, and the intensity of clinical follow-up. In the inguinal lymph nodes some surgeons will include pelvic lymph node dissections if either suspicious on CT scan or a positive Cloquet's node (node at entry to pelvis).
Sentinel lymph nodes
An important question to address is whether the sentinel lymph node needs to be mapped. This decision is based on the depth of the lesion (Breslow stage).
Lesions with the following characteristics should be considered for lymph node mapping:
greater than 0.75-1.0 mm in depth
Clark level IV (into the reticular dermis)
excess mitoses (>1/mm2)
Either of the latter two characteristics constitute a T1b stage. Lesions greater than 1mm are generally mapped at the time of the wide excision. At the time of sentinel lymph node biopsy it is reasonable to obtain a serum lactate dehydrogenase (LDH) and chest x-ray. The risk of lymph node disease increases with depth and ulceration of the primary.
Completion lymph node dissection
Standard of care remains completion lymph node dissection (CLND) for any positive sentinel lymph node, but the approach is evolving and there are ongoing studies to evaluate observation with periodic ultrasound versus CLND for positive sentinel lymph nodes. Some studies have suggested this group of patients may be followed with close observation. Some experts advocate against performing CLND on those with under 0.1 mm of tumor in their standard lymph node dissection (SLND).
Once staging of sentinel lymph node is completed, patients may generally proceed directly to a CLND. Systemic and brain imaging can be performed at completion of all surgery, when the entire T and N staging can accurately be defined and risk for distant outcomes is much better appreciated. This then completes the initial staging of melanoma and decisions concerning adjuvant therapy can be made.
There are some exceptions to this general rule including those patients with very deep ulcerated lesions (T4b) who may have systemic disease even in the absence of nodal disease. At the end of primary and regional staging, the AJCC staging criteria provides the patient and physician with an excellent understanding of their prognosis effecting their need or acceptance of adjuvant therapy with IFN, their eligibility on clinical trials, and the intensity of clinical follow-up.
Patients who present with palpable or symptomatic regional lymph node involvement with melanoma, whether synchronous with the primary melanoma, or asynchronous following the primary some time later, or without a known primary, should undergo complete staging of the body (PET or CT) and brain (MRI or CT).
If staging reveals no other disease, a CLND should be performed. In the inguinal lymph nodes some surgeons will include pelvic lymph node dissections if either suspicious on CT scan or a positive Cloquet's node (node at entry to pelvis).
Adjuvant therapy for high-risk surgically resected disease
There is still a great deal of controversy toward the treatment of high-risk melanoma with 12 months of high-dose interferon (IFN) adjuvant therapy. While mortality from therapy is very rare, there is a major impact on quality of life with depression, myalgias, arthralgias, anorexia and a number of other chronic adverse events.
Several Eastern Cooperative Oncology Group (ECOG) trials demonstrate a significant survival advantage for high-risk melanoma patients with either stage T4a/b or nodal disease (IIB, IIC, IIIA/B/C). However, overall survival benefit has been inconsistent among the many trials and meta-analyses show only a 3-5% absolute and 10% relative increase in survival. The benefit has not been consistently seen in one subset of high-risk patients versus another subset and varies among different clinical trials.
Several retrospective analyses have suggested that IFN largely benefits patients with ulcerated primaries and microscopic lymph node disease with little benefit to those without ulcerated lesions or with large macroscopically involved lymph nodes. There has been no question that high-dose IFN can delay the recurrence of melanoma by a number of months, but due to its toxicity and duration of treatment this has been seen as only a minimal advance by many.
High-dose IFN regimen:
IFN alfa-2b 20 million units/m2 IV 5 days per week for 4 weeks; followed by
IFN alfa-2b 10 million units/m2 subcutaneously three days per week for 11 months.
At the present time, IFN and more recently PEG-IFN are the only approved adjuvant treatment for stage III or high-risk stage II melanoma. Many other approaches have previously failed, including chemotherapy or vaccine-based treatment. However, today newer treatment options are being investigated in the adjuvant setting based on their impressive anti-tumor activity in the metastatic setting improving overall survival dramatically. These include immune checkpoint inhibitors such as anti-CTLA4 (ipilimumab) or targeted treatment with BRAF inhibitors.
Radiation therapy may be considered in two scenarios:
Desmoplastic melanoma - found primarily on scalp demonstrating a strong stromal fibrotic reaction, primarily dermal infiltration, and neurotropic growth pattern, are associated with a high incidence of local and in-transit recurrence and possibly a lower rate of lymph node involvement. Several single arm studies suggest a benefit to local radiation of the primary especially when margins appear inadequate.
High-risk regional lymph nodes - these include 4 or more lymph nodes, extracapsular extension frequently with matted lymph nodes, palpable head and neck lymph nodes. Only recently post-operative radiation in this group of patients have demonstrated a benefit from radiation, with a lower incidence of local and regional recurrence but a dismal overall survival from disseminated disease, and some increase in lymphedema in the treated arm.
Treatment of systemic stage IV and unresectable advanced stage IIIC
The AJCC has divided staging of M1 disease into M1a (soft tissue, skin, and distant lymph nodes), M1b (lung), or M1c (visceral organs or elevated serum LDH above the upper limit of normal (ULN). These stages have prognostic significance with median survival at approximately 13-15 months for M1a, 10-12 months for M1b, and 6-8 months for M1c. LDH alone may provide the most significant prognostic marker of poor outcome. In addition, as with most other cancers, performance status has prognostic significance.
When a patient presents with isolated metastases that can be resected, there is a potential for a long disease-free period and a long survival. These patients likely have a very unique biology that limits their metastases in number at a time. They can be managed over many years with surgery alone. They have a much better prognosis even if M1c (very unlikely high LDH).
Systemic treatment options according to molecular characterization of the melanoma are listed in
Evidence for adjuvant systemic therapy
E1684 - most patients at stage IIIB-C disease; small size of study (287 pts total)- demonstrate a real survival advantage of approximately 9% from 37% to 46% at 5 years and significant DFS improvement
E1690 - no statistical advantage to high dose IFN in terms of survival. Includes many without lymph node dissection T4a/b. Hypothesized that patients in observation arm who relapsed in regional LNs may have gotten IFN salvaged.
E1694- IFN compared to GM2-KLH vaccine - both overall survival and DFS benefit.
The EORTC trials with PEG-Intron demonstrate no overall survival benefit but definite DFS improvement.
The benefit is not consistently seen in one subset of high risk patients between different trials. There is no data that suggests the benefit is greater in IIIA than IIIB disease (initially suggested by EORTC). EORTC retrospective analysis does demonstrate what appears to be a benefit in patients with N1a disease and ulcerated lymph nodes and this will be assessed prospectively.
There is no question that high-dose IFN can delay the recurrence of melanoma by a number of months, but due to its toxicity and duration of treatment this has been seen as only a minimal advance by many. PEG-IFN administered weekly for 2 years has just recently been approved by the FDA based on previous trials under the guidance of the EORTC. While the trials did not demonstrate any survival advantage it did demonstrate a clear improvement in disease-free survival.
Early results from an EORTC trial (18071) have demonstrated superiority of ipilimumab at 10 mg/kg (not the approved dose) over a placebo control in terms of relapse-free survival (RFS) with a median RFS of 26 months versus 17 months (HR 0.75; 95% CI, 0.64-0.90; P=0.001). It is too early to draw any conclusions about overall survival. Trials comparing several doses (3 mg/kg and 10 mg/kg) of ipilimumab to high dose IFN are still underway with results pending. The ipilimumab arm experienced significant autoimmune related toxicities with both diarrhea and colitis of all grades in up to 40% and endocrinopathies of grade 3 and 4 in over 15% of patients. Five deaths were observed in the ipilimumab arm.
What should you tell the patient and the family about prognosis?
The prognosis of primary melanoma is well defined by a set of staging procedures and large database reviews by the AJCC with over 18,000 patients.
Based on T stage one can be assured of a very low risk of recurrence and death if disease is T1a.
Ulceration upstages each lesion.
Ulceration of the primary melanoma with regional lymph node involvement represents a very poor prognostic situation.
Presence of regional lymph node involvement is likely overall the most important prognostic factor for localized melanoma.
Those patients with N1b, N2b, or N3 disease have a much worse prognosis, with those with N3 disease having a risk of recurrence as high as 85-90%.
The disease can recur in-transit between the primary and the regional lymph nodes. This occurs primarily in those patients with a deep primary that is ulcerated or a desmoplastic melanoma on the scalp or elsewhere. Local recurrence or in-transit disease carries an extremely poor prognosis and will likely recur beyond the region, but can remain in the region for long periods of time (years) without distant metastases. Recurrence in regional lymph nodes has become less frequent due to the incidence of SLND, but is still a site of spread.
Metastatic disease is most frequent in soft tissue, skin, lymph nodes and lungs. Other visceral organs are also involved including liver, brain, adrenal glands, small intestines, and even bone. Metastatic disease carries a very poor prognosis but presently there are a number of factors which should be taken into consideration and mortality rates and duration of survival is influenced by a number of factors.
High-dose interleukin-2 (IL2)
In those patients deemed to be inappropriate for complete surgical resection, systemic treatments are the primary therapeutic approach. Since 1998, high-dose interleukin-2 (IL2) has been approved. This is a very toxic therapy that should be administered to select patients with excellent organ function (cardiac, pulmonary, and no active brain metastases) and aged under 70 years, in a setting and situation with expertise and significant experience in the use of the agent. It only has a 15-20% response rate.
However, after 5-10 years, a small number of patients (5-8%) are disease-free in complete remission. Almost no patients have relapsed after 3 years in complete remission. Therefore, for a very select group of patients, IL2 does hold out a potential for long-term cure. This regimen is associated with a capillary leak syndrome that can include hypotension, fluid retention, renal and hepatic hypoperfusion, and pulmonary edema.
High-dose IL2 regimen:
IL-2 600,000 or 720,000 IU/kg given in 15-minute infusions IV every 8 hours for a maximum of 14 doses on day 1 and day 15 schedule every 6 to 8 weeks.
Patients rarely receive all 28 doses, with most individuals receiving 18-22 doses.
Ipilimumab (Yervoy) is an anti-anti-cytotoxic T lymphocyte antigen 4 (CTLA4) monoclonal antibody which acts to inhibit a checkpoint in the activation of the T lymphocyte. These checkpoints act to modulate and bring an activated T cell down to its resting state. The drug can induce autoimmune events due to the release of an activated immune system not only against the cancer but also normal tissues. These events include colitis with diarrhea, hepatitis, uveitis, endocrinopathies (pituitary, thyroid, adrenal gland) and even neuropathies. However, ipilimumab has demonstrated a significant survival advantage compared to a peptide vaccine alone in patients who had failed primary therapy with IL2 or chemotherapy and in those patients who are treatment-naïve when combined with chemotherapy compared to chemotherapy alone.
Ipilimumab 3mg/kg IV every 3 weeks x 4 doses.
Pembrolizumab is an anti-programmed death 1 (PD1) monoclonal antibody. Similar to ipilimumab, it is considered a “checkpoint inhibitor” immunotherapy. It too is associated with multiple autoimmune toxicities. However, the adverse event profile of this class is somewhat different from anti-CTLA4 drugs, with less endocrinopathies and diarrhea, but potentially more pneumonitis. In clinical trials, response rates approximate 40% among patients who have not received prior CTLA4-targeted therapies, and 25-30% among those previously treated with ipilimumab. Responses tend to be durable, with a median duration of almost 2 years and 2-year overall survival rates approaching 50%. Pembrolizumab, the first PD1-directed therapy to be approved is indicated after treatment with ipilimumab and-in BRAF V600E mutant cases-after treatment with a BRAF inhibitor.
Pembrolizumab 2 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity.
Tyrosine kinase/signal transduction inhibitors
The 40-50% of cutaneous melanomas that express a V600 mutation in BRAF have activation of the MAP kinase pathway. Pre-clinical studies supported the importance of this activated oncogene in the proliferation and survival of melanomas.
An inhibitor to BRAF V600 mutant, called PLX4032/RG7204/vemurafenib (Zelboraf), has demonstrated an overall objective confirmed response rate of over 50%, a progression-free survival of nearly 7 months, and an overall survival of well over 14-16 months.
A phase III trial of treatment-naïve patients with BRAF V600 mutant melanoma were treated with vemurafenib versus dacarbazine. The improvement in overall survival and progression-free survival resulted in early termination of the trial at an interim monitoring point. A phase II trial of vemurafenib has demonstrated a median overall survival of nearly 16 months, an outcome far superior to those seen in other large trials.
Vemurafenib 960 mg orally twice daily.
Dose reduction may be needed due to rash, arthralgias or other systemic complaints. Cutaneous squamous cell tumors known primarily as keratoacanthomas are frequent in patients (found in up to 25% of patients) receiving BRAF inhibitors. Treatment with surgery is adequate and in general patients do not need dose interruption of vemurafenib. This effect appears largely due to the ability of vemurafenib to accelerate the growth of pre-cancerous RAS mutated skin lesions.
Another BRAF V600 inhibitor, dabrafenib has also demonstrated response rates in the 50+% range with median progression-free survival of 5.3 months, far superior to chemotherapy. The trial compareing dabrafenib to chemotherapy allowed crossover to dabrafenib in the chemotherapy progressing patients. This made the overall survival endpoint difficult to meet.
Toxicities include the same hyperproliferative skin lesions as with vemurafenib but a lower rate of cuSCC. The photosensitivity induced by vemurafenib was not seen in patients receiving dabrafenib. However, the incidence of fevers and chills is considerably higher than with vemurafenib. Arthralgias and rash also occur in a similar frequency to vemurafenib.
Dabrafenib 150 mg orally twice a day.
Single-agent therapy with trametinib, a MEK inhibitor, improved both PFS and OS compared to chemotherapy in a trial of patients with BRAF V600 mutant melanoma also allowing crossover. The response rates were lower than in the BRAF inhibitor trials, but PFS was approximately 4.8 months (only slightly lowshorter than dabrafenib). Principal toxicities include acneiform rash, fatigue, visual symptoms, and rare cardiac dysfunction
Trametinib 2 mg orally once per day.
The combination regimen has become the standard of care regimen for patients receiving BRAF directed therapy. The regimen has demonstrated an improvement in both PFS (against dabrafenib) and both PFS and OS (against vemurafenib). Certain toxicities are considerably less such as the hyperproliferative skin lesions including cuSCC, while others such as fever and chills are significantly increased.
Dabrafenib 150 mg orally twice daily + trametinib 2 mg orally once per day.
For patients whose tumors lack BRAF mutations, testing for CKIT mutations may be appropriate. There is clear clinical activity of c-kit inhibitors, but the consistency of response is much less than for BRAF inhibitors. Potentially up to 25% of patients will respond. Some these responses can be durable. C-kit inhibitors include:
Single-agent and combination chemotherapy regimens have shown modest activity in melanoma, particularly in individuals with good functional status and lung/non-visceral sites of disease. Response rates range between 5-15%, and there is no clear effect on overall survival.
Dacarbazine 800-1000 mg/m2 IV every 3 weeks
Temozolomide 150-200 mg/m2 orally for 5 days every 21-28 days
Carboplatin AUC 5-6 IV plus paclitaxel 175-225 mg/m2 IV every 21 days
What if scenarios in the treatment of melanoma.
What if a patient presents with isolated cutaneous lesion which is dermal and has no clear connection to the epidermis?
These are difficult cases where we do not know if this is a primary and where we simply do not see the characteristic atypical cellular activity at the epidermal/dermal junction or a dermal metastases from another melanoma.
In this situation it is most favorable to the patient to treat him/her as if this is a primary melanoma and perform a sufficient wide excision and sentinel lymph node mapping if indicated by the depth. In this case patients may have the best chance for long-term survival.
What if a patient has history of melanoma 3 years ago and now presents with an asymptomatic lesion found on chest x-ray?
In this case, imaging should determine the presence of other metastases (CT or PET and brain scan). If none are found, the pulmonary lesion should be resected. There is no need to attempt a biopsy, whether it is a metastatic lesion from melanoma or a primary lung cancer, surgery would be indicated.
Obviously this will be influenced by the actual appearance of the lesion. Infiltrative, cystic lesions or calcified lesions should lead to an evaluation for infection or chronic inflammatory disease. The extent of surgery can be determined intra-operatively when a frozen section if performed.
What if a patient presents with several nodules on the extremity proximal to his primary melanoma - what are the options?
This scenario is not infrequent, especially in association with lesions that are deep (>4 mm) and ulcerated. They can be managed by either:
Surgery - especially if there are few, their recurrences are infrequent and surgery has little morbidity. This can be a strategy for years in some cases.
Local injection of the lesions - this approach is taken when surgery is less practical, based on number or location of lesions. Injection has been with use of a number of agents including BCG, IFN, GM-CSF, or Interleukin-2. Application of imiquimod (Toll-like receptor [TLR] agonist) to the region could also be considered. A new treatment with an oncolytic virus, carrying the GM-CSF gene (T-VEC), that is directly injected into the lesions has shown promise and has gone through extensive testing and is close to approval.
Limb perfusion or infusion - this is the most aggressive approach but can be very successful in achieving regional control of disease when lesions are too numerous and/or diffuse to consider local measures alone. Likely, this would be the case when there are more than 5 lesions, lesions with wide distribution, and lesions that return after short periods of time (weeks to a few months). This approach attempts to isolate the extremity and then canulate either the artery or vein and while infusing high doses of melphalan, heat the leg to high temperatures above 41°C. This does carry risks including arterial thrombosis and compartment syndrome, but can control regional disease for years in well over 50% of patients.
Systemic therapy is a consideration either alone or in combination with surgery. Patients with in-transit lesions will generally go on to develop systemic disease and provide an excellent opportunity to look at new treatments on clinical trials. They also are ideal clinical settings to obtain serial biopsies for defining biomarkers associated with treatment. Standard chemotherapy does have a higher response rate with these patients than those with visceral disease, but these responses are frequently transient.
What if a patient is being evaluated for high-dose Interleukin-2 and found to have a serum LDH of over 3 times the upper limit of normal?
Interleukin-2 is the one treatment for metastatic melanoma where there is strong evidence for long-term “cures”. The one tumor characteristic that most strongly should dissuade one to administer IL-2 is serum LDH elevation.
This finding (elevated LDH) is associated with rapidly progressive disease and usually a tumor bulk that is increasing over a short time frame. In these cases immunotherapy such as Interleukin-2 is unlikely to be successful. Trials with IL-2 have rarely included those patients due to their frequent poor PS, but regardless of the actual tumor bulk and PS, I would not recommend treatment in this cohort.
The size of tumor metastases and even location in visceral organs does not make a durable response impossible. As illustrated in the algorithm. BRAF V600 mutant patients are able to receive dabrafenib plus trametinib with good success. If the melanoma does not express that mutation than options include Ipilimumab or experimental phase I, II or III therapy.
Finally chemotherapy is another option and this includes dacarbazine, temozolomide, or taxane-containing regimens. The selection of therapy depends on performance status. It is likely only the BRAF mutant tumor bearing patient will benefit consistently from therapy with vemurafenib.
What if a patient has rapidly growing symptomatic metastatic melanoma and you cannot get the patient's tumor analyzed for BRAF mutation due to long delays in getting the outside tissue; would you just empirically administer the BRAF inhibitor?
While there is a 50% chance for some cutaneous lesions to express this mutation, it would not be a good idea to empirically treat patients without knowledge of their melanoma mutation status. If the melanoma does not express the BRAF V600 mutation, it very well could have its growth accelerated.
An increase in frequency of cutaneous squamous cell carcinoma (cuSCC) with BRAF inhibitors is likely due to their ability to enhance activation of the wild type (WT) RAF molecules, especially in the setting of upstream activation primarily through RAS. WT BRAF melanomas might undergo accelerated growth through this same mechanism.
What if a patient has a BRAF V600 mutant melanoma and has limited asymptomatic disease in lung and lymph nodes for the past several months with little growth, what would you administer interleukin-2, ipilimumab, or dabrafenib plus trametinib?
In this case, all three options are reasonable. Over the next few years, how to use these agents in sequence or in combination will hopefully be sorted out. For now we know that Ipilimumab can extend survival if administered as initial therapy. However, after administration, responses and toxicities may occur late. This could make administration of IL-2 or even vemurafenib more difficult.
Interleukin-2 can only be administered to a small cohort of patients due to organ function and age limitations. However it is the only therapy where we have established an outcome with 10-20 years in complete remission for a small subset of patients (5-8%). There may be this same population of long-term disease-free patients receiving ipilimumab but the experience is not long enough at this point.
Finally, dabrafenib plus trametinib is the regimen most likely to achieve major tumor regression in a significant majority of patients. Those patients with normal serum LDH had a response rate of well over 80% to this combination of targeted agents. However, the responses to this targeted therapy are considerably less durable with a median of 10 months and only a few patients continuing on therapy over 18 months. On the other hand, once a patient progresses on the combination, they can be treated with one of the other agents.
Follow-up surveillance and therapy/management of recurrences.
There are few long-term studies evaluating the role of surveillance in melanoma patients that provide established evidence based guidelines. In all cases imaging should be considered to evaluate new signs and symptoms.
Stage IA, IB, IIA
There is no role for routine imaging.
History and physical exam every 3 months x 2 years, then every 6 months x 3 years, then annually after 5 years.
Role of serum LDH and Chest X-ray is unproven.
Stage IIB, IIC, IIIA
History and physical exam every 3 months x 2 years, then every 6 months x 3 years, then annually after 5 years.
Role of routine imaging is unproven.
Consideration to annual imaging with PET scan for the initial 3 years, but not recommended.
Chest X-ray and LDH every 6 months for initial 3 years given consideration.
Stage IIIB, IIIC
History and physical exam every 3 months x 2 years, then every 6 months x 3 years, then annually after 5 years.
Role of routine imaging is unproven.
However, consider imaging (PET scan or C/A/P CT scan) at 6 month intervals for the initial 3 years due to the very high risk.
Chest X-ray and LDH at 6 month intervals for years 4-5.
Stage IV (previously resected)
In most cases, consideration to imaging (PET scan or C/A/P CT scan) every 3 months for the initial 2 years and then every 6 months for a minimum of 3 additional years. After 5 years, consider annual imaging.
The type of imaging will be influenced by resected site of recurrence. For skin only disease this may be performed less frequently.
Treatment of isolated metastatic disease
Surgery is a treatment that should be considered in a number of metastatic disease settings. It can provide a palliative role for patients with:
Lymph node or soft tissue disease where tissue ulceration and necrosis creates a local problem for the patient.
Pain control of soft tissue or nodal disease.
Brain metastasis - for symptomatic lesions, rapid relief can be achieved by resection.
Either bleeding or obstruction from small bowel metastases.
Tumor with uncontrolled bleeding.
In some cases, surgery may provide more definitive therapy for patients with asymptomatic isolated metastases. Retrospective studies, adjuvant vaccine trials, and even prospective trials demonstrate 5 year survivals of 30-50% in patients with resected metastatic disease. The outcome is best when:
A single metastasis versus greater than 2 metastases.
Single organ versus multiple organ involvement.
Soft tissue or skin metastases versus visceral metastases.
Prolonged interval since previous disease recurrence.
In some of these patients who have a short disease-free duration when their metastasis occurs, consideration could be given to a short 3-6 month course of systemic therapy (clinical trial) prior to surgery. This approach may not only lead to disease regression but also provide some assurance that disease would not recur very soon after surgery.
Systemic treatment - treatment of disseminated disease
Until recently, options for systemic treatment of unresectable metastatic disease were very limited and in general clinical trials was recommended as standard therapy for most patients.
Chemotherapy has demonstrated some activity, but with more rigorous disease monitoring response rates have dipped to below 10% and the overall survival had not been improved from a median of approximately 8 months. Single agent therapy with Dacarbazine, Temozolomide, taxanes have all proven to have response rates in the 5-15% range and no major influence on survival.
Chemotherapy combinations with dacarbazine and platinums slightly improved response rates but at the cost of significantly more toxicity and no improvement in survival. Even the addition of biotherapy with Interleukin-2 and Interferon to combination chemotherapy ultimately was unable to improve overall survival. Therefore even today, the role of chemotherapy has not been defined and is rarely a good palliative approach.
Now there are better standard options which have changed the way we approach the patient with stage IV or unresectable stage III melanoma. A critical initial test in 2012 is to define the genetic mutation profile for patients with cutaneous or mucosal melanoma.
Those patients with BRAF V600 mutations are potentially sensitive to BRAF inhibitor based therapy. At present vemurafenib at 960 mg BID orally and dabrafenib at 150 mg BID orally are approved for this subset of patients. These agents have a high response rate (>50%) and offer patients the possibility of rapid tumor response and improved symptoms. The clinical activity of both agents is quite similar but there is a difference in toxicity with exquisite photosensitivity associated with vemurafenib and fevers and chills associated with dabrafenib.
In those patients needing immediate or short-term symptom relief, these agents are the only likely effective agent. However, drawbacks are the near universal progression with a median progression-free survival of less than 7 months though overall survival has been up to a median of about 14-16 months.
Additionally both have a number of bothersome, but not life-threatening, toxicities. These center around the skin with skin tags, verrucae, papillomas and cutaneous squamous cell carcinoma. These are generally of the keratoacanthoma type and can be treated with simple excision without dose interruption.
Additionally patients can experience rash, arthralgias, and even true inflammatory arthritis.
More recently trametinib, a MEK inhibitor given at 2 mg orally daily has also been approved for BRAF V600 mutant melanoma. This was based on superior survival (PFS and OS) compared to chemotherapy alone, even when those patients were allowed to crossover to trametinib at the time of progression. Its response frequency and duration of response and PFS are less than that of the BRAF inhibitors at 25% and 4.8 months. Its toxicity profile includes an acneiform rash, diarrhea, peripheral edema, fatigue and infrequently depressed LVF, or ocular symptoms.
It has recently been established that the combination of tramdtinib plus dabrafenib at full doses is superior to single agent BRAF inhibitor. When compared to dabrafenib alone there was a significant improvement in PFS and an early suggestion of an improved OS. The HR for PFS was 0.75, while the HR for OS was 0.63. In another large trial comparing this combination to single agent vemurafenib, there was a significant improvement in overall survival with a HR=0.69. These two large phase III studies along with an earlier phase II trial have established combination trametinib plus dabrafenib as the new standard of care. This regimen with the addition of a MEK inhibitor decreases the incidence of secondary cuSCC and papilloma as well as other signs of hyperproliferative skin disease. On the other hand, the combination of drugs led to an increase in some troublesome fever, chills, and occasional hypotension. These side effects require NSAID, drug interruptions and occasionally steroids to control the fever and chills which can get as high as 40°C.
For patients who are less symptomatic and whose melanoma is not rapidly progressing, there are several options. As stated previously, very healthy patients may have a prolonged response with nearly 10% being disease-free for 5-20 years and few relapsing after 3 years in CR or surgically induced CR when treated with high-dose interleukin-2.
This is generally administered in a setting with experience in acute care with the need for pressor support and close continuous monitoring. Doses are either 600,000 or 720,000 units/kg administered IV every 8 hours up to 14 doses in both week 1 and 3. Patients rarely receive all 28 doses but usually the median falls approximately in the 18-22 range of doses.
Patients can take 1-3 weeks to recover from acute toxicity. This should only be administered in an experienced center and patients must be carefully screened. Ipilimumab is the other choice for these patients. It can induce an immediate clinical response in the first 12 weeks in about only 5-10% of patients.
However, many patients develop responses after initial progression or after new isolated lesions and regression elsewhere. It is estimated that this effect is seen in up to 40% of patients in total. Most impressively is the benefit in survival in both first line or following previous therapy. The approved dose of ipilimumab is 3mg/kg IV every 3 weeks x 4. Subsequent doses have not been approved and cost may be prohibitive.
Patients must be monitored and very aware of toxicities which are largely a result of the immune activation against host tissues. This manifests itself in colitis, hepatitis, rash, endocrinopathies (pituitary, thyroid, adrenal), uveitis, and neuropathy. Rapid treatment of significant (grade 3) toxicities must be initiated early with steroids, then with TNF antagonists, and even mycophenalate.
The sequence of therapy is not well established, but in these patients, IL-2 may be a reasonable initial therapy, since evaluation of the benefit of Ipilimumab may take up to 24 weeks before progression or response is determined with certainty.
Anti-PD1/anti-PDL1 inhibitors (Pembrolizumab (MK-3475), Nivolumab, and MPDL3280A)
These agents are in the midst of changing the therapeutic landscape of melanoma and a number of other cancers as well. They are antibodies capable of blocking the interaction of the programmed death (PD) receptor on effector (previously activated) T lymphocytes and PDL-1 on the surface of the malignant cells as well as other inflammatory cells. Antibodies targeting PD1 also inhibit PDL2-PD1 interactions. The receptors are well known to be present on tumor cells originating from a wide range of histologies. The antibodies are IgG4a anti-PD1 and IgG1a (modified) anti-PDL1. They have been shown to induce responses in up to 40% of patients who have not received ipilimumab, previously and 25-30% in those who have failed prior ipilimumab.
These responses appear quite durable with the longest followup demonstrating a median response duration of 23 months. Furthermore, two and four year survival rates are at 48% and 32% in the initial 100+ melanoma patients followed with nivolumab therapy. In a BRAF WT melanoma patient population, nivolumab has demonstrated a response rate of 40% versus 11% for chemotherapy and a significantly improved survival with 1 year survival at 73% versus 42% for nivolumab and chemotherapy. More recently both nivolumab and pembrolizumab has demonstrated improved PFS and response rate in patients failing ipilimumab compared to chemotherapy. These improvements were far superior to chemotherapy alone. The anti-PDL1 antibody (MPDL3280A) appears to have similar clinical activity of around 30% in a much smaller cohort of melanoma patients.
All of these drugs have a less severe toxicity profile compared to ipilimumab with fewer incidences of both colitis or endocrinopathies. The one toxicity of concern has been development of a pneumonitis which can rarely be severe but its overall incidence is below 5%. Other toxicities such as fatigue and rash are present though again less severe than experienced with ipilimumab. Grade 3-4 toxicities are present in less than 10-15% of patients and it is rare to see any single toxicity present in more than a few patients (<5%). Extremely careful management for those who develop cough or shortness of breath with or without hypoxia is required. A rapid evaluation for other causes should be undertaken but if no obvious etiology is found it should be presumed due to drug-induced pneumonitis and steroid therapy is recommended.
At the present time, pembrolizumab is the only approved agent, but that will likely change very soon. It is approved only in those patients who have failed prior ipilimumab and if BRAF V600 mutated also a BRAF inhibitor. These restrictions will also likely be modified with time and further clinical trial results.
For those lacking BRAF mutations in their melanoma, testing for CKIT mutations may be appropriate. There is definite clinical activity for inhibitors of CKIT but the consistency of response is much less than for BRAF inhibitors. Possibly 25% of patients will respond but for some, these responses can be durable.
Drugs with activity include imatinib at 400-800 mg/d, dasatabine, nilotinib, or sunitinib. Clinical trials are greatly preferred. Testing of melanomas that have originated from areas of skin only exposed to intermittent sun may be extremely low yield. The other above 50% of patients have no defined driver mutation or have a NRAS mutation for which we have no effective targeted agent. These patients still have options including IL-2 or Ipilimumab as above for the BRAF mutant melanoma.
However, the major dilemma is how to proceed in those with rapidly progressive disease, high LDH and declining performance status. There are no correct answers, but chemotherapy may provide some relief in an occasional patient. These include DTIC or Temozolomide, or even taxane containing combinations with carboplatins. There is even some provocative phase II randomized data suggesting these chemotherapy agents with bevacizumab may be more effective in this poor prognostic subset.
This will need to be confirmed in larger phase III trials. There is no question we have a great deal to learn. There are tools such as Ipilimumab or vemurafenib we never had in the past, but still many patients either do not respond, or progress soon after treatment.
In 2012, physicians and patients have a choice of several treatments based on several factors, including whether their tumor expresses the V600 mutation in BRAF, the pace of their disease growth and whether there are significant symptoms from disease including their serum LDH, and their age and organ function. Certainly patients without the BRAF V600 mutation in their melanoma would generally initiate therapy with Ipilimumab unless they are good candidates for Interleukin-2.
It is unlikely either of these therapies will be successful in those with rapidly growing symptomatic tumors, but Ipilimumab would be preferred. On the other hand, a symptomatic patient who has a BRAF V600 mutant melanoma should receive vemurafenib. More detailed support information is found below.
Evidence for systemic therapy
Interleukin-2 is unlikely to change the median survival of the treatment population. However, its approval by the FDA was based on the fact that of those patients who did respond to IL-2 (16%), about half (8%) had gone on to a sustained complete remission or a partial remission converted by surgery into a complete remission. Those patients with sustained complete remissions rarely recur after 36 months and many are alive free of disease for well over 10 years.
The patients treated with Interleukin-2 must have excellent organ function (cardiac, pulmonary, and renal), be without active brain metastases, generally be less than 65-70 years of age, have a performance status of 0-1 (0 preferred), and be treated at a center where there are adequate facilities and experience with this treatment. This obviously limits its application to a small set of patients.
More recently, ipilimumab has been approved for the treatment of advanced unresectable melanoma. This approval was based on two randomized phase III clinical trials. First published in 2010 was a randomized double blinded trial where patients were randomized to Ipilimumab alone, ipilimumab with a peptide vaccine, or the peptide vaccine alone. Ipilimmab was administered at 3 mg/kg. The randomization was 1:3:1 and the peptide vaccine was derived from the gp100 protein and restricted for patients carrying the HLA-A0201.
Patients were all HLA-A0201 positive and had failed previous therapy. While the response rates were 11% or under for the Ipilimumab arms and the PFS increase was not impressive, there was a significant overall survival advantage to those on ipilimumab with or without peptide vaccine.
The median overall survival was 10.0 months among patients receiving ipilimumab plus peptide vaccine, as compared with 6.4 months among patients receiving peptide vaccine alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with peptide vaccine alone, 0.66; P = 0.003).
In 2011, another trial examined the benefit of ipilimumab as initial therapy in metastatic melanoma. This trial compared Dacarbazine with or without Ipilimumab and explored a higher dose of ipilimumab. Ipilimumab was given at 10mg/kg IV in this trial and at 3mg/kg IV in the trial discussed above in previously treated patients.
Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001).
Ipilimumab has a rather unique pattern of toxicity due to its mechanism of action. Patients develop manifestations of autoimmunity. These include colitis, hepatitis, uveitis, endocrinopathy (thyroid, pituitary, adrenal) and neuropathy. They are largely managed with immune suppression including corticosteroids, infliximab, and mycophenalate. Physicians must very closely follow patients on this drug and patients must be very compliant to react quickly to these symptoms.
It appeared that dacarbazine enhanced the hepatic toxicity of ipilimumab and does not warrant inclusion into therapy. While toxicity most frequently takes place during the initial 12 weeks of therapy, it can manifest itself weeks to months later.
Ipilimumab mechanism of anti-tumor effects
As stated above, anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. In an attempt to understand tumor variables that may influence the clinical benefit from this agent, whole-exome sequencing of tumors and matched blood samples from patients receiving anti-CTLA-4 antibody was performed. Somatic mutations and candidate neoantigens generated from these mutations were characterized. A discovery set of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit was examined. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genome-wide somatic neoepitope analysis and patient-specific HLA typing, the investigators identified candidate tumor neoantigens for each patient. There appeared to be a set of neoantigens specifically present in tumors responding to CTLA-4 blockade. This signature was validated in a second set of patients who were treated with anti-CTLA-4 antibodies. These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma.
Anti-PD1/anti-PDL1 inhibitors (Pembrolizumab (MK-3475), Nivolumab, and MPDL3280A)
These agents have changed the therapeutic landscape of melanoma.
The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. The IgG4 anti-PD-1 antibody pembrolizumab (MK-3475) was administered to patients with advanced melanoma intravenously at a dose of 10 mg/kg every 2 or 3 weeks or 2 mg/kg every 3 weeks to both patients who had received prior treatment with the immune checkpoint inhibitor ipilimumab and patients who had not. A total of 135 patients with advanced melanoma were treated.
Common side effects due to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were grade 1 and 2. The confirmed response rate across all dose cohorts, evaluated by central radiologic review, was 38%. In this early trial the response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not. Responses were durable in the majority of patients (median followup, 11 months among patients who had a response); 81% of the patients who had a response were still receiving treatment at the time of analysis. In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with pembrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects.
In another recent trial, 540 patients who had failed prior ipilimumab treatment were randomized between pembrolizumab 10 mg/kg or 2 mg/kg every 3 weeks versus chemotherapy of choice. All patients were required to progress within 24 weeks of ipilimumab and the 25% BRAF V600 mutated melanoma patients were required to fail prior BRAF inhibitor. PFS was the primary endpoint. 6-month PFS was 38% vs 34% vs 16%, respectively, for those receiving 10 mg/kg or 2 mg/kg pembrolizumab or chemotherapy. Nine-month PFS was 24% vs 29% vs 8%, respectively. Pembrolizumab was beneficial in all subsets examined including those patients with high LDH and mutant BRAF V600. RR was 21% (3 mg) vs 25% (10 mg) vs 4% (chemotherapy).
Nivolumab is another anti-PD1 agent with similar properties. It is not yet approved but likely will be in the near future. In a clinical trial, patients with advanced melanoma (N=107) received intravenous nivolumab every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Doses ranged from 0.1 mg/kg to 10 mg/kg without a clear dose response effect. Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma appears far superior to similar patient populations in the literature. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable.
The use of nivolumab in previously untreated patients with advanced melanoma was tested in a double-blind phase 3 study. Four hundred and eighteen previously untreated patients who had metastatic melanoma without a BRAF V600 mutation were randomized to receive nivolumab (at a dose of 3 mg/kg every 2 weeks) or dacarbazine chemotherapy every 3 weeks. The primary end point was overall survival. At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across pre-specified subgroups, including subgroups defined by programmed death ligand 1 (PD-L1) expression. Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation.
Four hundred and five melanoma patients all who had failed ipilimumab therapy were randomized 2:1 between either nivolumab 3 mg/kg versus chemotherapy of choice. With more than 6 months' follow-up of 20 nivolumab-treated patients and 47 patients treated with chemotherapy, response rate was 32% versus 11%. In a subset analysis, PDL1+ tumors had a 44% RR versus 20% in PDL1 negative tumors. BRAF V600 mutated tumors had a 23% RR, versus BRAF WT having a 34% RR.
Finally, combination therapy with ipilimumab plus nivolumab has been piloted based on abundant preclinical data in an attempt to block T cell activation at both phases of the T cell activation cascade. A phase 1 trial of nivolumab combined with ipilimumab was conducted in patients with advanced melanoma. A total of 53 patients received concurrent therapy with nivolumab and ipilimumab. Objective-response rate for all patients in the concurrent-regimen group was 40%.
Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for
One significant question is the role of PDL1 expression as a biomarker for response to anti-PD1-based therapy. In general, outside of the combination regimen described above, tumor PDL1 expression was associated with higher responses to anti-PD1 therapy. On the other hand, it appears that up to 20% of melanoma patients with PDL1-negative tumors could still respond to therapy. This is seen up to 20% of the time.
In 2010 and 2011, phase I, II, III trials with a BRAF inhibitor, vemurafenib had been reported. The phase I trial reported that the drug was tolerable at 960mg BID orally, was able to inhibit its intended target, the MAPkinase pathway (ERK phosphorylation) almost completely in tumors and could lead to responses in a very large number of patients with a BRAF V600E mutant melanoma.
While the reported response rate was 81%, only 56% were confirmed. Additionally, a large percentage of patients developed cuSCC of the keratoacanthoma type within the initial 8-12 weeks of treatment. These were easily controlled by surgery alone. BRIM2 was a large multicenter phase II trial of vemurafenib in 132 patient with V600 mutant BRAF melanoma who failed prior standard therapy, where responses were all validated and confirmed by an independent radiologic committee.
There was a confirmed response rate of 53% with a progression-free survival of 6.7 months, and an estimated 12 month survival of over 50% (58%). CuSCC was again seen frequently in approximately 25% of patients.
In June 2011, the results of the phase III trial in treatment-naive patients were reported, all of which had V600 mutant BRAF melanoma who were randomized between dacarbazine and vemurafenib. In the analysis of overall survival and progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons).
At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group, response rates were 48% for vemurafenib and 5% for dacarbazine. After a review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended.
Subsequently, dabrafenib, another BRAF inhibitor, has been tested in a phase III trial allowing crossover from chemotherapy to dabrafenib at progression.
Patients with BRAFV600E mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg orally twice daily) or dacarbazine. Two hundred and fifty patients were randomly assigned. Median PFS was 5.1 months for dabrafenib and 2.7 months for dacarbazine, with a hazard ratio (HR) of 0.30 (95% CI, 0.18-0.51; P<0.0001). Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. Grade 3-4 adverse events were uncommon in both groups. This led to approval of dabrafenib.
The MEK inhibitor trametinib was also compared to chemotherapy in the BRAF V600 mutant melanoma population. Three hundred and twenty-two patients with a V600 BRAF mutant melanoma received either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or chemotherapy. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% CI, 0.33-0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32-0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. This trial led to approval of trametinib in 2013
Subsequently, several trials demonstrated an advantage of adding trametinib to dabrafenib over single-agent BRAF inhibitor therapy. First a phase II trial randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg/BID of dabrafenib and 2 mg/daily of trametinib (combination 150/2). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the dabrafenib arm (hazard ratio for progression or death, 0.39; 95% CI, 0.25-0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). Dabrafenib and trametinib were safely combined at full monotherapy doses. Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%).
Following this trial a phase III trial randomized patients in a blinded placebo design between the combination trametinib plus dabrafenib versus dabrafenib. Four hundred and twenty-three previously untreated patients with melanoma harbouring a BRAF V600E or V600K mutation received either combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% CI, 0.57-0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas fever occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group.
A phase III trial compared the same combination to vemurafenib alone. The trial randomly assigned 704 metastatic melanoma patients with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. At the pre-planned interim overall survival analysis, the overall survival rate at 12 months was 72% in the combination-therapy group and 65% in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53-0.89; P=0.005). The pre-specified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46-0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.
Finally a still unapproved MEK inhibitor (cobimetinib) was added to vemurafenib in a randomized comparison to vemurafenib plus placebo. Four hundred and ninety-five patients with previously untreated advanced BRAF V600 mutation-positive melanoma were randomized to receive vemurafenib and cobimetinib or vemurafenib and placebo. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% CI, 0.39-0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Interim analyses of overall survival showed 9-month survival rates of 81% in the combination group and 73% in the control group. Combination vemurafenib and cobimetinib was associated with a slightly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.
This clinical evidence supports the use of combination therapy as the initial approach for BRAF inhibition in BRAF V600 mutated melanoma.
NRAS mutant melanoma has been studied in far fewer clinical trials. However one such trial demonstrated a 10-20% response rate for a MEK inhibitor, trametinib, with a median duration of response of 3-4 months only. This is being followed up in a Phase III trial compared to chemotherapy alone.
Molecular biology of cutaneous melanoma
Great advances have taken place over the past few years in understanding the underlying molecular biology of melanoma. The large majority of melanomas have activation of their MAP kinase pathway which leads to uncontrolled growth, angiogenesis, and resistance to apoptosis. This activated is largely driven by either the BRAF activating mutations (V600) or NRAS activating mutations at 12,13,61 amino acids.
The work of The Cancer Genome Atlas (TCGA) and others also demonstrates a large number of other molecular alterations capable of activating the MAP kinase pathway in melanoma. These include loss of function mutations or deletions in the NF1 gene (which regulates NRAS activation), KRAS or HRAS mutations, CRAF activating mutations, and even mutations in the MEK family of kinases.
However BRAF activation is not sufficient to drive the melanocyte to a melanoma. This is based in part on the finding that 70-80% of benign nevi carry the BRAF V600 mutation. In this case the mutation leads only to hyperplasia and senescence.
Another key step in the process is the loss of cell cycle regulation. Most frequently there is a loss of the gene products of the CDKN2A gene. These include p16INK4A and p19ARF. The loss of one or both of these proteins results in the suppression of retinoblastoma (Rb) protein or p53 activity. These are two critical tumor suppressors that regulate the cell cycle pathway.
Other components of the cell cycle regulatory pathway can also be lost including CDK4 which is the target of the p16INK4A molecule. Additionally Cyclin D1, a driver of the cell cycle can be amplified or activated in a number of melanomas. Therefore, development of melanoma requires both a loss of tumor suppressor gene function and gain of oncogene function as true with many cancers.
Additionally, other molecules play a potentially important role. This includes the PI3kinase/Akt pathway, where PTEN (a tumor suppressor gene) is lost and its phosphatase no longer down regulates phospho-Akt. PTEN loss may occur through deletion or mutation in up to 40% of melanomas. In addition, Akt3 has been shown to be activated through gene amplification in some melanomas.
Also, activated receptor tyrosine kinases driving either the MAP kinase pathway or the PI3kinase/Akt pathway may be amplified or activated through mutations. These include c-KIT in a subset of acral and mucosal melanomas.
Additionally, a small subset of melanomas have amplification of the MITF gene. MITF amplification may also drive these similar pathways and has been associated with a poor prognosis. In general, in the untreated melanoma only one of these molecules is seen to be mutated at BRAF, NRAS or c-KIT. The non-overlapping nature of these mutations is likely due to the dominant effect each of these driver mutations have in the melanoma.
What other clinical manifestations may help me to diagnose melanoma?
There are several essential components of the history and physical exam of a patient with melanoma. History must include a very thorough family history for cancer including melanoma, pancreatic cancer, breast cancer, especially male breast cancer (BRCA2) and history of other family members with many atypical nevi (large and asymmetrical).
Some effort should also be made to determine the hair color and skin sensitivity to sun and presence of freckles in other family members.
A critical component to the physical exam is a thorough and complete skin exam, with all under garments off, including an exam of the genitalia, rectum, and oral mucosa. Other melanomas may be found, and the presence of other suspicious nevi that require close follow-up can be identified.
Lastly, the hair color, eye color and presence of very light skin and many freckles should also be considered in terms of the risk of other melanomas and relationship of sun burns to development of melanoma.
What's the evidence?
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