Therapy for metastatic melanoma: the past, present, and future
© Finn et al; licensee BioMed Central Ltd. 2012
Received: 9 November 2011
Accepted: 2 March 2012
Published: 2 March 2012
Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise.
KeywordsMelanoma Vemurafenib Ipilimumab BRAF Therapy
With approximately 13,000 annual deaths and a median overall survival (OS) of 8 to 18 months, metastatic melanoma is the most aggressive form of skin cancer . Until 2011, only two FDA therapies for metastatic melanoma were approved, dacarbazine and high dose interleukin 2 (HD IL-2), both of which do not increase median OS [2–4]. Dacarbazine is limited by a low response rate (10% to 15%) and an overall survival of eight months . HD IL-2 is limited by an even lower response rate (6% to 10%) and severe toxicity with only a minority of patients achieving a long-term, durable response [3, 4].
Recognition of key molecular mutations that drive tumorigenesis in melanoma has led to the development of promising agents that selectively target and inhibit these mutations and, in turn, provide improved response rates with decreased toxicity. Secondarily, advancements in our understanding of tumor immunology and immune escape have led to the emergence of newer immunologic agents that are less toxic than HD IL-2 but still provide long-term benefits. While these breakthroughs are encouraging, several limitations remain. In the case of vemurafenib, the duration of response is relatively short. In the case with ipilimumab, the response rate is low. The purpose of this review is to summarize the recent advances in the treatment of metastatic melanoma, further describe the current limitations, and comment on promising future strategies to overcome these limitations.
Summary of BRAF inhibitor trials
Ribas et al. 
Vemurafenib in previously treated metastatic melanoma
Not yet reached
Met primary end point of best overall survival target of 30% (95% CI: 43 to 61%)
Chapman et al. 
dacarbazine in untreated metastatic melanoma
Not yet reached
Compared vemurafenib and dacarbazine with co-primary endpoints of overall survival and progression free survival.
84% vs 64% OS at 6 months (95% CI: 78 to 89)
Summary of Ipilimumab Trials
Hodi et al. 
Ipilimumab plus gp100
previously treated metastatic melanoma
Ipilimumab with significant improvement in OS versus gp-100.
Robert et al. 
Ipilimumab plus dacarbazine
dacarbazine in untreated metastatic melanoma
Ipilimumab plus dacarbazine significantly with significant improvement in OS over dacarbazine.
Hersh et al. 
Ipilimumab plus dacarbazine in chemotherapy naïve patients with metastatic melanoma
Ipilimumab plus dacarbazine improved RR and OS compared to single agent ipilimumab.
The recent success of both vemurafenib and ipilimumab instilled hope into physicians and patients with metastatic melanoma; however, the limitations of both therapies emphasize the importance of developing novel treatment strategies. One of the major challenges in overcoming the limitations of these novel therapies is both increasing the duration of response to BRAF inhibitors and improving the response rate of ipilimumab. We will discuss multiple strategies to address the limitations of vemurafenib below.
Overcoming resistance to BRAF inhibitors using additional targeted therapies
Improving upon ipilimumab
While ipilimumab is capable of inducing long-term responses in a minority of patients, the relatively low response rate (10% to 15%) and meager improvement in median survival (two months) limit its utility. A key area of improving the clinical benefit of ipilimumab is to increase the response rate either through improved patient selection or through combination with other therapies. At present, there is no reliable predictor of benefit for ipilimumab. One group recently reported that the presence of a BRAF mutation does not predict clinical benefit of ipilimumab . Other groups have shown that ipilimumab increases the frequency of T cells with inducible co-stimulatory molecule (ICOS)  and that ICOS T cells are necessary for response to ipilimumab . Whether or not baseline ICOS T cells predict benefit to ipilimumab remains to be determined. Finally, there is ample evidence to suggest that a higher dose of ipilimumab (10 mg/kg) results in an increased response than the approved dose (3 mg/kg) and a randomized phase 3 study is underway to address this question.
In addition to improved patient identification, many investigators are combining ipilimumab with other treatment modalities in order to increase the response rate. As mentioned above, the phase 3 study of dacarbazine plus ipilimumab did not yield a higher than expected response rate; however, this study was not designed to answer this question. In a randomized phase 2 study of ipilimumab versus ipilimumab and dacarbazine, the ipilimumab/dacarbazine combination resulted in an increased response rate (15% versus 5%) and improved one-, two-, and three-year survival . In a single arm phase 2 study, the combination of ipilimumab and temozolamide resulted in an overall disease control rate (CR/PR and SD) of 67% which is much higher than seen in single agent studies . A phase 1 study testing the combination of ipilimumab and bevacizumab resulted in a RR of 36% and overall disease control rate of 67%, but immune-related adverse reactions also seemed to be greatly enhanced with this combination . Ipilimumab is also being combined with multiple other agents including granulocyte-macrophage colony-stimulating factor (GM-CSF), vaccines and other immune modulators with a goal to overcoming the immune tolerance of melanoma. In summary, there is no agent that is proven to increase the response rate of ipilimumab in a phase 3 trial and until that evidence exists, we do not recommend combining ipilimumab with any other therapy outside the setting of a clinical trial.
Ipilimumab combined with radiation
Finally, an additional area of research to improve on the success of ipilimumab is through the combination of ipilimumab with radiation therapy with two trials currently enrolling patients. The first is a pilot study of ipilimumab in stage IV melanoma patients who are receiving palliative radiation therapy . The second is the RADVAX study, a stratified phase 1/2 dose escalation trial of stereotactic body radiotherapy followed by ipilimumab in patients with metastatic melanoma . The toxicity profile of this combination therapy will be of interest as both therapies can elicit similar toxicities such as colitis . Trials combining vemurafenib and radiation therapy are also in the planning phases.
Additional targeted therapies
As mentioned above, approximately 50% of patients with melanoma harbor BRAF mutations and are eligible for treatment with the novel BRAF inhibitors. In addition to BRAF, other mutations in genes as well as alterations in cancer related pathways have been identified in patients with melanoma, thereby leading investigators to target these pathways as well.
c-kit, also known as CD117, is a receptor tyrosine kinase that is mutated in approximately 20% of acral, mucosal, and chronically sun-damaged skin . The ligand for KIT is stem cell factor (SCF) and binding of SCF to c-kit induces activation of downstream signaling pathways that are involved in mediating growth and survival signals within the cell including the P13K-AKT-mTOR pathway and the RAS-RAF-MEK-ERK pathway. KIT has been implicated in the pathogenesis of several cancers including acute myeloid leukemia and gastrointestinal stromal tumors (GIST) [46–49]. Unlike in GIST where c-kit mutations tend to be deletions or insertions in exon 11, c-kit mutations in melanoma occur at multiple sites along the gene including both the juxta-membrane domain at exon 11 and exon 13 and the kinase domain at exon 17 and are usually point mutations that do not correlate with KIT copy number or CD117 expression [50, 51].
Summary of C-KIT Trials
Single Arm Phase 2
Kim KB et al. 
Imatinib mesylate 400 mg bid in advanced unresectable melanoma
Imatinib mesylate demonstrated a response in 1 patient who also had high c-kit expression and alternate splicing variant in c-kit mRNA transcript.
Single Arm Phase 2
Carvajal et al. 
Imatinib mesylate 400 mg bid in advanced unresectable melanoma
Imatinib mesylate demonstrated a significant clinical response in subset of patients with cKit mutation and advanced melanomaa
Single Arm Phase 2
Guo et al. 
Imatinib mesylate 400 mg daily in metastatic melanoma
Imatinib mesylate demonstrated a significant clinical response in a subset of patients with cKit mutation and metastatic melanomaa
ERBB4 (HER4) is a protein tyrosine kinase that activates both the ERK and AKT signaling pathways [56, 57]. In a genome wide search of the tyrosine kinome, ERBB4 mutations were identified in 19% of patients with melanoma. In vitro assays demonstrated that lapatinib, a pan-ERBB inhibitor had activity in cell lines with these mutations and not in cell lines without these mutations . In this same study, it was noted the ERBB4 mutations were found in patients with and without BRAF mutations suggesting that ERBB4 is perhaps an independent and complementary driver of tumorigenesis. A phase 2 trial of lapatanib in stage IV melanoma patients who harbor an ERBB4 mutation is currently enrolling . Future therapeutic combinations of lapatinib and other ERBB4 inhibitors with either other targeted, immune, or chemotherapeutic agents hold promise.
Summary of VEGF Trials
Single Arm Phase 2
Perez et al. 
Carboplatin plus paclitaxel and bevacizumab in unresectable metastatic melanoma
Carboplatin plus paclitaxel and bevacizumab was well tolerated and clinically beneficial
Randomized Phase 2
Kim et al. 
Carboplatin plus paclitaxel and bevacizumab versus
Carboplatin plus paclitaxel in untreated metastatic melanoma
Carboplatin plus paclitaxel and bevacizumab demonstrated statistically significant improvement in OS
Kottschade et al. 
Carboplatin plus nab-paclitaxel in chemotherapy naïve(CN) and previously treated (PT) metastatic melanoma
Carboplatin plus nab-paclitaxel has clinical activity in chemotherapy naïve patients
Single Arm Phase 2
Fruehauf et al. 
Axitiniba in metastatic melanoma after maximum on one prior therapy
Axitinib demonstrated clinical activity in metastatic melanoma.
Future of immunotherapy
One mechanism by which melanoma is thought to evade the immune system is through tumor expression of programmed death ligand 1 (PD-L1). PD-L1 is a negative regulator of the immune system that acts through binding of the PD-1 present on activated lymphocytes and PD-L1/PD-1 interaction causes immune tolerance through apoptosis of the activated lymphocyte [66–68]. MDX-1106 is a genetically engineered fully human immunoglobulin G4 monoclonal antibody specific for human PD-1 . A phase 1 study of anti-PD-1 antibody, MDX-1106, demonstrated single agent responses in a variety of previously treated, refractory solid tumors including melanoma with few treatment-related immune toxicities . The clinical experience with anti-PD1 treatment is limited but encouraging and a dose escalation study of the combination of MDX-1106 and ipilimumab is currently recruiting . In addition to antibodies that target PD-1, phase 1 trials of anti-PD-L1 are also underway.
Adoptive T cell therapy
The presence of tumor infiltrating lymphocytes (TIL) in resected melanoma samples is one of the reasons melanoma is often characterized as an immunogenic malignancy. Attempts to isolate, expand and infuse TIL for the treatment of cancer is termed adoptive cell therapy (ACT) and has shown promise for the treatment of patients with metastatic melanoma [70–73]. Early studies using TIL and IL-2 produced a response rate of 34%. Later studies using nonmyeloblative lymphodepletion with cytotoxic chemotherapy, with or without total body irradiation, induced response rates as high as 72% [70–75]. One of the limitations of ACT is that TIL expansion is not possible for all patients although it was recently reported that TIL is successfully generated in > 60% of all patients with melanoma and this figure is even higher in patients who did not receive prior chemotherapy . In order to circumvent the process of tumor resection and isolation of TIL, investigators have developed methods to genetically modify autologous peripheral T cells to express a T cell receptor that targets melanoma antigens. This approach has induced a response rate in a subset of patients with melanoma and a similar approach has also yielded results in patients with refractory chronic lymphocytic leukemia . In summary, ACT for the treatment of melanoma is a promising, albeit resource consuming method for the treatment of metastatic melanoma.
With the approval of ipilimumab, the role of HD IL-2 remains in question. While the clinical benefit of HD IL-2 is roughly similar to ipilimumab, the toxicity is worse and tolerability is less. Multiple strategies have attempted to identify biomarkers to predict clinical benefit of HD IL-2. Recently, a retrospective study found that patients with an NRAS mutation have a higher likelihood to respond to HD IL-2 . In addition, a prospective study of patients with metastatic melanoma and renal cell carcinoma found that elevated pre-treatment serum VEGF and fibronectin are inversely correlated with the response rate to HD-IL-2 . Both of these findings require further study at additional centers before changing clinical practice. Multiple efforts to increase the response rate of HD IL-2 while maintaining the duration of response have been attempted. The addition of a peptide vaccine (gp-100) to HD IL-2 demonstrated an improved objective response rate (16% versus 6%, P = 0.03) and overall survival (17.8 versus 11.1 months, P = 0.06) . There are plans to improve upon this finding by using more potent vaccines.
Finally, it is becoming more evident that patients who progress on HD IL-2 do derive clinical benefit from ipilimumab. In the phase 3 study of previously treated patients, patients who progressed on prior HD-IL-2 received a similar benefit to ipilimumab as those who did not . Similarly, a retrospective study analyzing patients who progressed on HD IL-2 and then received ipilimumab had a response rate (19%) and OS (12 months) to ipilimumab that was similar to previously reported historical controls . Given the lack of approved agents and the limited but quantifiable benefit, we believe there still remains a role for HD IL-2 in patients who are fit enough to receive it.
Combined immune and targeted therapy
As we learn more about the molecular pathways and immune modulation of melanoma, novel combinations of immune and targeted therapies have the potential of overcoming the low response rates of immune therapy and the short durations of response in targeted therapies. Pre-clinical work has suggested that BRAF inhibition leads to increased tumor recognition by T-cells providing a rational for the combination of BRAF inhibitors with agents that stimulate the immune system such as ipilimumab . In addition, BRAF inhibitors and other targeted therapies will likely be combined with ipilimumab, IL-2, anti-PD-1, and other immunotherapies that are currently being tested.
Role of surgery in metastatic disease
Patients with oligometastatic disease present a clinical dilemma of whether to treat systemically or locally. Highly selected patients with isolated lung or liver metastasis, good performance status, and less aggressive tumor biology have benefited from metastasectomy with improved five-year survival rates and median OS rates of 20 to 25 months [83–87]. Again, patient selection is the key for success in this setting. A recent phase 2 study enrolled 77 patients for complete resection of metastatic disease and demonstrated a relapsed free survival of five months and 36% of patients alive at three years . While this trial demonstrates that long-term survival can be achieved through surgery, the trial did not further identify patients more likely to benefit from surgery. Currently, a prospective trial of patients with oligometastatic disease is randomizing patients to either surgery versus systemic therapy. This will hopefully shed more light on which patients are most likely to benefit from metastasectomy.
In 2011, the FDA approval of vermurafenib and ipilimumab instilled optimism in clinicians treating patients with metastatic melanoma. While these therapies have limitations, many promising strategies exist to overcome these limitations. Understanding and overcoming resistance pathways, combining current and future agents, identifying biomarkers to improve patient selection, and discovering future therapeutic targets will hopefully lead to further treatment advances.
LF is a fellow in Hematology and Oncology at Mayo Clinic Florida. SM is a Professor of Medicine and Oncology at Mayo Clinic Rochester with a clinical and research focus on melanoma. RJ is a Clinical Instructor at Mayo Clinic Florida with a clinical and research focus on melanoma and genitourinary malignancies.
Adoptive cell therapy
cytotoxic T-lymphocyte-associated antigen 4
gastrointestinal stromal tumors
glycoprotein 100 peptide vaccine
granulocyte-macrophage colony-stimulating factor
- HD IL-2:
high dose IL-2
inducible co-stimulatory molecule
mitogen activated kinase pathway
overall response rate
programmed death ligand 1
progression free survival
squamous cell carcinoma
stem cell factor
tumor infiltrating lymphocytes
vascular endothelial growth factor.
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