Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment
Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma
- Signal transduction inhibitors.
- BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
- MEK inhibitors.
- Combination therapy with signal transduction inhibitors.
- Dabrafenib plus trametinib.
- Multikinase inhibitors.
- KIT inhibitors.
- Palliative local therapy.
Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—have demonstrated improvement in overall survival (OS) in randomized trials versus the use of dacarbazine (DTIC) or in comparison to DTIC. Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.
Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to down-regulate T-cell activation, proliferation, and effector function.
Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials, and was approved by the U.S. Food and Drug Administration (FDA) in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.[1,2]
- Previously treated patients: A total of 676 patients with previously treated, unresectable stage III or stage IV disease, and who were HLA-A*0201 positive, were entered into a three-arm, multinational, randomized (3:1:1), double-blind, double-dummy trial. A total of 403 patients were randomly assigned to receive ipilimumab (3 mg/kg every 3 weeks for 4 doses) with glycoprotein 100 (gp100) peptide vaccine. One hundred thirty-seven patients received ipilimumab (3 mg/kg every 3 weeks for 4 doses), and 136 patients received the gp100 vaccine. Patients were stratified by baseline metastases and previous receipt or nonreceipt of interleukin-2 (IL-2) therapy. Eighty-two of the patients had metastases to the brain at baseline.[Level of evidence: 1iA]
- The median OS was 10 months among patients receiving ipilimumab alone and 10.1 months among those receiving ipilimumab with the gp100 vaccine, compared with 6.4 months for patients receiving the vaccine alone (hazard ratio [HR] of ipilimumab alone vs. gp100 alone, 0.66; P <.003; HR of ipilimumab plus vaccine vs. gp100 alone, 0.68; P < .001).
- An analysis at 1 year showed that among patients treated with ipilimumab, 44% of those treated with ipilimumab and 45% of those treated with ipilimumab and the vaccine were alive, compared with 25% of the patients who received the vaccine only.
- Grade 3 or grade 4 immune-related adverse events (irAEs) occurred in 10% to 15% of patients treated with ipilimumab. These irAEs most often included diarrhea or colitis, and endocrine-related events (e.g., inflammation of the pituitary). These events required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or, in four cases, infliximab (an antitumor necrosis factor-alpha antibody).
- There were 14 drug-related deaths (2.1%), and seven deaths were associated with irAEs.
- Previously untreated patients: A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to receive ipilimumab (10 mg/kg) plus DTIC (850 mg/m2) or placebo plus DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of patients had stage M1c disease.[Level of evidence: 1iA]
- The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) for the ipilimumab-DTIC group, versus 9.1 months (95% CI, 7.8–10.5) for the placebo-DTIC group. Estimated survival rates in the ipilimumab-DTIC group were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years (HR for death, 0.72; P < .001); and in the placebo-DTIC group, the rates were 36.3% at 1 year, 17.9% at 2 years, and 12.2% at 3 years.
- The most common study-drug–related adverse events (AEs) were those classified as immune related. Grade 3 or grade 4 irAEs were seen in 38.1% of patients treated with ipilimumab plus DTIC versus 4.4% of patients treated with placebo plus DTIC, the most common events were hepatitis and enterocolitis.
- No drug-related deaths occurred.
Clinicians and patients should be aware that immune-mediated adverse reactions may be severe or fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated adverse reaction management guide provided by the manufacturer, are necessary.
Anti–PD-1 and PD-L1
The PD-1 pathway is a key immunoinhibitory mediator of T-cell exhaustion. Blockade of this pathway can lead to T-cell activation, expansion, and enhanced effector functions. PD-1 has 2 ligands, PD-L1 and PD-L2 (Programmed Death-2 Ligand 2).
Pembrolizumab was granted accelerated approval by the FDA in September 2014 for patients with unresectable or metastatic melanoma who have progressed despite therapy with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Pembrolizumab is a human monoclonal antibody that binds to the PD-1 receptor, preventing it from binding to its ligands, PD-L1 and PD-L2. The FDA granted accelerated approval based on the surrogate endpoint of durable response rate in an international, multicenter, open-label, randomized, dose-comparative trial. As a condition to accelerated approval, randomized trials to assess clinical benefit, e.g., improvement in progression-free survival (PFS) and OS versus standard therapy, is required.
- Previously treated patients. A total of 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation positive, previous treatment with a BRAF inhibitor, were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.
- The median age was 61 years; 60% were male; 67% had an ECOG PS of 0, and 33% had an ECOG PS of 1. Eighteen percent of patients had tumors that were BRAF V600 mutation positive, 39% had an elevated lactate dehydrogenase (LDH), 64% had M1c disease, 9% had brain metastases, and 72% had undergone two or more therapies for advanced disease. The primary outcome measure was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria as assessed by blinded independent central review.[Level of evidence: 1iiDiv]
- The ORR determined by independent central review was 26% (95% CI, -14–13; P = .96) in the 2 mg/kg arm, consisting of one complete response (CR) and 20 partial responses (PRs) in 81 patients. Median follow-up was 8 months, and all patients had a minimum of 6 months of follow-up. Among the 21 patients with an objective response, 18 had ongoing responses, ranging from 1.4+ months to 8.5+ months.
- Response rate in the 10 mg/kg arm was similar at 26%, consisting of 20 responses in 76 patients. Responses were seen in patients with and without BRAF V600 mutations.
- The approved dose was 2 mg/kg administered as an intravenous (IV) infusion for 30 minutes every 3 weeks.
Pembrolizumab was discontinued because of AEs in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related AEs by the investigators. The most common AEs in the 2 mg/kg versus 10 mg/kg arms were:
- Fatigue (33% vs. 37%).
- Pruritus (23% vs. 19%).
- Rash (18% vs. 18%).
Other common AEs included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious AEs that occurred in more than 2% of a total of 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.
The FDA label provides recommendations for suspected irAEs, including withholding drug and administering corticosteroids.
High-dose interleukin-2 (IL-2)
IL-2 was approved by the FDA in 1998 on the basis of durable CRs in eight phase I and II studies. Phase III trials comparing high-dose IL-2 to other retreatments, providing an assessment of relative impact on OS, have not been conducted.
Evidence (high-dose IL-2):
- Based on a pooled analysis of 270 patients from eight single- and multi-institutional trials in 22 institutions conducted between 1985 and 1993:
Strategies to improve this therapy are an active area of investigation.
T-cells coexpress several receptors that inhibit T-cell function. Preclinical data and early clinical data suggest that coblockade of the two inhibitory receptors, CTLA-4 and PD-1, may be more effective than blockade of either alone. This has led to a phase III trial comparing each single agent to the combination (NCT01844505).
Signal transduction inhibitors
Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can significantly impact the natural history of melanoma, although they do not appear to provide a cure.
Vemurafenib is an orally available, small molecule, selective BRAF kinase inhibitor that was approved by the FDA in 2011 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation.
Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models have demonstrated that BRAF inhibitors can enhance rather than down-regulate the MAPK pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[7-10]
- Previously untreated patients: The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or DTIC (1,000 mg/m2 IV every 3 weeks). Coprimary endpoints were rates of OS and PFS. At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the DTIC group be allowed to cross over to receive vemurafenib.[Levels of evidence: 1iiA and 1iiDiii]
- A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the DTIC arm.
- The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor stage, lactic dehydrogenase, and geographic region.
- The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the DTIC arm.
- Twenty patients had non-BRAF V600E mutations: 19 with BRAF V600K and 1 with BRAF V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.
- AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving DTIC. The most common AEs with vemurafenib were cutaneous events (i.e., arthralgia and fatigue). Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both developed in 18% of patients and were treated by simple excision. The most common AEs with DTIC were fatigue, nausea, vomiting, and neutropenia. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
- Previously treated patients: A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily. Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months.[Level of evidence: 3iiiDiv]
- An independent review committee (IRC) reported a 53% response rate (95% CI, 44–62), with eight patients (6%) achieving CR.
- Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until after receiving therapy for more than 6 months.
Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib and other BRAF inhibitors are not recommended for treatment of BRAF wild type melanomas, as in vitro experiments suggest there may be a paradoxical stimulation of MAPK signaling resulting in tumor promotion.
- An international, multicenter trial (BREAK-3 [NCT01227889]) compared dabrafenib with DTIC. A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1,000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.[Level of Evidence: 1iiDiii]
- With 126 events, the HR for PFS was 0.30 (95% CI, 0.18–0.51; P < .0001). The estimated median PFS was 5.1 months for dabrafenib versus 2.7 months for DTIC. OS data are limited by the median duration of follow-up and crossover. The PR rate was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.
- The most frequent AEs in patients treated with dabrafenib were cutaneous findings (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in 12 patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.
Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2. BRAF activates MEK1 and MEK2 proteins, which in turn, activate MAP kinases. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAPK.
In 2013, trametinib was approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as determined by an FDA-approved test.
- A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with BRAF V600E, 40 with BRAF V600K, and one with both mutations). One previous treatment (biologic or chemotherapy) was allowed; however, no previous treatment with a BRAF or MEK inhibitor was permitted. Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover for patients randomly assigned to chemotherapy was allowed; therefore, the primary endpoint was PFS.
- The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). A radiology review blinded-to-treatment arm resulted in similar outcomes. Median OS has not been reached.
- AEs leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. AEs leading to dose reductions occurred in 27% of patients receiving trametinib and in 10% of those receiving chemotherapy.
- The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Cardiomyopathy (7%), interstitial lung disease (2.4%), central serous retinopathy (<1%), and retinal-vein occlusion (<1%) are uncommon but serious AEs associated with trametinib. On-study cutaneous SCCs were not observed. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
Combination therapy with signal transduction inhibitors
Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAPK pathway. Combinations of signal transduction inhibitors that block different sites in the same pathway or sites in multiple pathways are an active area of research.
Evidence (combination therapy with signal transduction inhibitors):
- In January 2014, the FDA granted accelerated approval to dabrafenib and trametinib in combination to treat patients with unresectable or metastatic melanomas who carry the BRAF V600E or V600K mutation as detected by an FDA-approved test. Accelerated approval was granted on the basis of objective response rates from an open-label phase II trial that randomly assigned 162 patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation in a 1:1:1 ratio to receive dabrafenib alone (150 mg twice a day) or with trametinib (at a dose of either 1 mg or 2 mg twice a day). Patients who had disease progression on dabrafenib monotherapy could cross over to receive the combination of dabrafenib 150 mg plus trametinib 2 mg twice a day. Patients were allowed to have received one previous therapy other than a BRAF or MEK inhibitor.[Level of evidence: 1iiDiv].
- Patients treated with the combination had a response rate of 76%, with an average duration of 10.5 months. Patients treated with dabrafenib alone had a response rate of 54%, with an average duration of 5.6 months.
- The development of a new SCC of the skin associated with single-agent dabrafenib was reduced in the combination arm (19% with dabrafenib and 7% with the combination).
- The most frequent AEs in the combination were pyrexia and chills, fatigue, nausea, vomiting, and diarrhea, although symptoms were rarely grade 3 or grade 4.
- In the combination group, 58% of patients required dose reductions because of AEs, most associated with pyrexia. Re-escalation was possible in most patients.
- Rare, serious AEs with the combination included decreased ejection fraction (<2%) and chorioretinopathy (<1%).
Full approval for the combination will depend on demonstration of improvements in PFS and survival from ongoing trials.
These early phase II data with combinations of BRAF and MEK inhibitors, in addition to the mechanistic understanding of pathways, have led to testing this combination in multiple phase III trials, such as NCT01584648, NCT01597908, and NCT01689519. Combination therapy to address other mechanisms of resistance (e.g., via activation of the PI3K/Akt pathway) are in early-phase trials.
The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase.
This agent had minimal activity as a single agent in melanoma treatment. Two large, multicenter, placebo-controlled, randomized trials of carboplatin and paclitaxel plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[13,16]
Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[17-19] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[1,11,20-22] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.
Temozolomide (TMZ), an oral alkylating agent that hydrolyzes to the same active moiety as DTIC, appeared to be similar to DTIC (IV administration) in a randomized, phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[20,23-25] Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a CR.[23,25]
A randomized trial compared IV DTIC with TMZ, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for TMZ (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ; therefore, demonstration of similarity did not result in approval of TMZ by the FDA.[Level of evidence: 1iiA]
An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients (EORTC-18032 [NCT00101218]). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent DTIC.[Level of evidence: 1iiA]
Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib  and ipilimumab ) included DTIC as the standard therapy arm. Both vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.
Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[27,28] combinations of chemotherapy and tamoxifen,[29-31] and combinations of chemotherapy and immunotherapy [5,6,27,32-35]) have not demonstrated an improvement in OS.
A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) reported no impact on OS.[Level of evidence:1iiA]
Palliative local therapy
Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[33-35]
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:[37,38]
- Multiple brain metastases.
- Bone metastases.
- Spinal cord compression.
The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. (Refer to the PDQ summary on Pain for more information.)
A phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma; results are pending.
Treatment Options Under Clinical Evaluation for Unresectable Stage III, Stage IV, and Recurrent Melanoma
- Immunotherapy, single agent, and combination immunomodulation.
- Targeted therapy—single-agent and combination therapy.
- Signal transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B) inhibitors, CDK (cyclin-dependent kinase) in addition to BRAF and MEK.
- Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.
- Targeted therapy for specific melanoma populations.
- In smaller subsets of melanoma, activating mutations may occur in NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.
- Intralesional injections (for example, oncologic viruses).
- Complete surgical resection of all known disease versus best medical therapy.
- Isolated limb perfusion for unresectable extremity melanoma.
- Systemic therapy for unresectable disease.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma, stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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- Hodi FS, O'Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363 (8): 711-23, 2010. [PUBMED Abstract]
- Yervoy (Ipilimumab): Serious and Fatal Immune-Mediated Adverse Reactions [Medication Guide]. Princeton, NJ: Bristol-Myers Squibb, 2011. Available online. Last accessed May 15, 2014.
- Robert C, Ribas A, Wolchok JD, et al.: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384 (9948): 1109-17, 2014. [PUBMED Abstract]
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- Heidorn SJ, Milagre C, Whittaker S, et al.: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140 (2): 209-21, 2010. [PUBMED Abstract]
- Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464 (7287): 431-5, 2010. [PUBMED Abstract]
- Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464 (7287): 427-30, 2010. [PUBMED Abstract]
- Su F, Viros A, Milagre C, et al.: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366 (3): 207-15, 2012. [PUBMED Abstract]
- Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
- Sosman JA, Kim KB, Schuchter L, et al.: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366 (8): 707-14, 2012. [PUBMED Abstract]
- Hauschild A, Grob JJ, Demidov LV, et al.: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380 (9839): 358-65, 2012. [PUBMED Abstract]
- Flaherty KT, Robert C, Hersey P, et al.: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367 (2): 107-14, 2012. [PUBMED Abstract]
- Flaherty KT, Infante JR, Daud A, et al.: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367 (18): 1694-703, 2012. [PUBMED Abstract]
- Flaherty KT, Lee SJ, Zhao F, et al.: Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 31 (3): 373-9, 2013. [PUBMED Abstract]
- Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008. [PUBMED Abstract]
- Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011. [PUBMED Abstract]
- Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011. [PUBMED Abstract]
- Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999. [PUBMED Abstract]
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