Original Article
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
N Engl J Med 2011; 364:2507-2516June 30, 2011
- Abstract
Background
Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
Methods
We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.
Results
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. In the interim analysis for overall survival and final analysis for 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). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.
Conclusions
Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
Media in This Article
Figure 1
Overall Survival.Figure 2
Progression-free Survival.Article Activity
- Article
Metastatic melanoma has a poor prognosis, with the median survival for patients with stage IV melanoma ranging from 8 to 18 months after diagnosis, depending on the substage.1 In the United States last year, 8700 deaths from melanoma were projected, with an estimated rate of death of 2.6 in 100,000.2 Rates of death from melanoma in Australia and New Zealand are slightly higher (3.5 in 100,000), whereas rates in Western Europe are slightly lower (1.8 in 100,000).3
In phase 3 studies, dacarbazine, the only chemotherapeutic agent approved by the Food and Drug Administration for the treatment of metastatic melanoma, was associated with a response rate of 7 to 12% and a median overall survival of 5.6 to 7.8 months after the initiation of treatment.4-7 Although higher response rates can be achieved with combination chemotherapy, these combinations have not resulted in improved rates of overall survival. Recently, the use of ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) on lymphocytes, has been associated with improved overall survival, as compared with a peptide vaccine,8 and in combination with dacarbazine has been associated with better overall survival than dacarbazine alone.9
Approximately 40 to 60% of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signaling through the MAPK pathway.10,11 Approximately 90% of these mutations result in the substitution of glutamic acid for valine at codon 600 (BRAF V600E), although other activating mutations are known (e.g., BRAF V600K and BRAF V600R).
Vemurafenib (PLX4032) is a potent inhibitor of mutated BRAF.12 It has marked antitumor effects against melanoma cell lines with the BRAF V600E mutation but not against cells with wild-type BRAF.12-14 A phase 1 trial established the maximum tolerated dose to be 960 mg twice daily and showed frequent tumor responses.15 A phase 2 trial involving patients who had received previous treatment for melanoma with the BRAF V600E mutation showed a confirmed response rate of 53%, with a median duration of response of 6.7 months.16 We conducted a randomized phase 3 trial to determine whether vemurafenib would prolong the rate of overall or progression-free survival, as compared with dacarbazine.
Methods
Patients
All patients in our study had unresectable, previously untreated stage IIIC or stage IV melanoma that tested positive for the BRAF V600E mutation on real-time polymerase-chain-reaction assay (Cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems). The test was performed at one of five central laboratories in the United States, Germany, and Australia. In approximately one third of the patients, BRAF was sequenced retrospectively by Sanger and 454 sequencing at a central laboratory. Other inclusion criteria were age of 18 years or older, a life expectancy of 3 months or longer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active and able to carry on all performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), and adequate hematologic, hepatic, and renal function. Patients were excluded if they had a history of cancer within the past 5 years (except for basal- or squamous-cell carcinoma of the skin or carcinoma of the cervix) or metastases to the central nervous system, unless such metastases had been definitively treated more than 3 months previously with no progression and no requirement for continued glucocorticoid therapy. Concomitant treatment with any other anticancer therapy was not allowed.
The protocol was approved by the institutional review board at each participating institution and was conducted in accordance with the ethical principles of the Declaration of Helsinki and within the Good Clinical Practice guidelines, as defined by the International Conference on Harmonization. All patients provided written informed consent before enrollment.
Study Design and Treatment
From January 2010 through December 2010, a total of 2107 patients underwent screening at 104 centers in 12 countries worldwide. The most common reason for screening failure was a negative test for the BRAF V600 mutation. A total of 675 patients were randomly assigned in a 1:1 ratio to receive either vemurafenib (at a dose of 960 mg twice daily orally) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area by intravenous infusion every 3 weeks) (Fig. A in the Supplementary Appendix, available with the full text of this article at NEJM.org). These patients included 20 with non-V600E mutations (19 with V600K and 1 with V600D), as identified on Sanger and 454 sequencing. Baseline characteristics of the patients were well balanced (Table 1Table 1
Baseline Demographic and Clinical Characteristics of Patients in the Intention-to-Treat Population.).Study patients were stratified according to American Joint Committee on Cancer stage (IIIC, M1a, M1b, or M1c), ECOG performance status (0 or 1), geographic region (North America, Western Europe, Australia or New Zealand, or other region), and serum lactate dehydrogenase level (normal or elevated).
Dose reductions for both vemurafenib and dacarbazine were prespecified for intolerable grade 2 toxic effects or worse. The development of cutaneous squamous-cell carcinoma did not require dose modification. The administration of vemurafenib was interrupted until the resolution of the toxic effect to at least grade 1 and restarted at 720 mg twice daily (480 mg twice daily for grade 4 events), with a dose reduction to 480 mg twice daily if the toxic effects recurred. If the toxic effect did not improve to grade 1 or lower or recurred at the 480-mg twice-daily dose, treatment was discontinued permanently. The administration of dacarbazine was interrupted for grade 3 or 4 toxic effects and could be restarted on recovery within 1 week to grade 1 (at full dose) or grade 2 (at 75% dose) or at 75% dose for grade 4 neutropenia or febrile neutropenia. A second dose reduction was allowed, if needed. Antiemetics and granulocyte colony-stimulating factor were administered according to standards at each study center. Treatment was discontinued on disease progression unless continued treatment was in the best interest of the patient in the judgment of the investigator and the sponsor.
Assessments
At baseline, patients underwent computed tomography with contrast material or magnetic resonance imaging of the brain, chest, abdomen, pelvis, and other anatomical regions, as clinically indicated. Patients also underwent physical and dermatologic examinations and electrocardiography. Patients were examined every 3 weeks; tumor assessments were performed at baseline, at weeks 6 and 12, and every 9 weeks thereafter. Tumor responses were determined by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Electrocardiograms were repeated every other cycle. Blood counts, biochemical analyses, and measurements of lactate dehydrogenase levels were performed at each visit.
Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. Monitoring of adverse events continued for up to 28 days after the last dose of a study drug had been administered or until any ongoing event resolved or stabilized. An independent data and safety monitoring board provided oversight and evaluated interim results on efficacy data.
Study Oversight
The trial was designed jointly by the senior academic authors and representatives of the sponsor, Hoffmann–La Roche. Data were collected by the sponsor and analyzed in collaboration with the senior academic authors, who vouch for the completeness and accuracy of the data and analyses and for the conformance of this report to the protocol, as amended. The corresponding academic author prepared an initial draft of the manuscript in collaboration with the sponsor. All the authors contributed to subsequent drafts and made the decision to submit the manuscript for publication. The protocol and statistical analysis plan are available at NEJM.org.
Statistical Analysis
The original primary end point was the rate of overall survival. The statistical plan was revised in October 2010 on the basis of phase 1 and 2 efficacy and safety results and after consultation with global regulatory authorities. Under the revised plan, the rates of overall survival and progression-free survival were coprimary end points. The final analysis was planned after 196 deaths, and an interim analysis was planned after 50% of the projected deaths had occurred (Pocock boundary, P≤0.028 at the interim analysis and P≤0.0247 at the final analysis by the log-rank test). According to the revised plan, the final analysis of progression-free survival would be performed at the time of the interim analysis of overall survival. Secondary end points included the confirmed response rate, duration of response, and time to response.
The trial was designed for 680 patients to be randomly assigned to receive either vemurafenib or dacarbazine. The trial had a power of 80% to detect a hazard ratio of 0.65 for overall survival with an alpha level of 0.045 (an increase in median survival from 8 months for dacarbazine to 12.3 months for vemurafenib) and a power of 90% to detect a hazard ratio of 0.55 for progression-free survival with an alpha level of 0.005 (an increase in median survival from 2.5 months for dacarbazine to 4.5 months for vemurafenib). Survival was defined as the time from randomization to death from any cause. Progression-free survival was the time from randomization to documented disease progression or death. We used a two-sided unstratified log-rank test to compare survival rates in the two study groups. Hazard ratios for treatment with vemurafenib, as compared with dacarbazine, were estimated with the use of unstratified Cox regression. We estimated event–time distributions using the Kaplan–Meier method. All reported P values are two-sided, and confidence intervals are at the 95% level. Descriptive statistics are used for adverse events.
This report is based on data as of December 30, 2010. Efficacy analyses were performed in the intention-to-treat population. In order to ensure adequate follow-up for each efficacy end point, patients could be evaluated for the analysis of overall survival, progression-free survival, and confirmed response if they had undergone randomization at least 2, 9, and 14 weeks, respectively, before the cutoff date. The safety analysis was performed in all patients who received a study drug and who had undergone at least one assessment during the study.
Results
Patients and Treatments
A total of 118 patients had died at the time of the interim analysis. The data and safety monitoring board determined that both the overall survival and progression-free survival end points had met the prespecified criteria for statistical significance in favor of vemurafenib. The board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib, and the protocol was amended accordingly on January 14, 2011. Median follow-up for the interim analysis was 3.8 months for patients in the vemurafenib group and 2.3 months for those in the dacarbazine group.
Efficacy
A total of 672 patients were evaluated for overall survival. The hazard ratio for death in the vemurafenib group was 0.37 (95% confidence interval [CI], 0.26 to 0.55; P<0.001) (Figure 1AFigure 1
Overall Survival.). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, according to age, sex, ECOG performance status, tumor stage, lactate dehydrogenase level, and geographic region (Figure 1B). At the time of the interim analysis, there were an inadequate number of patients in follow-up beyond 7 months in either study group to provide reliable Kaplan–Meier estimates of the survival curves.17 At 6 months, overall survival was 84% (95% CI, 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. Further follow-up is required.Progression-free survival could be evaluated in 549 patients. The hazard ratio for tumor progression in the vemurafenib group was 0.26 (95% CI, 0.20 to 0.33; P<0.001) (Figure 2AFigure 2
Progression-free Survival.). The estimated median progression-free survival was 5.3 months in the vemurafenib group and 1.6 months in the dacarbazine group. Superior progression-free survival with vemurafenib over dacarbazine was observed in all subgroups that were analyzed (Figure 2B).A total of 439 patients (65%) could be evaluated for tumor response on the basis of having undergone randomization at least 14 weeks before the clinical cutoff date of December 30, 2010. In the vemurafenib group, most patients had a detectable decrease in tumor size (Figure 3AFigure 3
Best Tumor Response for Each Patient.), and 106 of 219 patients (48%; 95% CI, 42 to 55) had a confirmed objective response (including 2 patients with a complete response and 104 with a partial response), with a median time to response of 1.45 months. Ten patients in the vemurafenib group were later found to have BRAF V600K mutations; of these patients, 4 had a partial response (40%). In the dacarbazine group, a minority of patients had a detectable decrease in tumor size (Figure 3B), and only 12 of 220 patients (5%; 95% CI, 3 to 9) met the criteria for a confirmed response (all partial responses), with a median time to response of 2.7 months. The difference in confirmed response rates between the two study groups (48% vs. 5%) was highly significant (P<0.001 by the chi-square test).Adverse Events
A total of 618 patients (92%) underwent at least one assessment as of the clinical cutoff date and were evaluated for toxic effects. Adverse events of grade 2 or more that were reported in more than 5% of the patients in either study group are shown in Table 2Table 2
Adverse Events in 618 Patients.; adverse events of any grade that were reported in more than 5% of the patients are shown in Table A in the Supplementary Appendix. The most common adverse events in the vemurafenib group were cutaneous events, arthralgia, and fatigue; photosensitivity skin reactions of grade 2 or 3 were seen in 12% of the patients, with grade 3 reactions characterized by blistering that often could be prevented with sunblock. As expected, the most common severe toxic effects in the dacarbazine group were fatigue, nausea, vomiting, and neutropenia. Adverse events led to dose modification or interruption in 129 of 336 patients (38%) in the vemurafenib group and in 44 of 282 patients (16%) in the dacarbazine group.In the vemurafenib group, a cutaneous squamous-cell carcinoma, keratoacanthoma, or both developed in 61 patients (18%). All lesions were treated by simple excision. Pathological analyses of skin-biopsy specimens from these patients are currently being performed by an independent dermatology working group.
Discussion
In our study, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of tumor progression in patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation, as compared with dacarbazine. Benefit was seen in all subgroups of patients who were included in the analysis, including patients with stage M1c disease or an elevated lactate dehydrogenase level, both of which are associated with particularly poor prognoses.
Recently, ipilimumab, an anti-CTLA4 antibody, was shown to improve overall survival in patients with metastatic melanoma, as compared with a peptide vaccine, although there was only a modest effect on rates of response and progression-free survival.8 The use of ipilimumab combined with dacarbazine has also been associated with improved rates of survival over dacarbazine alone.9
Overall, 48% of the patients who were treated with vemurafenib met the criteria for a confirmed response, although most patients had some tumor shrinkage. This finding was consistent with the confirmed response rates seen in the phase 1 extension cohort15 and in a recent phase 2 trial involving previously treated patients.16 Furthermore, 4 of 10 patients with the BRAF V600K mutation had a response to vemurafenib, indicating that melanomas with this variant are also sensitive to vemurafenib.
The confirmed response rate in the dacarbazine cohort was 5%, which is slightly lower than that in recent phase 3 trials.4-7 Our study was a randomized trial comparing vemurafenib with dacarbazine in which only patients with BRAF-mutated melanomas were treated. Recent studies have raised the possibility that melanomas with the BRAF V600E mutation are more aggressive18,19 and less sensitive to chemotherapy18,20 than BRAF wild-type melanomas. Also, 48 patients (14%) in the dacarbazine group (29 of whom were available for evaluation in this report) did not receive any treatment, most commonly because the patient withdrew consent (Fig. A in the Supplementary Appendix). Patients receiving vemurafenib reported relatively few grade 3 or worse adverse events. Other than cutaneous squamous-cell carcinoma and keratoacanthomas, the most common drug-related grade 3 (or worse) toxic effects were rash, arthralgias, photosensitivity, and fatigue. Overall, 38% of the patients receiving vemurafenib required dose modification because of adverse events.
Among patients treated with vemurafenib, 18% were reported to have at least one squamous-cell carcinoma of the skin or keratoacanthoma. These lesions were excised, and none required dose modification of vemurafenib. These rates are slightly lower than those in the phase 1 and 2 trials of vemurafenib,15,16 probably because of shorter follow-up in our study. Cutaneous squamous-cell cancer and keratoacanthomas have also been seen in patients treated with sorafenib,21,22 another compound with inhibitory activity against RAF kinases. No other secondary neoplasia was observed in our patients.
The mechanism of the induction of cutaneous neoplasia is under investigation, but it is speculated to involve the activating effect of vemurafenib on preneoplastic cells in which wild-type BRAF is further primed by upstream pathway activation. Several investigators have shown that vemurafenib and other inhibitors of RAF kinases can potentiate the activity of the MAPK pathway in cells with wild-type BRAF.23-25 This finding might explain the favorable therapeutic index of vemurafenib in patients who have melanoma with the BRAF V600E mutation but also suggests that vemurafenib could accelerate the growth of some tumors with wild-type BRAF.
An important, related ongoing effort by many research groups is to clarify how melanomas become resistant to vemurafenib. Initial studies from several groups have indicated that the MAPK pathway is reactivated in resistant tumors.26-28 Although the precise mechanisms of reactivation are still being investigated, gatekeeper mutations in BRAF, which would prevent vemurafenib from binding BRAF, have not been observed.
Our results show that single-agent vemurafenib improved the rates of response and of both progression-free and overall survival, as compared with dacarbazine, in patients with metastatic melanoma with the BRAF V600E mutation. These findings provide a solid foundation for the development of future combination therapies.
Supported by Hoffmann–La Roche.
Dr. Chapman reports receiving consulting fees, payment for serving on scientific advisory boards, and grant support from Roche and consulting fees from GlaxoSmithKline; Dr. Hauschild, receiving consulting fees from Abraxis/Celgene, AstraZeneca, Bayer, Biovex, Bristol-Myers Squibb, Boehringer Ingleheim, Eisai, GlaxoSmithKline, Merck, Novartis, and Roche, grant support from Bayer and Merck, and lecture fees from Abraxis/Celgene, AstraZeneca, Biovex, Bristol-Myers Squibb, Merck, Novartis, and Roche; Dr. Robert, receiving consulting fees from Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Merck and travel payments from Bristol-Myers Squibb; Dr. Ascierto, serving as a board member for Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough, Merck, and Roche and lecture fees from Schering-Plough and Merck; Dr. Garbe, receiving consulting fees from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Philogen, grant support from Bristol-Myers Squibb, Philogen, and Swedish Orphan, and travel payments from Bristol-Myers Squibb, Roche, and Merck; Dr. Maio, serving on advisory boards for Bristol-Myers Squibb and Pfizer and receiving lecture fees from Bristol-Myers Squibb; Dr. Hogg, receiving consulting fees from Roche, GlaxoSmithKline, and Bristol-Myers Squibb and lecture fees from Roche; Dr. Lorigan, receiving consulting fees from Roche and an educational grant from Roche; Dr. Lebbe, serving on paid advisory boards for Roche and Bristol-Myers Squibb and receiving payments for the development of educational presentations and travel payments from Bristol-Myers Squibb; Dr. Jouary, serving on an advisory board for Bristol-Myers Squibb and receiving consulting fees from Bristol-Myers Squibb and Schering-Plough; Dr. Schadendorf, receiving consulting fees from Roche, GlaxoSmithKline, Bristol-Myers Squibb, and Merck, serving on advisory boards for Roche, GlaxoSmithKline, Bristol-Myers Squibb, Merck, and Schering-Plough, receiving grant support from Schering-Plough and Plexxikon, receiving lecture fees from Bristol-Myers Squibb, Merck, Schering-Plough, and Roche, and receiving payment for developing presentations for Bristol-Myers Squibb; Dr. Ribas, receiving consulting fees from Roche/Genentech; Dr. O'Day, receiving consulting fees from GlaxoSmithKline, receiving consulting fees, grant support, lecture fees, and payment for the development of educational presentations from Bristol-Myers Squibb, and serving as an expert witness in a private lawsuit; Dr. Sosman, receiving grant support from Roche, Millennium, and GlaxoSmithKline and consulting fees from Roche and Millennium; Dr. Kirkwood, serving as a board member for Morphotek and receiving consulting fees from GlaxoSmithKline and Vical, lecture fees from Merck, and payment for the development of educational presentations from Imedex; Dr. Eggermont, receiving consulting fees from Bristol-Myers Squibb, Merck, and GlaxoSmithKline; Dr. Dreno, receiving consulting fees from Roche; Dr. Nolop, being an employee of and having an equity interest in Plexxikon; Mrs. Li and Dr. Lee, being employees of Roche; Miss Nelson and Dr. Hou, being employees of Genentech and having an equity interest in Roche; Dr. Flaherty, receiving consulting fees from GlaxoSmithKline; and Dr. McArthur, receiving grant support from Pfizer. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
Drs. Flaherty and McArthur contributed equally to this article.
This article (10.1056/NEJMoa1103782) was published on June 5, 2011, at NEJM.org.
Source Information
The authors' affiliations are listed in the Appendix.
Address reprint requests to Dr. Chapman at the Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, or at chapmanp@mskcc.org.
Members of the BRAF Inhibitor in Melanoma 3 (BRIM-3) study group are listed in the Supplementary Appendix at NEJM.org.
Appendix
The authors' affiliations are as follows: the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York (P.B.C.); University of Kiel, Kiel (A.H.), University Hospital Essen, Essen (D.S.), and University of Tübingen, Tübingen (C.G.) — all in Germany; Institut Gustave Roussy (C.R., A.M.M.E.) and Service de Dermatologie, Hôpital Saint Louis (C.L.) — both in Paris; the Netherlands Cancer Institute, Amsterdam (J.B.H.); Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.), and Istituto Toscano Tumori, Florence (M.M.) — both in Italy; the Department of Medical Oncology, Royal Marsden Hospital, London (J. Larkin); the Department of Dermatology, University of Zurich, Zurich, Switzerland (R.D.); Istituto Europeo di Oncologia, Milan (A.T.); Princess Margaret Hospital and University Health Network, Toronto (D.H.); University of Manchester, Manchester, United Kingdom (P.L.); Saint Andre Hospital, Bordeaux (T.J.), and the Department of Dermatology, Nantes University Hospital, Nantes (B.D.) — both in France; the Department of Medicine, David Geffen School of Medicine at UCLA (A.R.), and the Angeles Clinic and Research Institute (S.J.O.) — both in Los Angeles; the Department of Medicine, Vanderbilt University School of Medicine, Nashville (J.A.S.); the Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh (J.M.K.); Plexxikon, Berkeley, CA (K.N.); Hoffmann–La Roche, Nutley, NJ (J. Li, R.J.L.); Genentech, San Francisco (B.N., J.H.); the Department of Medicine, Massachusetts General Hospital, Boston (K.T.F.); and the Peter MacCallum Cancer Center, Melbourne, VIC, Australia (G.A.M.).
- References
References
1
Balch CM ,Gershenwald JE ,Soong S-J , et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199-6206
CrossRef | Web of Science | Medline2
Jemal A ,Siegel R ,Xu J ,Ward E . Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300[Erratum, CA Cancer J Clin 2011;61:133-4.]
CrossRef | Web of Science | Medline3
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, cancer incidence and mortality worldwide: IARC CancerBase no. 10. Lyon, France: International Agency for Research on Cancer, 2010. (http://globocan.iarc.fr.)
4
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 1999;17:2745-2751
Web of Science | Medline5
Middleton MR ,Grob JJ ,Aaronson N , et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000;18:158-166
Web of Science | Medline6
Avril MF ,Aamdal S ,Grob JJ , et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004;22:1118-1125
CrossRef | Web of Science | Medline7
Bedikian AY ,Millward M ,Pehamberger H , et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006;24:4738-4745
CrossRef | Web of Science | Medline8
Hodi FS ,O'Day SJ ,McDermott DF , et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010;363:711-723[Erratum, N Engl J Med 2010;363:1290.]
Full Text | Web of Science | Medline9
Wolchok JD ,Thomas L ,Bondarenko IN , et al. A phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma. J Clin Oncol 2011;29:Suppl:LBA5-LBA510
Davies H ,Bignell GR ,Cox C , et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-954
CrossRef | Web of Science | Medline11
Curtin JA ,Fridlyand J ,Kageshita T , et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-2147
Full Text | Web of Science | Medline12
Bollag G ,Hirth P ,Tsai J , et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467:596-599
CrossRef | Web of Science | Medline13
Tsai J ,Lee JT ,Wang W , et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008;105:3041-3046
CrossRef | Web of Science | Medline14
Joseph EW ,Pratilas CA ,Poulikakos PI , et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A 2010;107:14903-14908
CrossRef | Web of Science | Medline15
Flaherty KT ,Puzanov I ,Kim KB , et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-819
Full Text | Web of Science | Medline16
Ribas A ,Kim KB ,Schuchter LM , et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutation-positive melanoma. J Clin Oncol 2011;29:Suppl:8509-850917
Pocock SJ ,Clayton TC ,Altman DG . Survival plots of time-to-event outcomes in clinical trials: good practice and pitfalls. Lancet 2002;359:1686-1689
CrossRef | Web of Science | Medline18
Long GV ,Menzies AM ,Nagrial AM , et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011;29:1239-1246
CrossRef | Web of Science | Medline19
Arozarena I ,Sanchez-Laorden B ,Packer L , et al. Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A. Cancer Cell 2011;19:45-57
CrossRef | Web of Science | Medline20
Kumar R ,Angelini S ,Czene K , et al. BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res 2003;9:3362-3368
Web of Science | Medline21
Williams VL ,Cohen PR ,Stewart DJ . Sorafenib-induced premalignant and malignant skin lesions. Int J Dermatol 2011;50:396-402
CrossRef | Web of Science | Medline22
Kwon EJ ,Kish LS ,Jaworsky C . The histologic spectrum of epithelial neoplasms induced by sorafenib. J Am Acad Dermatol 2009;61:522-527
CrossRef | Web of Science | Medline23
Poulikakos PI ,Zhang C ,Bollag G ,Shokat KM ,Rosen N . RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010;464:427-430
CrossRef | Web of Science | Medline24
Hatzivassiliou G ,Song K ,Yen I , et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010;464:431-435
CrossRef | Web of Science | Medline25
Heidorn SJ ,Milagre C ,Whittaker S , et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140:209-221
CrossRef | Web of Science | Medline26
Johannessen CM ,Boehm JS ,Kim SY , et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468:968-972
CrossRef | Web of Science | Medline27
Nazarian R ,Shi H ,Wang Q , et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010;468:973-977
CrossRef | Web of Science | Medline28
Villanueva J ,Vultur A ,Lee JT , et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010;18:683-695
CrossRef | Web of Science | Medline
- Citing Articles (150)
Citing Articles
1
Harkanwal Halait, Kelli DeMartin, Sweta Shah, Stephen Soviero, Rachel Langland, Suzanne Cheng, Grantland Hillman, Lin Wu, H. Jeffrey Lawrence. (2012) Analytical Performance of a Real-time PCR-based Assay for V600 Mutations in the BRAF Gene, Used as the Companion Diagnostic Test for the Novel BRAF Inhibitor Vemurafenib in Metastatic Melanoma. Diagnostic Molecular Pathology 21:1, 1-8
CrossRef2
Michael Krathen. (2012) Malignant Melanoma: Advances in Diagnosis, Prognosis, and Treatment. Seminars in Cutaneous Medicine and Surgery 31:1, 45-49
CrossRef3
Raffaele Califano, Aidalena Z. Abidin, Rahul Peck, Corinne Faivre-Finn, Paul Lorigan. (2012) Management of Small Cell Lung Cancer. Drugs 72:4, 471-490
CrossRef4
Sosman, Jeffrey A., Kim, Kevin B., Schuchter, Lynn, Gonzalez, Rene, Pavlick, Anna C., Weber, Jeffrey S., McArthur, Grant A., Hutson, Thomas E., Moschos, Stergios J., Flaherty, Keith T., Hersey, Peter, Kefford, Richard, Lawrence, Donald, Puzanov, Igor, Lewis, Karl D., Amaravadi, Ravi K., Chmielowski, Bartosz, Lawrence, H. Jeffrey, Shyr, Yu, Ye, Fei, Li, Jiang, Nolop, Keith B., Lee, Richard J., Joe, Andrew K., Ribas, Antoni, . (2012) Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib. New England Journal of Medicine 366:8, 707-714
Full Text5
Bertil Jonsson, Jonas Bergh. (2012) Hurdles in anticancer drug development from a regulatory perspective. Nature Reviews Clinical Oncology
CrossRef6
Keith T. Flaherty. (2012) Targeting Metastatic Melanoma. Annual Review of Medicine 63:1, 171-183
CrossRef7
Francesco Spagnolo, Paola Queirolo. (2012) Upcoming strategies for the treatment of metastatic melanoma. Archives of Dermatological Research
CrossRef8
Ana Slipicevic, Meenhard Herlyn. (2012) Narrowing the knowledge gaps for melanoma. Upsala Journal of Medical Sciences1-7
CrossRef9
Junjie Li, Feng Chen, Marlein Miranda Cona, Yuanbo Feng, Uwe Himmelreich, Raymond Oyen, Alfons Verbruggen, Yicheng Ni. (2012) A review on various targeted anticancer therapies. Targeted Oncology
CrossRef10
Doron Lipson, Marzia Capelletti, Roman Yelensky, Geoff Otto, Alex Parker, Mirna Jarosz, John A Curran, Sohail Balasubramanian, Troy Bloom, Kristina W Brennan, Amy Donahue, Sean R Downing, Garrett M Frampton, Lazaro Garcia, Frank Juhn, Kathy C Mitchell, Emily White, Jared White, Zac Zwirko, Tamar Peretz, Hovav Nechushtan, Lior Soussan-Gutman, Jhingook Kim, Hidefumi Sasaki, Hyeong Ryul Kim, Seung-il Park, Dalia Ercan, Christine E Sheehan, Jeffrey S Ross, Maureen T Cronin, Pasi A Jänne, Philip J Stephens. (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nature Medicine
CrossRef11
Timothy A. Yap, Paul Workman. (2012) Exploiting the Cancer Genome: Strategies for the Discovery and Clinical Development of Targeted Molecular Therapeutics. Annual Review of Pharmacology and Toxicology 52:1, 549-573
CrossRef12
Gary J. Kelloff, Caroline C. Sigman. (2012) Cancer biomarkers: selecting the right drug for the right patient. Nature Reviews Drug Discovery
CrossRef13
Dummer, Reinhard, Rinderknecht, Jeannine, Goldinger, Simone M., . (2012) Ultraviolet A and Photosensitivity during Vemurafenib Therapy. New England Journal of Medicine 366:5, 480-481
Full Text14
Annette S. Little, Kathryn Balmanno, Matthew J. Sale, Paul D. Smith, Simon J. Cook. (2012) Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Biochemical Society Transactions 40:1, 73-78
CrossRef15
P. Bachireddy, K. Rakhra, D. W. Felsher. (2012) Immunology in the clinic review series; focus on cancer: multiple roles for the immune system in oncogene addiction. Clinical & Experimental Immunology 167:2, 188-194
CrossRef16
Matthias Preusser, David Capper, Aysegül Ilhan-Mutlu, Anna Sophie Berghoff, Peter Birner, Rupert Bartsch, Christine Marosi, Christoph Zielinski, Minesh P. Mehta, Frank Winkler, Wolfgang Wick, Andreas Deimling. (2012) Brain metastases: pathobiology and emerging targeted therapies. Acta Neuropathologica 123:2, 205-222
CrossRef17
Anne O. Rodriguez. (2012) Personalized ovarian cancer treatment. Current Opinion in Obstetrics and Gynecology 24:1, 1-2
CrossRef18
Zhenyu Ji, Ching Ni Njauw, Michael Taylor, Victor Neel, Keith T Flaherty, Hensin Tsao. (2012) p53 Rescue through HDM2 Antagonism Suppresses Melanoma Growth and Potentiates MEK Inhibition. Journal of Investigative Dermatology 132:2, 356-364
CrossRef19
David Capper, Anna Sophie Berghoff, Manuel Magerle, Aysegül Ilhan, Adelheid Wöhrer, Monika Hackl, Josef Pichler, Stefan Pusch, Jochen Meyer, Antje Habel, Peter Petzelbauer, Peter Birner, Andreas Deimling, Matthias Preusser. (2012) Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathologica 123:2, 223-233
CrossRef20
Mythili Koneru, Richard D Carvajal. (2012) A new era for the management of metastatic melanoma. Expert Review of Dermatology 7:1, 27-35
CrossRef21
Katie E Lacy, Sophia N Karagiannis, Frank O Nestle. (2012) Immunotherapy for melanoma. Expert Review of Dermatology 7:1, 51-68
CrossRef22
Rosalie Fisher, Paul Cahalin, Martin Gore, James Larkin. (2012) A tale of two tumours and a plea for progress. The Lancet Oncology 13:2, 124-125
CrossRef23
Janet E. Dancey, Philippe L. Bedard, Nicole Onetto, Thomas J. Hudson. (2012) The Genetic Basis for Cancer Treatment Decisions. Cell 148:3, 409-420
CrossRef24
Robert L Yauch, Jeff Settleman. (2012) Recent advances in pathway-targeted cancer drug therapies emerging from cancer genome analysis. Current Opinion in Genetics & Development
CrossRef25
Marinus W Lobbezoo, A Hilary Calvert, Elizabeth A Eisenhauer, Giuseppe Giaccone. (2012) Methodology for the Development of Innovative Cancer Therapies Task Force addresses methodological issues in the clinical development of innovative cancer therapies. Clinical Investigation 2:2, 133-138
CrossRef26
Adrienne D. Cox, Channing J. Der. (2012) The RAF Inhibitor Paradox Revisited. Cancer Cell 21:2, 147-149
CrossRef27
R. Russell-Jones. (2012) When will selective lymphadenectomy become standard of care in melanoma?. International Journal of Clinical Practiceno-no
CrossRef28
Rolf W. Sparidans, Selvi Durmus, Alfred H. Schinkel, Jan H.M. Schellens, Jos H. Beijnen. (2012) Liquid chromatography-tandem mass spectrometric assay for the mutated BRAF inhibitor vemurafenib in human and mouse plasma. Journal of Chromatography B
CrossRef29
Jaap Verweij, Maja de Jonge, Ferry Eskens, Stefan Sleijfer. (2012) Moving molecular Targeted drug therapy towards personalizeD medicinE: Issues related to clinical trial design. Molecular Oncology
CrossRef30
Jessica L. F. Teh, Suzie Chen. (2012) Glutamatergic signaling in cellular transformation. Pigment Cell & Melanoma Researchno-no
CrossRef31
Emily C. Shaw, Peter W.M. Johnson. (2012) Stratified medicine for cancer therapy. Drug Discovery Today
CrossRef32
Mathew J. Garnett, Ultan McDermott. (2012) Exploiting genetic complexity in cancer to improve therapeutic strategies. Drug Discovery Today
CrossRef33
Vijay Walia, Euphemia W. Mu, Jimmy C. Lin, Yardena Samuels. (2012) Delving into somatic variation in sporadic melanoma. Pigment Cell & Melanoma Researchno-no
CrossRef34
Ken Dutton-Regester, Nicholas K. Hayward. (2012) Reviewing the somatic genetics of melanoma: from current to future analytical approaches. Pigment Cell & Melanoma Researchno-no
CrossRef35
Jame Abraham. (2012) Vemurafenib in melanoma with the BRAF V600E mutation. Community Oncology
CrossRef36
K Sakaizawa, Y Goto, Y Kiniwa, A Uchiyama, K Harada, S Shimada, T Saida, S Ferrone, M Takata, H Uhara, R Okuyama. (2012) Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level. British Journal of Cancer
CrossRef37
Anirudh Prahallad, Chong Sun, Sidong Huang, Federica Di Nicolantonio, Ramon Salazar, Davide Zecchin, Roderick L. Beijersbergen, Alberto Bardelli, René Bernards. (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature
CrossRef38
Martin W. Rowbottom, Raffaella Faraoni, Qi Chao, Brian T. Campbell, Andiliy G. Lai, Eduardo Setti, Maiko Ezawa, Kelly G. Sprankle, Sunny Abraham, Lan Tran, Brian Struss, Michael Gibney, Robert C. Armstrong, Ruwanthi N. Gunawardane, Ronald R. Nepomuceno, Ianina Valenta, Helen Hua, Michael F. Gardner, Merryl D. Cramer, Dana Gitnick, Darren E. Insko, Julius L. Apuy, Susan Jones-Bolin, Arup K. Ghose, Torsten Herbertz, Mark A. Ator, Bruce D. Dorsey, Bruce Ruggeri, Michael Williams, Shripad Bhagwat, Joyce James, Mark W. Holladay. (2012) Identification of 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea Hydrochloride (CEP-32496), a Highly Potent and Orally Efficacious Inhibitor of V-RAF Murine Sarcoma Viral Oncogene Homologue B1 (BRAF) V600E. Journal of Medicinal Chemistry120123085222000
CrossRef39
Su, Fei, Viros, Amaya, Milagre, Carla, Trunzer, Kerstin, Bollag, Gideon, Spleiss, Olivia, Reis-Filho, Jorge S., Kong, Xiangju, Koya, Richard C., Flaherty, Keith T., Chapman, Paul B., Kim, Min Jung, Hayward, Robert, Martin, Matthew, Yang, Hong, Wang, Qiongqing, Hilton, Holly, Hang, Julie S., Noe, Johannes, Lambros, Maryou, Geyer, Felipe, Dhomen, Nathalie, Niculescu-Duvaz, Ion, Zambon, Alfonso, Niculescu-Duvaz, Dan, Preece, Natasha, Robert, Lídia, Otte, Nicholas J., Mok, Stephen, Kee, Damien, Ma, Yan, Zhang, Chao, Habets, Gaston, Burton, Elizabeth A., Wong, Bernice, Nguyen, Hoa, Kockx, Mark, Andries, Luc, Lestini, Brian, Nolop, Keith B., Lee, Richard J., Joe, Andrew K., Troy, James L., Gonzalez, Rene, Hutson, Thomas E., Puzanov, Igor, Chmielowski, Bartosz, Springer, Caroline J., McArthur, Grant A., Sosman, Jeffrey A., Lo, Roger S., Ribas, Antoni, Marais, Richard, . (2012) RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors. New England Journal of Medicine 366:3, 207-215
Full Text40
H.E. Gabbert, T. Kirchner. (2012) Prädiktive Biomarker als Entscheidungsgrundlage für die onkologische Therapie. Forum
CrossRef41
Jeffrey B Cheng, Raymond J Cho. (2012) Genetics and Epigenetics of the Skin Meet Deep Sequence. Journal of Investigative Dermatology
CrossRef42
T. L. Biechele, R. M. Kulikauskas, R. A. Toroni, O. M. Lucero, R. D. Swift, R. G. James, N. C. Robin, D. W. Dawson, R. T. Moon, A. J. Chien. (2012) Wnt/ -Catenin Signaling and AXIN1 Regulate Apoptosis Triggered by Inhibition of the Mutant Kinase BRAFV600E in Human Melanoma. Science Signaling 5:206, ra3-ra3
CrossRef43
Z.-m. Huang, M. Chinen, P. J. Chang, T. Xie, L. Zhong, S. Demetriou, M. P. Patel, R. Scherzer, E. V. Sviderskaya, D. C. Bennett, G. L. Millhauser, D. H. Oh, J. E. Cleaver, M. L. Wei. (2012) Targeting protein-trafficking pathways alters melanoma treatment sensitivity. Proceedings of the National Academy of Sciences 109:2, 553-558
CrossRef44
Alexander M. M. Eggermont, Caroline Robert. (2012) Melanoma in 2011: A new paradigm tumor for drug development. Nature Reviews Clinical Oncology
CrossRef45
Vasiliki A Nikolaou, Alexander J Stratigos, Keith T Flaherty, Hensin Tsao. (2012) Melanoma: New Insights and New Therapies. Journal of Investigative Dermatology
CrossRef46
A P Algazi, J S Weber, S C Andrews, P Urbas, P N Munster, R C DeConti, J Hwang, V K Sondak, J L Messina, T McCalmont, A I Daud. (2012) Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma. British Journal of Cancer 106:1, 85-91
CrossRef47
Felipe Ades, Otto Metzger-Filho. (2012) Targeting the Cellular Signaling: BRAF Inhibition and Beyond for the Treatment of Metastatic Malignant Melanoma. Dermatology Research and Practice 2012, 1-9
CrossRef48
Rahul R. Naik, Alan Saven. (2012) My Treatment Approach to Hairy Cell Leukemia. Mayo Clinic Proceedings 87:1, 67-76
CrossRef49
B. Rousseau pour l’Aerio. (2012) Mécanismes de résistances aux inhibiteurs de RAF : revue de la littérature. Oncologie 14:1, 2-4
CrossRef50
Ken Dutton-Regester, Lauren G. Aoude, Derek J. Nancarrow, Mitchell S. Stark, Linda O'Connor, Cathy Lanagan, Gulietta M. Pupo, Varsha Tembe, Candace D. Carter, Michael O'Rourke, Richard A. Scolyer, Graham J. Mann, Christopher W. Schmidt, Adrian Herington, Nicholas K. Hayward. (2012) Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene. Genes, Chromosomes and Cancern/a-n/a
CrossRef51
Ichiro Yajima, Mayuko Y. Kumasaka, Nguyen Dinh Thang, Yuji Goto, Kozue Takeda, Osamu Yamanoshita, Machiko Iida, Nobutaka Ohgami, Haruka Tamura, Yoshiyuki Kawamoto, Masashi Kato. (2012) RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy. Dermatology Research and Practice 2012, 1-5
CrossRef52
M Colombino, P Sperlongano, F Izzo, F Tatangelo, G Botti, A Lombardi, M Accardo, L Tarantino, I Sordelli, M Agresti, A Abbruzzese, M Caraglia, G Palmieri. (2012) BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy. Cell Death and Disease 3:1, e259
CrossRef53
Gayane Badalian-Very, Jo-Anne Vergilio, Barbara A. Degar, Carlos Rodriguez-Galindo, Barrett J. Rollins. (2012) Recent advances in the understanding of Langerhans cell histiocytosis. British Journal of Haematology 156:2, 163-172
CrossRef54
Grazia Graziani, Lucio Tentori, Pierluigi Navarra. (2012) Ipilimumab: A novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacological Research 65:1, 9-22
CrossRef55
Pamela Jo Harris, Giovanna Speranza, Claudio Dansky Ullmann. (2012) Targeting embryonic signaling pathways in cancer therapy. Expert Opinion on Therapeutic Targets 16:1, 131-145
CrossRef56
Roger S Lo. (2012) Combinatorial therapies to overcome B-RAF inhibitor resistance in melanomas. Pharmacogenomics 13:2, 125-128
CrossRef57
Camila Ferreira de Souza, Alice Santana Morais, Miriam Galvonas Jasiulionis. (2012) Biomarkers as Key Contributors in Treating Malignant Melanoma Metastases. Dermatology Research and Practice 2012, 1-14
CrossRef58
S A Holstein, R J Hohl. (2012) Therapeutic Additions and Possible Deletions in Oncology in 2011. Clinical Pharmacology & Therapeutics 91:1, 15-17
CrossRef59
S. Kruijff, H.J. Hoekstra. (2012) The current status of S-100B as a biomarker in melanoma. European Journal of Surgical Oncology (EJSO)
CrossRef60
Libero Santarpia, Scott M Lippman, Adel K El-Naggar. (2012) Targeting the MAPK–RAS–RAF signaling pathway in cancer therapy. Expert Opinion on Therapeutic Targets 16:1, 103-119
CrossRef61
Zhenyu Ji, Keith T. Flaherty, Hensin Tsao. (2012) Targeting the RAS pathway in melanoma. Trends in Molecular Medicine 18:1, 27-35
CrossRef62
Irene Sánchez-Hernández, Pablo Baquero, Laura Calleros, Antonio Chiloeches. (2012) Dual inhibition of V600EBRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism. Cancer Letters 314:2, 244-255
CrossRef63
Chandrani Chattopadhyay, Julie A. Ellerhorst, Suhendan Ekmekcioglu, Victoria R. Greene, Michael A. Davies, Elizabeth A. Grimm. (2012) Association of activated c-Met with NRAS-mutated human melanomas. International Journal of Cancern/a-n/a
CrossRef64
Gopa Iyer, Matthew I. Milowsky. (2012) Fibroblast growth factor receptor-3 in urothelial tumorigenesis
. Urologic Oncology: Seminars and Original Investigations
CrossRef65
Reinhard Dummer, Keith T. Flaherty. (2012) Resistance patterns with tyrosine kinase inhibitors in melanoma. Current Opinion in Oncology1
CrossRef66
Alfonso Zambon, Ion Niculescu-Duvaz, Dan Niculescu-Duvaz, Richard Marais, Caroline J Springer. (2012) Small molecule inhibitors of BRAF in clinical trials. Bioorganic & Medicinal Chemistry Letters 22:2, 789-792
CrossRef67
Jim Jinn-Chyuan Sheu, Bin Guan, Fuu-Jen Tsai, Erin Yi-Ting Hsiao, Chih-Mei Chen, Raquel Seruca, Tian-Li Wang, Ie-Ming Shih. (2012) Mutant BRAF Induces DNA Strand Breaks, Activates DNA Damage Response Pathway, and Up-Regulates Glucose Transporter-1 in Nontransformed Epithelial Cells. The American Journal of Pathology
CrossRef68
Casey W. Shuptrine, Rishi Surana, Louis M. Weiner. (2012) Monoclonal antibodies for the treatment of cancer. Seminars in Cancer Biology
CrossRef69
W. Deng, Y. N. Vashisht Gopal, A. Scott, G. Chen, S. E. Woodman, M. A. Davies. (2012) Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell & Melanoma Researchno-no
CrossRef70
Ha Linh Vu, Andrew E. Aplin. (2012) The Yin-Yang of RAF inhibitors. Pigment Cell & Melanoma Researchno-no
CrossRef71
A. Bottos, M. Martini, F. Di Nicolantonio, V. Comunanza, F. Maione, A. Minassi, G. Appendino, F. Bussolino, A. Bardelli. (2011) PNAS Plus: Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia. Proceedings of the National Academy of Sciences
CrossRef72
F. Murphy, F. V. Gleeson, M. R. Middleton. (2011) Pulmonary nodules in patients with melanoma--assume nothing. Annals of Oncology
CrossRef73
Schwartz, Robert, . (2011) The Emperor of All Maladies — The Beginning of the Beginning. New England Journal of Medicine 365:25, 2353-2355
Full Text74
Rochet, Nicole M., Kottschade, Lisa A., Markovic, Svetomir N., . (2011) Vemurafenib for Melanoma Metastases to the Brain. New England Journal of Medicine 365:25, 2439-2441
Full Text75
Ira Mellman, George Coukos, Glenn Dranoff. (2011) Cancer immunotherapy comes of age. Nature 480:7378, 480-489
CrossRef76
Dorothy M. K. Keefe, Emma H. Bateman. (2011) Tumor control versus adverse events with targeted anticancer therapies. Nature Reviews Clinical Oncology
CrossRef77
Hugo Lavoie, Marc Therrien. (2011) Cancer: A drug-resistant duo. Nature 480:7377, 329-330
CrossRef78
Rui-Ru Ji, Scott D. Chasalow, Lisu Wang, Omid Hamid, Henrik Schmidt, John Cogswell, Suresh Alaparthy, David Berman, Maria Jure-Kunkel, Nathan O. Siemers, Jeffrey R. Jackson, Vafa Shahabi. (2011) An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunology, Immunotherapy
CrossRef79
Manish R. Sharma, Richard L. Schilsky. (2011) Role of randomized phase III trials in an era of effective targeted therapies. Nature Reviews Clinical Oncology
CrossRef80
Edward H. Flach, Vito W. Rebecca, Meenhard Herlyn, Keiran S. M. Smalley, Alexander R. A. Anderson. (2011) Fibroblasts Contribute to Melanoma Tumor Growth and Drug Resistance. Molecular Pharmaceutics 8:6, 2039-2049
CrossRef81
Michael C. Rowbotham, Stanley P.L. Leong. (2011) How to reduce the incidence of neuropathic pain: Sentinel node biopsy for diagnosis of metastatic malignant melanoma. PAIN 152:12, 2681-2682
CrossRef82
Michael S. Edwards, Dominic A. Solimando, J. Aubrey Waddell. (2011) Cancer Chemotherapy Update - Brentuximab Vedotin and Vemurafenib. Hospital Pharmacy 46:12, 934-937
CrossRef83
William E. Damsky, David P. Curley, Manjula Santhanakrishnan, Lara E. Rosenbaum, James T. Platt, Bonnie E. Gould Rothberg, Makoto M. Taketo, David Dankort, David L. Rimm, Martin McMahon, Marcus Bosenberg. (2011) β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas. Cancer Cell 20:6, 741-754
CrossRef84
L. V. Sequist, R. S. Heist, A. T. Shaw, P. Fidias, R. Rosovsky, J. S. Temel, I. T. Lennes, S. Digumarthy, B. A. Waltman, E. Bast, S. Tammireddy, L. Morrissey, A. Muzikansky, S. B. Goldberg, J. Gainor, C. L. Channick, J. C. Wain, H. Gaissert, D. M. Donahue, A. Muniappan, C. Wright, H. Willers, D. J. Mathisen, N. C. Choi, J. Baselga, T. J. Lynch, L. W. Ellisen, M. Mino-Kenudson, M. Lanuti, D. R. Borger, A. J. Iafrate, J. A. Engelman, D. Dias-Santagata. (2011) Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Annals of Oncology 22:12, 2616-2624
CrossRef85
Gaëlle Quéreux, Brigitte Dréno. (2011) Fotemustine for the treatment of melanoma. Expert Opinion on Pharmacotherapy 12:18, 2891-2904
CrossRef86
Xiang-Yang Wang, Daming Zuo, Devanand Sarkar, Paul B Fisher. (2011) Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma. Expert Opinion on Pharmacotherapy 12:17, 2695-2706
CrossRef87
Anna I. Hooijkaas, Jules Gadiot, Hester van Boven, Christian Blank. (2011) Expression of the embryological morphogen Nodal in stage III/IV melanoma. Melanoma Research 21:6, 491-501
CrossRef88
Rachel E. Bell, Carmit Levy. (2011) The three M’s: melanoma, microphthalmia-associated transcription factor and microRNA. Pigment Cell & Melanoma Research 24:6, 1088-1106
CrossRef89
N. Basset-Séguin. (2011) Quoi de neuf en dermato-cancérologie ?. Annales de Dermatologie et de Vénéréologie 138, S253-S262
CrossRef90
Vladimir N. Ivanov, Tom K. Hei. (2011) Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy. Apoptosis 16:12, 1268-1284
CrossRef91
Thierry Passeron, Jean-Philippe Lacour, Maryline Allegra, Coralie Ségalen, Anne Deville, Antoine Thyss, Damien Giacchero, Jean-Paul Ortonne, Corine Bertolotto, Robert Ballotti, Philippe Bahadoran. (2011) Signalling and chemosensitivity assays in melanoma: is mutated status a prerequisite for targeted therapy?. Experimental Dermatology 20:12, 1030-1032
CrossRef92
Clara Alsinet, Augusto Villanueva. (2011) Pronóstico genómico en el carcinoma hepatocelular. Gastroenterología y Hepatología
CrossRef93
Tamar Nijsten, Robert S Stern. (2011) How Epidemiology Has Contributed to a Better Understanding of Skin Disease. Journal of Investigative Dermatology
CrossRef94
Luke Whitesell, Nancy U. Lin. (2011) HSP90 as a platform for the assembly of more effective cancer chemotherapy. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
CrossRef95
Clara Alsinet, Augusto Villanueva, Josep M. Llovet. (2011) Cell population genetics and deep sequencing: a novel approach for drivers discovery in hepatocellular carcinoma. Journal of Hepatology
CrossRef96
S. Roychowdhury, M. K. Iyer, D. R. Robinson, R. J. Lonigro, Y.-M. Wu, X. Cao, S. Kalyana-Sundaram, L. Sam, O. A. Balbin, M. J. Quist, T. Barrette, J. Everett, J. Siddiqui, L. P. Kunju, N. Navone, J. C. Araujo, P. Troncoso, C. J. Logothetis, J. W. Innis, D. C. Smith, C. D. Lao, S. Y. Kim, J. S. Roberts, S. B. Gruber, K. J. Pienta, M. Talpaz, A. M. Chinnaiyan. (2011) Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study. Science Translational Medicine 3:111, 111ra121-111ra121
CrossRef97
Miriam Martini, Loredana Vecchione, Salvatore Siena, Sabine Tejpar, Alberto Bardelli. (2011) Targeted therapies: how personal should we go?. Nature Reviews Clinical Oncology
CrossRef98
Giampietro Gasparini, Raffaele Longo. (2011) The paradigm of personalized therapy in oncology. Expert Opinion on Therapeutic Targets1-10
CrossRef99
Almass-Houd Aguissa-Touré, Gang Li. (2011) Genetic alterations of PTEN in human melanoma. Cellular and Molecular Life Sciences
CrossRef100
Samia Arifi, El Mehdi Tazi, Omar Mesbahi, Hassan Errihani. (2011) Activity of Imatinib Mesylate in Metastatic Anorectal Melanoma: A Case Report. Journal of Gastrointestinal Cancer
CrossRef101
Robert Williams. (2011) Discontinued drugs in 2010: oncology drugs. Expert Opinion on Investigational Drugs 20:11, 1479-1496
CrossRef102
Richard L Schilsky. (2011) Drug approval challenges in the age of personalized cancer treatment. Personalized Medicine 8:6, 633-640
CrossRef103
Shuang Cai, Taryn R Bagby, M Laird Forrest. (2011) Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies. Therapeutic Delivery 2:11, 1467-1484
CrossRef104
Iván Márquez-Rodas, Salvador Martín Algarra, José Antonio Avilés Izquierdo, Sara Custodio Cabello, Miguel Martín. (2011) A new era in the treatment of melanoma: from biology to clinical practice. Clinical and Translational Oncology 13:11, 787-792
CrossRef105
Anna Minchom, Kate Young, James Larkin. (2011) Ipilimumab: showing survival benefit in metastatic melanoma. Future Oncology 7:11, 1255-1264
CrossRef106
Vincent T. DeVita. (2011) Opinion: A personal note—40 years after the signing of the Cancer Act. Nature Reviews Clinical Oncology 8:12, 693-694
CrossRef107
Jennifer Nam Choi. (2011) Chemotherapy-induced iatrogenic injury of skin: New drugs and new concepts. Clinics in Dermatology 29:6, 587-601
CrossRef108
Keith. T Flaherty, Uma Yasothan, Peter Kirkpatrick. (2011) Vemurafenib. Nature Reviews Drug Discovery 10:11, 811-812
CrossRef109
(2011) Vemurafenib in Melanoma with BRAF V600E Mutation. New England Journal of Medicine 365:15, 1448-1450
Full Text110
Y M Thu, Y Su, J Yang, R Splittgerber, S Na, A Boyd, C Mosse, C Simons, A Richmond. (2011) NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the β-catenin pathway. Oncogene
CrossRef111
Olivier Vittecoq, Thierry Lequerré. (2011) Les applications en rhumatologie : perspectives. Revue du Rhumatisme 78, S191-S195
CrossRef112
Pablo Lopez-Bergami. (2011) The role of mitogen- and stress-activated protein kinase pathways in melanoma. Pigment Cell & Melanoma Research 24:5, 902-921
CrossRef113
Dimitrios H Roukos. (2011) Cancer genome sequencing and functional genomics: from translational to clinical medicine. Pharmacogenomics 12:10, 1371-1374
CrossRef114
Antonio T Baines, Dapeng Xu, Channing J Der. (2011) Inhibition of Ras for cancer treatment: the search continues. Future Medicinal Chemistry 3:14, 1787-1808
CrossRef115
Thomas I. Peng Soh, Wei Peng Yong, Federico Innocenti. (2011) Review: Recent progress and clinical importance on pharmacogenetics in cancer therapy. Clinical Chemistry and Laboratory Medicine---
CrossRef116
W Li, D W Melton. (2011) Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. Oncogene
CrossRef117
K J Basile, E V Abel, A E Aplin. (2011) Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells. Oncogene
CrossRef118
Asifa Akhtar, Elaine Fuchs, Tim Mitchison, Reuben J. Shaw, Daniel St Johnston, Andreas Strasser, Susan Taylor, Claire Walczak, Marino Zerial. (2011) A decade of molecular cell biology: achievements and challenges. Nature Reviews Molecular Cell Biology 12:10, 669-674
CrossRef119
Jean-François Morère. (2011) Melanoma: a new landmark in targeted oncology. Targeted Oncology 6:3, 131-131
CrossRef120
C. Hafner. (2011) Therapie des metastasierten Melanoms mit BRAF-Inhibitoren. Der Hautarzt 62:9, 696-698
CrossRef121
Robert A. Copeland. (2011) Protein methyltransferase inhibitors as personalized cancer therapeutics. Drug Discovery Today: Therapeutic Strategies
CrossRef122
Teri A. Manolio, Eric D. Green. (2011) Genomics Reaches the Clinic: From Basic Discoveries to Clinical Impact. Cell 147:1, 14-16
CrossRef123
David Carter. (2011) New Drug for Metastatic Melanoma Increases Survival Rate. AJN, American Journal of Nursing 111:9, 16
CrossRef124
Dimosthenis E Ziogas, Dimitrios H Roukos. (2011) Genome diagnostics: next-generation sequencing, new genome-wide association studies and clinical challenges. Expert Review of Molecular Diagnostics 11:7, 663-666
CrossRef125
Jame Abraham. (2011) Personalized medicine: myth to reality. Community Oncology 8:9, 395-396
CrossRef126
V. E. Velculescu, L. A. Diaz. (2011) Understanding the Enemy. Science Translational Medicine 3:98, 98ps37-98ps37
CrossRef127
Jan P. Deroose, Alexander M. M. Eggermont, Albertus N. Geel, Johannes H. W. Wilt, Jacobus W. A. Burger, Cornelis Verhoef. (2011) 20 Years Experience of TNF-Based Isolated Limb Perfusion for In-Transit Melanoma Metastases: TNF Dose Matters. Annals of Surgical Oncology
CrossRef128
Matti L. Gild, Martyn Bullock, Bruce G. Robinson, Roderick Clifton-Bligh. (2011) Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nature Reviews Endocrinology 7:10, 617-624
CrossRef129
S. Kruijff, E. Bastiaannet, A. H. Brouwers, W. B. Nagengast, M. J. Speijers, A. J. H. Suurmeijer, G. A. Hospers, H. J. Hoekstra. (2011) Use of S-100B to Evaluate Therapy Effects during Bevacizumab Induction Treatment in AJCC Stage III Melanoma. Annals of Surgical Oncology
CrossRef130
Ignacio Garrido-Laguna, Manuel Hidalgo, Razelle Kurzrock. (2011) The inverted pyramid of biomarker-driven trials. Nature Reviews Clinical Oncology 8:9, 562-566
CrossRef131
Steven A. Rosenberg. (2011) Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know. Nature Reviews Clinical Oncology 8:10, 577-585
CrossRef132
Gareth Rees. (2011) Industry Update: The latest developments in therapeutic delivery. Therapeutic Delivery 2:8, 975-985
CrossRef133
W. Joost Lesterhuis, John B. A. G. Haanen, Cornelis J. A. Punt. (2011) Cancer immunotherapy – revisited. Nature Reviews Drug Discovery 10:8, 591-600
CrossRef134
Sandrine Medves, Jean-Baptiste Demoulin. (2011) Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies. Journal of Cellular and Molecular Medicineno-no
CrossRef135
Steven O'Day. (2011) Progress in the management of metastatic melanoma. Community Oncology 8:8, 17-19
CrossRef136
Vernon K. Sondak, Lawrence E. Flaherty. (2011) Targeted therapies: Improved outcomes for patients with metastatic melanoma. Nature Reviews Clinical Oncology 8:9, 513-515
CrossRef137
Miguel A. Materin, Mark Faries, Harriet M. Kluger. (2011) Molecular Alternations in Uveal Melanoma. Current Problems in Cancer 35:4, 211-224
CrossRef138
Mark B. Faries, Stephan Ariyan. (2011) Current Surgical Treatment in Melanoma. Current Problems in Cancer 35:4, 173-184
CrossRef139
Ernstoff, Marc S., . (2011) Been There, Not Done That — Melanoma in the Age of Molecular Therapy. New England Journal of Medicine 364:26, 2547-2548
Full Text140
Neus Masqué-Soler, Monika Szczepanowski, Ivo Leuschner, Christian Vokuhl, Jochen Haag, Gabriele Calaminus, Wolfram Klapper. (2011) Absence of BRAF mutation in pediatric and adolescent germ cell tumors indicate biological differences to adult tumors. Pediatric Blood & Cancern/a-n/a
CrossRef141
John A. Jakob, Roland L. Bassett, Chaan S. Ng, Jonathan L. Curry, Richard W. Joseph, Gladys C. Alvarado, Michelle L. Rohlfs, Jessie Richard, Jeffrey E. Gershenwald, Kevin B. Kim, Alexander J. Lazar, Patrick Hwu, Michael A. Davies. (2011) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancern/a-n/a
CrossRef142
Keith T. Flaherty. (2011) BRAF Inhibitors and Melanoma. The Cancer Journal 17:6, 505-511
CrossRef143
Lara E. Davis, Motomi Mori, Charles Keller. (2011) Personalized cancer care: Opportunities and challenges in pediatric neuro-oncology. Pediatric Blood & Cancern/a-n/a
CrossRef144
Daniela Göppner, Martin Leverkus. (2011) Prognostic Parameters for the Primary Care of Melanoma Patients: What Is Really Risky in Melanoma?. Journal of Skin Cancer 2011, 1-13
CrossRef145
Daniela Sia, Augusto Villanueva. (2011) Signaling Pathways in Hepatocellular Carcinoma. Oncology 81:s1, 18-23
CrossRef146
Wisut Lamlertthon, Michele C. Hayward, David Neil Hayes. (2011) Emerging Technologies for Improved Stratification of Cancer Patients. The Cancer Journal 17:6, 451-464
CrossRef147
Darko Katalinic, Branimir Anic, Ranka Stern-Padovan, Miroslav Mayer, Mirna Sentic, Nada Cikes, Kamelija Zarkovic, Snjezana Dotlic, Stjepko Plestina. (2011) Low back pain as the presenting sign in a patient with primary extradural melanoma of the thoracic spine - A metastatic disease 17 Years after complete surgical resection. World Journal of Surgical Oncology 9:1, 150
CrossRef148
Ryan J. Sullivan, Keith T. Flaherty. (2011) BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance. Journal of Skin Cancer 2011, 1-8
CrossRef149
David A. Fenstermacher, Robert M. Wenham, Dana E. Rollison, William S. Dalton. (2011) Implementing Personalized Medicine in a Cancer Center. The Cancer Journal 17:6, 528-536
CrossRef150
Christopher Zito, Harriet M. Kluger. (2011) Immunotherapy for metastatic melanoma. Journal of Cellular Biochemistryn/a-n/a
CrossRef
- Letters
