Keith T Flaherty

Publications (103)1192.64 Total impact

• Article: Pharmacodynamic Effects and Mechanisms of Resistance to Vemurafenib in Patients With Metastatic Melanoma.

  Kerstin Trunzer, Anna C Pavlick, Lynn Schuchter, Rene Gonzalez, Grant A McArthur, Thomas E Hutson, Stergios J Moschos, Keith T Flaherty, Kevin B Kim, Jeffrey S Weber, [......], Mark Kockx, Olivia Spleiss, Annette Schell-Steven, Houston N Gilbert, Louise Cockey, Gideon Bollag, Richard J Lee, Andrew K Joe, Jeffrey A Sosman, Antoni Ribas
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  ABSTRACT: PURPOSETo assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling.ResultsVemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.
  Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
• Article: BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma.

  Dennie Tompers Frederick, Adriano Piris, Alexandria P Cogdill, Zachary A Cooper, Cecilia Lezcano, Cristina R Ferrone, Devarati Mitra, Andrea Boni, Lindsay P Newton, Chengwen Liu, [......], Ryan J Sullivan, Donald P Lawrence, F Stephen Hodi, Willem W Overwijk, Gregory Lizee, George F Murphy, Patrick Hwu, Keith T Flaherty, David E Fisher, Jennifer A Wargo
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  ABSTRACT: PURPOSE: To evaluate the effects BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10-14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib), and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T cell markers, and immunomodulatory cytokines. RESULTS: Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines (IL-6 & IL-8) and an increase in markers of T cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 were increased on treatment. A decrease in melanoma antigen expression and CD8 T cell infiltrate was noted at time of progression on BRAF inhibitor alone, and was reversed with combined BRAF and MEK inhibition. CONCLUSIONS: Together, this data suggests that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.
  Clinical Cancer Research 01/2013; · 7.74 Impact Factor
• Article: MRI assessment of early tumor response in metastatic renal cell carcinoma patients treated with sorafenib.

  Hyunseon Christine Kang, Kay-See Tan, Stephen M Keefe, Daniel F Heitjan, Evan S Siegelman, Keith T Flaherty, Peter J O'Dwyer, Mark A Rosen
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  ABSTRACT: The purpose of this study was to examine early MRI changes in renal cell carcinoma (RCC) treated with the antiangiogenic agent sorafenib and to identify MRI biomarkers of RCC response to sorafenib. Sixteen patients with RCC were evaluated by MRI before and 3-12 weeks after commencing treatment with sorafenib. Two experienced MR radiologists, blinded to treatment status, independently graded tumor appearance on T1-weighted, T2-weighted, and gadolinium-enhanced images. The proportional odds mixed model was used to compare qualitative appearance of tumors before and after therapy. Time-to-progression was correlated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and MR-modified Choi criteria, incorporating changes in both tumor enhancement and size. After sorafenib therapy, there was a significant increase in T1 signal intensity of tumors (p < 0.0001) and a significant decrease in degree of tumor enhancement (p < 0.0001). The sum of unidimensional tumor diameters decreased significantly after therapy (p = 0.005). However, the average decrease in size at early follow-up was 13%, and all patients except one had stable disease by RECIST 1.0. Early responders defined by MR-modified Choi criteria had increased time-to-progression compared with nonresponders, whereas early RECIST evaluation did not predict clinical outcome. Decreased enhancement and T1 shortening of tumors on MRI may be useful biomarkers of RCC response to angiogenesis inhibitors. Response criteria combining early changes in size and enhancement lead to better correlation with clinical outcome compared with size decrease alone.
  American Journal of Roentgenology 01/2013; 200(1):120-6. · 2.78 Impact Factor
• Article: The Anti-Melanoma Activity of Dinaciclib, a Cyclin-Dependent Kinase Inhibitor, Is Dependent on p53 Signaling.

  Brijal M Desai, Jessie Villanueva, Thierry-Thien K Nguyen, Mercedes Lioni, Min Xiao, Jun Kong, Clemens Krepler, Adina Vultur, Keith T Flaherty, Katherine L Nathanson, Keiran S M Smalley, Meenhard Herlyn
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  ABSTRACT: Although cyclin dependent kinase (CDK)-2 is known to be dispensable for the growth of most tumors, it is thought to be important for the proliferation of melanoma cells, where its expression is controlled by the melanocyte-lineage specific transcription factor MITF. Treatment of a panel of melanoma cells with the CDK inhibitor dinaciclib led to a concentration-dependent inhibition of growth under both 2D adherent and 3D organotypic cell culture conditions. Dinaciclib targeted melanoma cell lines regardless of cdk2 or MITF levels. Inhibition of growth was associated with a rapid induction of G2/M cell arrest and apoptosis. Treatment of human melanoma mouse xenografts with dinaciclib led to tumor regression associated with reduced retinoblastoma protein phosphorylation and Bcl-2 expression. Further mechanistic studies revealed that dinaciclib induces p53 expression whilst simultaneously downregulating the expression of the anti-apoptotic factors Mcl-1 and XIAP. To clarify the role of p53 activation in the dinaciclib-induced cell death, we generated melanoma cell lines in which p53 expression was knocked down using a shRNA lentiviral vector. Knockdown of p53 completely abolished the induction of apoptosis seen following dinaciclib treatment as shown by a lack of annexin-V staining and caspase-3 cleavage. Altogether, these data show that dinaciclib induces apoptosis in a large panel of melanoma cell lines through a mechanism requiring p53 expression.
  PLoS ONE 01/2013; 8(3):e59588. · 4.09 Impact Factor
• Article: Phase III Trial of Carboplatin and Paclitaxel With or Without Sorafenib in Metastatic Melanoma.

  Keith T Flaherty, Sandra J Lee, Fengmin Zhao, Lynn M Schuchter, Lawrence Flaherty, Richard Kefford, Michael B Atkins, Philip Leming, John M Kirkwood
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  ABSTRACT: PURPOSEThe primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma. PATIENTS AND METHODS In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m(2) intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity.ResultsIn all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference. CONCLUSION Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.
  Journal of Clinical Oncology 12/2012; · 18.37 Impact Factor
• Article: Elucidating distinct roles for NF1 in melanomagenesis.

  Ophélia Maertens, Bryan Johnson, Pablo Hollstein, Dennie T Frederick, Zachary A Cooper, Ludwine Messaien, Roderick T Bronson, Martin McMahon, Scott Granter, Keith T Flaherty, Jennifer A Wargo, Richard Marais, Karen Cichowski
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  ABSTRACT: BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations tumor development is restricted by oncogene-induced senescence (OIS). Here we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both PI3K and ERK pathways. As such, Nf1/Braf mutant tumors are resistant to BRAF inhibitors but are sensitive to combined MEK/mTOR inhibition. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and demonstrate that NF1-inactivation may impact responses to targeted therapies.
  Cancer discovery. 11/2012;
• Source

  Available from: Zhi Rong Qian

  Dataset: nature11183-s1

  Ravid Straussman, Teppei Morikawa, Kevin Shee, Michal Barzily-Rokni, Zhi Rong Qian, Jinyan Du, Ashli Davis, Margaret M Mongare, Joshua Gould, Dennie T Frederick, Zachary A Cooper, Paul B Chapman, David B Solit, Antoni Ribas, Roger S Lo, Keith T Flaherty, Shuji Ogino, Jennifer A Wargo, Todd R Golub
• Article: Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations.

  Keith T Flaherty, Jeffery R Infante, Adil Daud, Rene Gonzalez, Richard F Kefford, Jeffrey Sosman, Omid Hamid, Lynn Schuchter, Jonathan Cebon, Nageatte Ibrahim, [......], Igor Puzanov, Peter Lebowitz, Ajay Singh, Shonda Little, Peng Sun, Alicia Allred, Daniele Ouellet, Kevin B Kim, Kiran Patel, Jeffrey Weber
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  ABSTRACT: Background Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. Methods In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. Results Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). Conclusions Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175 .).
  New England Journal of Medicine 09/2012; · 53.30 Impact Factor
• Source

  Available from: Zhi Rong Qian

  Article: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

  Ravid Straussman, Teppei Morikawa, Kevin Shee, Michal Barzily-Rokni, Zhi Rong Qian, Jinyan Du, Ashli Davis, Margaret M Mongare, Joshua Gould, Dennie T Frederick, Zachary A Cooper, Paul B Chapman, David B Solit, Antoni Ribas, Roger S Lo, Keith T Flaherty, Shuji Ogino, Jennifer A Wargo, Todd R Golub
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  ABSTRACT: Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.
  Nature 07/2012; 487(7408):500-4. · 36.28 Impact Factor
• Article: Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.

  Daniel C Cho, Thomas E Hutson, Wolfram Samlowski, Peter Sportelli, Brad Somer, Paul Richards, Jeffrey A Sosman, Igor Puzanov, M Dror Michaelson, Keith T Flaherty, Robert A Figlin, Nicholas J Vogelzang
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  ABSTRACT: BACKGROUND: The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)-kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)-targeted therapy. METHODS: In the Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). Perifosine 231 enrolled 2 groups that received daily oral perifosine (100 mg daily): Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor. RESULTS: In the Perifosine 228 trial, 1 patient achieved a partial response (objective response rate, 4%; 95% confidence interval, 0.7%-20%), and 11 patients (46%) had stable disease as their best response. The median progression-free survival was 14.2 weeks (95% confidence interval, 7.7-21.6 weeks). In the Perifosine 231 trial, 5 patients achieved a partial response (objective response rate, 10%; 95% confidence interval, 4.5%-22.2%) and 16 patients (32%) had stable disease as their best response. The median progression-free survival was 14 weeks (95% confidence interval, 12.9, 20.7 weeks). Overall, perifosine was well tolerated, and there were very few grade 3 and 4 events. The most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue. CONCLUSIONS: Although perifosine demonstrated activity in patients with advanced RCC after failure on VEGF-targeted therapy, its activity was not superior to currently available second-line agents. Nonetheless, perifosine may be worthy of further study in RCC in combination with other currently available therapies. Cancer 2012. © 2012 American Cancer Society.
  Cancer 06/2012; · 4.77 Impact Factor
• Source

  Available from: Dirk Schadendorf

  Article: Improved survival with MEK inhibition in BRAF-mutated melanoma.

  Keith T Flaherty, Caroline Robert, Peter Hersey, Paul Nathan, Claus Garbe, Mohammed Milhem, Lev V Demidov, Jessica C Hassel, Piotr Rutkowski, Peter Mohr, [......], Marta Nyakas, Mark R Middleton, Jürgen C Becker, Michelle Casey, Laurie J Sherman, Frank S Wu, Daniele Ouellet, Anne-Marie Martin, Kiran Patel, Dirk Schadendorf
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  ABSTRACT: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
  New England Journal of Medicine 06/2012; 367(2):107-14. · 53.30 Impact Factor
• Article: From genes to drugs: targeted strategies for melanoma.

  Keith T Flaherty, F Stephen Hodi, David E Fisher
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  ABSTRACT: The past decade has revealed that melanoma is comprised of multiple subclasses that can be categorized on the basis of key features, including the clinical stage of disease, the oncogenic molecular 'drivers', the anatomical location or the behaviour of the primary lesion and the expression of specific biomarkers. Although exercises in subclassification are not new in oncology, progress in this area has produced both conceptual and clinical breakthroughs, which, for melanoma, are unprecedented in the modern history of the disease. This Review focuses on these recent striking advances in the strategy of molecularly targeted approaches to the therapy of melanoma in humans.
  Nature Reviews Cancer 04/2012; 12(5):349-61. · 29.54 Impact Factor
• Article: Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma.

  Grant A McArthur, Igor Puzanov, Ravi Amaravadi, Antoni Ribas, Paul Chapman, Kevin B Kim, Jeffrey A Sosman, Richard J Lee, Keith Nolop, Keith T Flaherty, Jason Callahan, Rodney J Hicks
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  ABSTRACT: Imaging with [(18)F]fluorodeoxyglucose (FDG) -positron emission tomography (PET) allows early recognition of a response to agents that target key driver mutations in human cancer. We aimed to determine the metabolic response rate to vemurafenib in patients with advanced BRAF-mutant melanoma. Baseline and day 15 FDG-PET was evaluated in 31 patients with advanced melanoma treated in a phase I study of dose escalation of vemurafenib (PLX06-02), which included four patients treated at subtherapeutic doses and 24 patients treated at 960 mg twice a day, which is the maximum-tolerated dose of vemurafenib. All 27 patients treated at potentially therapeutic levels had at least a partial metabolic response, and three patients achieved a complete metabolic response. In the 27 patients, there was an 80% ± 3% reduction in the maximum standardized uptake value (SUVmax) of target lesions and an 87% ± 3% decrease in the percentage of injected dose (%ID) in all identified disease sites. There was a positive correlation between %ID in all identified disease and target-lesion SUVmax (r(2) = 0.66; P < .001) that indicated a significant homogeneity of the response between lesions in individual patients. Although no relationship was found between the reduction in target lesion SUVmax and best response according to RECIST (Response Evaluation Criteria in Solid Tumors), there was a trend for patients with greater reductions in uptake of FDG to have longer progression-free survival. FDG-PET is a useful marker of an early biologic response to vemurafenib. Little variability in PET response was found between lesions in individual patients, which suggested minimal intrapatient molecular heterogeneity. FDG-PET is a useful tool for the evaluation of the biologic impact of inhibiting mutant BRAF and may allow for the more effective development of novel agents.
  Journal of Clinical Oncology 03/2012; 30(14):1628-34. · 18.37 Impact Factor
• Article: Resistance patterns with tyrosine kinase inhibitors in melanoma: new insights.

  Reinhard Dummer, Keith T Flaherty
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  ABSTRACT: After years of therapeutic approaches with limited effects in metastatic melanoma, new inhibitors of serine-threonine and tyrosine kinases have demonstrated impressive clinical efficacy and improved survival. This review explains the molecular background for the development of specific kinase inhibitors and briefly summarizes their clinical impact on advanced melanoma. Despite robust early clinical efficacy, the antiproliferative effect of these kinase inhibitors is limited. The resistance mechanisms are explored currently and will help to identify new targets for melanoma therapy.
  Current opinion in oncology 03/2012; 24(2):150-4. · 4.09 Impact Factor
• Article: Photodynamic therapy for multiple eruptive keratoacanthomas associated with vemurafenib treatment for metastatic melanoma.

  Allireza Alloo, Lilit Garibyan, Nicole LeBoeuf, George Lin, Andrew Werchniak, F Stephen Hodi, Keith T Flaherty, Donald P Lawrence, Jennifer Y Lin
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  ABSTRACT: The development of keratoacanthomas (KAs) and well-differentiated squamous cell carcinomas (SCCs) is a known adverse effect of novel BRAF inhibitors such as vemurafenib. With multiple such neoplasms often arising after BRAF inhibitor therapy, surgical excision is often impractical. We describe a patient with stage IV melanoma who received the BRAF inhibitor vemurafenib (recently approved by the US Food and Drug Administration) as part of a clinical trial and developed numerous diffuse, pathology-proven KAs and SCCs. The high number of lesions across a broad area precluded surgical treatment; instead, a noninvasive field approach using photodynamic therapy (PDT) was initiated. Compared with untreated tumors, most lesions demonstrated significant clinical regression following successive cycles of PDT. Given vemurafenib's recent approval by the US Food and Drug Administration, we provide a timely case report on the effective use of PDT in the treatment of BRAF inhibitor-associated KAs and SCCs. Although further studies are needed to better understand the biological processes of these secondary neoplasms, our observation provides an alternative noninvasive solution for improving the quality of life for patients receiving BRAF inhibitor therapy.
  Archives of dermatology 03/2012; 148(3):363-6. · 4.76 Impact Factor
• Article: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.

  Jeffrey A Sosman, Kevin B Kim, Lynn Schuchter, Rene Gonzalez, Anna C Pavlick, Jeffrey S Weber, Grant A McArthur, Thomas E Hutson, Stergios J Moschos, Keith T Flaherty, [......], Ravi K Amaravadi, Bartosz Chmielowski, H Jeffrey Lawrence, Yu Shyr, Fei Ye, Jiang Li, Keith B Nolop, Richard J Lee, Andrew K Joe, Antoni Ribas
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  ABSTRACT: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
  New England Journal of Medicine 02/2012; 366(8):707-14. · 53.30 Impact Factor
• Article: p53 rescue through HDM2 antagonism suppresses melanoma growth and potentiates MEK inhibition.

  Zhenyu Ji, Ching Ni Njauw, Michael Taylor, Victor Neel, Keith T Flaherty, Hensin Tsao
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  ABSTRACT: Oncogenesis reflects an orchestrated interaction between misguided growth signals. Although much effort has been launched to pharmacologically disable activated oncogenes, one sidelined approach is the restoration of tumor suppressive signals. As TP53 is often structurally preserved, but functionally crippled, by CDKN2A/ARF loss in melanoma, rescue of p53 function represents an attractive point of vulnerability in melanoma. In this study, we showed that both p53 protein and activity levels in melanoma cells were strongly induced by nutlin-3, a canonical HDM2 antagonist. Among a test panel of 51 cell lines, there was a marked reduction in melanoma viability that was directly linked to TP53 status. Moreover, we also found that the melanoma growth suppression mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibition was potentiated by HDM2 antagonism. These results provide fundamental insights into the intact p53 circuitry, which can be restored through small molecule inhibitors and potentially deployed for therapeutic gain.
  Journal of Investigative Dermatology 02/2012; 132(2):356-64. · 6.31 Impact Factor
• Article: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.

  Fei Su, Amaya Viros, Carla Milagre, Kerstin Trunzer, Gideon Bollag, Olivia Spleiss, Jorge S Reis-Filho, Xiangju Kong, Richard C Koya, Keith T Flaherty, [......], Rene Gonzalez, Thomas E Hutson, Igor Puzanov, Bartosz Chmielowski, Caroline J Springer, Grant A McArthur, Jeffrey A Sosman, Roger S Lo, Antoni Ribas, Richard Marais
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  ABSTRACT: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
  New England Journal of Medicine 01/2012; 366(3):207-15. · 53.30 Impact Factor
• Article: Melanoma: new insights and new therapies.

  Vasiliki A Nikolaou, Alexander J Stratigos, Keith T Flaherty, Hensin Tsao
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  ABSTRACT: Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. However, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. The discovery of BRAF mutations in melanoma created the first opportunity to develop oncogene-directed therapy in this disease and led to the development of compounds that inhibit aberrant BRAF activity. A decade later, vemurafenib, an orally available and well-tolerated selective BRAF inhibitor, ushered in a new era of molecular treatments for advanced disease. Additional targets have been identified, and novel agents that impact on various signaling pathways or modulate the immune system hold the promise of a whole new therapeutic landscape for patients with metastatic melanoma. One of the major thrusts in melanoma therapy is now focused on understanding and targeting the network of signal transduction pathways and on attacking elements that underlie the tumor's propensity for growth and chemoresistance. In this article, we review the novel targeted anticancer approaches that are under consideration in melanoma treatment.
  Journal of Investigative Dermatology 01/2012; 132(3 Pt 2):854-63. · 6.31 Impact Factor
• Article: Targeting metastatic melanoma.

  Keith T Flaherty
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  ABSTRACT: Metastatic melanoma has historically been one of the most treatment-refractory types of cancer. Recent headway has been made in understanding the genetic underpinnings of this cancer. A subset of oncogenic events is amenable to targeting with drug therapy. BRAF-targeted therapies represent the first major breakthrough in systemic therapy for melanoma leveraging the new genetic knowledge. Ongoing translational research seeks to identify the most scientifically rational combination treatment strategies to build on single-agent targeted therapy.
  Annual review of medicine 01/2012; 63:171-83. · 9.94 Impact Factor