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Brigitte Dréno - One of the best experts on this subject based on the ideXlab platform.
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Impact of depth of response on survival in patients treated with cobimetinib ± Vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.
British Journal of Cancer, 2019Co-Authors: Karl D. Lewis, Brigitte Dréno, James Larkin, Antoni Ribas, Keith T. Flaherty, Grant A. Mcarthur, Paolo A Ascierto, Matthew Wongchenko, Yibing Yan, Edward MckennaAbstract:Author(s): Lewis, Karl D; Larkin, James; Ribas, Antoni; Flaherty, Keith T; McArthur, Grant A; Ascierto, Paolo A; Dreno, Brigitte; Yan, Yibing; Wongchenko, Matthew; McKenna, Edward; Zhu, Qian; Mun, Yong; Hauschild, Axel | Abstract: BACKGROUND:This pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with Vemurafenib or cobimetinib plus Vemurafenib. METHODS:The data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures. RESULTS:Greater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with Vemurafenib; not estimable with cobimetinib plus Vemurafenib). Cobimetinib plus Vemurafenib improved depth of response versus Vemurafenib monotherapy regardless of other prognostic factors, including gene signatures. CONCLUSIONS:Greater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus Vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses.
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Effect of concomitant dosing with acid-reducing agents and Vemurafenib dose on survival in patients with BRAFV600 mutation-positive metastatic melanoma treated with Vemurafenib ± cobimetinib.
European journal of cancer (Oxford England : 1990), 2019Co-Authors: Karl D. Lewis, Brigitte Dréno, Axel Hauschild, James Larkin, Antoni Ribas, Keith T. Flaherty, Grant A. Mcarthur, Edward Mckenna, Qian Zhu, Yeung-chul MunAbstract:Abstract Background We conducted a retrospective analysis to evaluate the impact of concomitant acid-reducing agents (ARAs) and Vemurafenib dose on the efficacy of Vemurafenib in patients with BRAFV600 mutation–positive unresectable or metastatic melanoma treated with Vemurafenib or cobimetinib plus Vemurafenib. Methods Data were pooled for patients treated with Vemurafenib or cobimetinib plus Vemurafenib in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. The primary end-points were progression-free survival and overall survival across patient subgroups defined by Vemurafenib dose (full vs reduced) and concomitant ARA use (yes vs no). Objective response rate (ORR) was also analysed. Steady-state Vemurafenib concentrations were evaluated according to Vemurafenib dosing and concomitant ARA use across treatment cohorts in a subset of patients from BRIM-7 and coBRIM with available concentration data. Results Efficacy analyses included 920 patients: 641 in the Vemurafenib cohort and 279 in the cobimetinib plus Vemurafenib cohort. Overall, no significant differences in survival outcomes were observed across subgroups according to Vemurafenib dose and ARA use, with or without adjustment for known prognostic covariates, in both treatment cohorts. ORR was also similar across subgroups in both treatment cohorts. Steady-state Vemurafenib concentrations were analysed in 389 patients (193 in the Vemurafenib cohort and 196 in the cobimetinib plus Vemurafenib cohort) and were generally similar across Vemurafenib dose subgroups, regardless of ARA use in both treatment cohorts. Conclusions Results of this retrospective pooled analysis suggest that ARAs can be used concomitantly with Vemurafenib, alone or in combination with cobimetinib, without compromising the efficacy of Vemurafenib.
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Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017Co-Authors: Matthew Wongchenko, Brigitte Dréno, James Larkin, Grant A. Mcarthur, Paolo A Ascierto, Jeffrey A. Sosman, Luc Andries, Mark M. Kockx, Stephen D. Hurst, Ivor CaroAbstract:Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with Vemurafenib or cobimetinib combined with Vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the Vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among Vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3–2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0–2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with Vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7–1.8; P = 0.66). Conclusions: In Vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with Vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with Vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238–45. ©2017 AACR.
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Profile of Vemurafenib-induced severe skin toxicities
Journal of the European Academy of Dermatology and Venereology, 2016Co-Authors: Lucie Peuvrel, Gaelle Quéreux, Mélanie Saint-jean, A. Brocard, Jean Michel Nguyen, Amir Khammari, Anne Chantal Knol, Emilie Varey, Brigitte DrénoAbstract:BACKGROUND: Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. OBJECTIVE: To determine the rate of permanent Vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. METHODS: Retrospective cohort study of 131 patients treated with Vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for Vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. RESULTS: Among the 131 Vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on Vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. CONCLUSION: In this study, Vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates Vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed.
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Early-Onset Vemurafenib-Induced DRESS Syndrome
Dermatology (Basel Switzerland), 2015Co-Authors: Marion Munch, Lucie Peuvrel, A. Brocard, Amir Khammari, Brigitte Dréno, Mélanie Saint Jean, Gaelle QuéreuxAbstract:Vemurafenib is a BRAF inhibitor indicated in metastatic or unresectable melanoma in patients with BRAF mutations. Vemurafenib is frequently toxic, but the toxicity is often not serious. The third case of Vemurafenib-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is reported herein. The case is unusual in that the onset was early, with symptoms emerging as of day 8 of treatment. Treatment of DRESS syndrome is not currently based on precise recommendations, but systemic corticosteroid therapy is effective in serious cases. Severe toxidermias under Vemurafenib are exceptional; immediate discontinuation of treatment upon diagnosis is imperative. Switching from Vemurafenib to dabrafenib then seems to constitute an interesting therapeutic alternative, since its efficacy is the same but with fewer cutaneous adverse reactions. This case highlights the importance of awareness of the risk of DRESS syndrome associated with Vemurafenib and monitoring for warning signs from treatment initiation.
Duane D. Miller - One of the best experts on this subject based on the ideXlab platform.
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Abstract B19: Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with Vemurafenib overcome acquired Vemurafenib resistance in BRAF mutated melanoma
Principles of Novel Therapeutics in Combinations, 2015Co-Authors: Jin Wang, Jianjun Chen, Duane D. MillerAbstract:Acquired clinical resistance to BRAF inhibitors such as Vemurafenib or dabrafefnib arises frequently after short term of these targeted therapy. We hypothesized that a combined therapy using Vemurafenib with a G2/M phase blocking agent will arrest resistant cells and overcome Vemurafenib resistance. To test this hypothesis, we performed combination studies using our recently discovered tubulin inhibitor ABI-274 and Vemurafenib on both Vemurafenib-sensitive cells and a resistant A375RF21 sub line. The combination showed strong synergy in vitro, synergistically arrested cells in G1/G2/M phase, and significantly enhanced cancer cell apoptosis. In vivo co-administration of Vemurafenib with ABI-274 showed strong synergistic efficacy in the Vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current Vemurafenib therapy. This work was supported by NIH grants R01CA148706, 1S10OD010678-01 and 1S10RR026377-01. Citation Format: Jin Wang, Jianjun Chen, Duane D. Miller, Wei Li. Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with Vemurafenib overcome acquired Vemurafenib resistance in BRAF mutated melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B19.
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Synergistic Combination of Novel Tubulin Inhibitor ABI-274 and Vemurafenib Overcome Vemurafenib Acquired Resistance in BRAFV600E Melanoma
Molecular cancer therapeutics, 2013Co-Authors: Jin Wang, Jianjun Chen, Duane D. MillerAbstract:Acquired clinical resistance to Vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short term chemotherapy. Since inhibitions of targets in the RAF-MEK-ERK pathway result in G0/G1 cell cycle arrest, Vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using Vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome Vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and Vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to Vemurafenib and confirmed the strong synergistic effect. Next we studied the potential mechanisms of overcoming Vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and Vemurafenib synergistically arrested cells in G1/G2/M phase, and significantly increased apoptosis in both parental A375 and the Vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of ERK phosphorylation. Finally, in vivo co-administration of Vemurafenib with ABI-274 showed strong synergistic efficacy in the Vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current Vemurafenib therapy.
James Larkin - One of the best experts on this subject based on the ideXlab platform.
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Impact of depth of response on survival in patients treated with cobimetinib ± Vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.
British Journal of Cancer, 2019Co-Authors: Karl D. Lewis, Brigitte Dréno, James Larkin, Antoni Ribas, Keith T. Flaherty, Grant A. Mcarthur, Paolo A Ascierto, Matthew Wongchenko, Yibing Yan, Edward MckennaAbstract:Author(s): Lewis, Karl D; Larkin, James; Ribas, Antoni; Flaherty, Keith T; McArthur, Grant A; Ascierto, Paolo A; Dreno, Brigitte; Yan, Yibing; Wongchenko, Matthew; McKenna, Edward; Zhu, Qian; Mun, Yong; Hauschild, Axel | Abstract: BACKGROUND:This pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with Vemurafenib or cobimetinib plus Vemurafenib. METHODS:The data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures. RESULTS:Greater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with Vemurafenib; not estimable with cobimetinib plus Vemurafenib). Cobimetinib plus Vemurafenib improved depth of response versus Vemurafenib monotherapy regardless of other prognostic factors, including gene signatures. CONCLUSIONS:Greater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus Vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses.
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Effect of concomitant dosing with acid-reducing agents and Vemurafenib dose on survival in patients with BRAFV600 mutation-positive metastatic melanoma treated with Vemurafenib ± cobimetinib.
European journal of cancer (Oxford England : 1990), 2019Co-Authors: Karl D. Lewis, Brigitte Dréno, Axel Hauschild, James Larkin, Antoni Ribas, Keith T. Flaherty, Grant A. Mcarthur, Edward Mckenna, Qian Zhu, Yeung-chul MunAbstract:Abstract Background We conducted a retrospective analysis to evaluate the impact of concomitant acid-reducing agents (ARAs) and Vemurafenib dose on the efficacy of Vemurafenib in patients with BRAFV600 mutation–positive unresectable or metastatic melanoma treated with Vemurafenib or cobimetinib plus Vemurafenib. Methods Data were pooled for patients treated with Vemurafenib or cobimetinib plus Vemurafenib in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. The primary end-points were progression-free survival and overall survival across patient subgroups defined by Vemurafenib dose (full vs reduced) and concomitant ARA use (yes vs no). Objective response rate (ORR) was also analysed. Steady-state Vemurafenib concentrations were evaluated according to Vemurafenib dosing and concomitant ARA use across treatment cohorts in a subset of patients from BRIM-7 and coBRIM with available concentration data. Results Efficacy analyses included 920 patients: 641 in the Vemurafenib cohort and 279 in the cobimetinib plus Vemurafenib cohort. Overall, no significant differences in survival outcomes were observed across subgroups according to Vemurafenib dose and ARA use, with or without adjustment for known prognostic covariates, in both treatment cohorts. ORR was also similar across subgroups in both treatment cohorts. Steady-state Vemurafenib concentrations were analysed in 389 patients (193 in the Vemurafenib cohort and 196 in the cobimetinib plus Vemurafenib cohort) and were generally similar across Vemurafenib dose subgroups, regardless of ARA use in both treatment cohorts. Conclusions Results of this retrospective pooled analysis suggest that ARAs can be used concomitantly with Vemurafenib, alone or in combination with cobimetinib, without compromising the efficacy of Vemurafenib.
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Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study
Annals of Oncology, 2017Co-Authors: Paul B. Chapman, James Larkin, Antoni Ribas, Caroline Robert, John B. A. G. Haanen, David Hogg, Omid Hamid, P.a. Ascierto, Alessandro Testori, Paul LoriganAbstract:Background: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for Vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods: Patients were randomly assigned in a 1 : 1 ratio to receive Vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to Vemurafenib. Results: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to Vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to Vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for Vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for Vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the Vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. Conclusions: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to Vemurafenib and receipt of subsequent anticancer therapies. ClinicalTrials.gov: NCT01006980
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Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017Co-Authors: Matthew Wongchenko, Brigitte Dréno, James Larkin, Grant A. Mcarthur, Paolo A Ascierto, Jeffrey A. Sosman, Luc Andries, Mark M. Kockx, Stephen D. Hurst, Ivor CaroAbstract:Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with Vemurafenib or cobimetinib combined with Vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the Vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among Vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3–2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0–2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with Vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7–1.8; P = 0.66). Conclusions: In Vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with Vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with Vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238–45. ©2017 AACR.
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The combination of Vemurafenib and cobimetinib in advanced melanoma
Expert Opinion on Orphan Drugs, 2016Co-Authors: Lavinia Spain, Emily Goode, Yevette Mcgovern, Kroopa Joshi, James LarkinAbstract:Introduction: Advanced melanoma with a BRAF V600 mutation responds to treatment with BRAF inhibitors such as Vemurafenib, with great improvement in tumour response and patient survival. Despite early and often dramatic responses, resistance to Vemurafenib develops. Concurrent inhibition of a downstream protein, MEK, also involved in the MAPK oncogenic signalling pathway, defers development of resistance. The MEK inhibitor cobimetinib has been successfully and safely combined with Vemurafenib, further improving response rate and survival when compared to Vemurafenib monotherapy.Areas covered: This article covers the mechanism of action of both Vemurafenib and cobimetinib, in addition to describing results from the key Phase I and Phase III studies which led to registration of the combination in the US and Europe as a therapeutic option for advanced BRAF mutant melanoma. The safety profile of these agents is also discussed in detail, including similarities with and differences from the competitor compounds dabrafenib and trametinib.Expert opinion: Vemurafenib in combination with cobimetinib provides an alternative BRAF/MEK blockade. The combination is tolerable, safe and effective and results in fewer skin toxicities than Vemurafenib monotherapy.
Jin Wang - One of the best experts on this subject based on the ideXlab platform.
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Abstract B19: Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with Vemurafenib overcome acquired Vemurafenib resistance in BRAF mutated melanoma
Principles of Novel Therapeutics in Combinations, 2015Co-Authors: Jin Wang, Jianjun Chen, Duane D. MillerAbstract:Acquired clinical resistance to BRAF inhibitors such as Vemurafenib or dabrafefnib arises frequently after short term of these targeted therapy. We hypothesized that a combined therapy using Vemurafenib with a G2/M phase blocking agent will arrest resistant cells and overcome Vemurafenib resistance. To test this hypothesis, we performed combination studies using our recently discovered tubulin inhibitor ABI-274 and Vemurafenib on both Vemurafenib-sensitive cells and a resistant A375RF21 sub line. The combination showed strong synergy in vitro, synergistically arrested cells in G1/G2/M phase, and significantly enhanced cancer cell apoptosis. In vivo co-administration of Vemurafenib with ABI-274 showed strong synergistic efficacy in the Vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current Vemurafenib therapy. This work was supported by NIH grants R01CA148706, 1S10OD010678-01 and 1S10RR026377-01. Citation Format: Jin Wang, Jianjun Chen, Duane D. Miller, Wei Li. Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with Vemurafenib overcome acquired Vemurafenib resistance in BRAF mutated melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B19.
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Synergistic Combination of Novel Tubulin Inhibitor ABI-274 and Vemurafenib Overcome Vemurafenib Acquired Resistance in BRAFV600E Melanoma
Molecular cancer therapeutics, 2013Co-Authors: Jin Wang, Jianjun Chen, Duane D. MillerAbstract:Acquired clinical resistance to Vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short term chemotherapy. Since inhibitions of targets in the RAF-MEK-ERK pathway result in G0/G1 cell cycle arrest, Vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using Vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome Vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and Vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to Vemurafenib and confirmed the strong synergistic effect. Next we studied the potential mechanisms of overcoming Vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and Vemurafenib synergistically arrested cells in G1/G2/M phase, and significantly increased apoptosis in both parental A375 and the Vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of ERK phosphorylation. Finally, in vivo co-administration of Vemurafenib with ABI-274 showed strong synergistic efficacy in the Vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current Vemurafenib therapy.
Celeste Lebbe - One of the best experts on this subject based on the ideXlab platform.
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Vemurafenib-induced neutrophilic panniculitis.
Melanoma research, 2012Co-Authors: J.-b. Monfort, Cécile Pagès, P. Schneider, Bart Neyns, Christelle Comte, Martine Bagot, Marie-dominique Vignon-pennamen, Manuelle Viguier, Celeste LebbeAbstract:Vemurafenib is a targeted therapy, used in patients with metastatic cutaneous melanoma who carry the BRAF V600E mutation, with a relative reduction of 63% in the risk of death. Several adverse events have been described previously, such as photosensitivity or squamous-cell carcinomas. Two cases of panniculitis have been reported recently with two different selective BRAF inhibitors. We report two cases of neutrophilic panniculitis in patients treated by Vemurafenib for a metastatic melanoma. Clinical and biological examinations showed no indications for an immune nor an infectious cause of neutrophilic panniculitis. Thus, we believe that Vemurafenib caused this panniculitis. Treatment with Vemurafenib was maintained in both patients because of the clinical and radiological tumoral responses. One patient showed spontaneous recovery, whereas the other patient presented several recurrences of panniculitis. We believe that physicians should be aware of this cutaneous side effect of Vemurafenib, but it should not lead to discontinuation of this treatment.
