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Brigitte Dréno - One of the best experts on this subject based on the ideXlab platform.

  • Cobimetinib plus atezolizumab in brafv600 wild type melanoma primary results from the randomized phase iii imspire170 study
    Annals of Oncology, 2021
    Co-Authors: Helen Gogas, Brigitte Dréno, Lev V Demidov, Daniil Stroyakovskiy, Piotr Rutkowski, J Larkin, Zeynep Eroglu, Francesco P Ferrucci, Jacopo Pigozzo, Jacek Mackiewicz
    Abstract:

    Background Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. Patients and methods IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive Cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive Cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for Cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with Cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with Cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with Cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

  • 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, 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Paolo A Ascierto, Antoni Ribas, Yibing Yan, Matthew Wongchenko
    Abstract:

    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: BackgroundThis 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.MethodsThe 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.ResultsGreater 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.ConclusionsGreater 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.

  • 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), 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, Axel Hauschild, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Edward Mckenna, Qian Zhu, Yeung-chul Mun
    Abstract:

    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.

  • genomic features of exceptional response in vemurafenib Cobimetinib treated patients with brafv600 mutated metastatic melanoma
    Clinical Cancer Research, 2019
    Co-Authors: Yibing Yan, Brigitte Dréno, James Larkin, Paolo A Ascierto, Matthew Wongchenko, Caroline Robert, Michele Maio, Claus Garbe, Paul B Chapman, Jeffrey A. Sosman
    Abstract:

    Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti–programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma. Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with Cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling. Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response–related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression. Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

  • 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, 2017
    Co-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 Caro
    Abstract:

    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.

Paolo A Ascierto - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Paolo A Ascierto, Antoni Ribas, Yibing Yan, Matthew Wongchenko
    Abstract:

    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: BackgroundThis 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.MethodsThe 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.ResultsGreater 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.ConclusionsGreater 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.

  • genomic features of exceptional response in vemurafenib Cobimetinib treated patients with brafv600 mutated metastatic melanoma
    Clinical Cancer Research, 2019
    Co-Authors: Yibing Yan, Brigitte Dréno, James Larkin, Paolo A Ascierto, Matthew Wongchenko, Caroline Robert, Michele Maio, Claus Garbe, Paul B Chapman, Jeffrey A. Sosman
    Abstract:

    Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti–programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma. Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with Cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling. Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response–related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression. Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

  • 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, 2017
    Co-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 Caro
    Abstract:

    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.

  • incidence course and management of toxicities associated with Cobimetinib in combination with vemurafenib in the cobrim study
    Annals of Oncology, 2017
    Co-Authors: Brigitte Dréno, Isabelle Rooney, Axel Hauschild, James Larkin, Paolo A Ascierto, Antoni Ribas, L Thomas, J J Grob, Daniel O Koralek, Jessie J Hsu
    Abstract:

    Background In the coBRIM phase III trial, the addition of Cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either Cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (Cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received Cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions These data indicate that most AEs arising from treatment with Cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. ClinicalTrials.gov NCT01689519.

  • Clinical features of serous retinopathy observed with Cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Luis De La Cruz-merino, James Larkin, Grant A. Mcarthur, Paolo A Ascierto, Antoni Ribas, Lorenza Di Guardo, Jean-jacques Grob, Alfredo Venosa, Jeffrey T. R. Evans, Antonio Gomez-escobar
    Abstract:

    Abstract Background Serous chorioretinopathy has been associated with MEK inhibitors, including Cobimetinib. We describe the clinical features of serous retinopathy observed with Cobimetinib in patients with BRAF V600-mutated melanoma treated in the Phase III coBRIM study. Methods In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: Cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms. Results Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 Cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during Cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of Cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014). Conclusions Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600-mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking Cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 201

Grant A. Mcarthur - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Paolo A Ascierto, Antoni Ribas, Yibing Yan, Matthew Wongchenko
    Abstract:

    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: BackgroundThis 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.MethodsThe 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.ResultsGreater 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.ConclusionsGreater 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.

  • 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), 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, Axel Hauschild, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Edward Mckenna, Qian Zhu, Yeung-chul Mun
    Abstract:

    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.

  • 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, 2017
    Co-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 Caro
    Abstract:

    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.

  • Clinical features of serous retinopathy observed with Cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Luis De La Cruz-merino, James Larkin, Grant A. Mcarthur, Paolo A Ascierto, Antoni Ribas, Lorenza Di Guardo, Jean-jacques Grob, Alfredo Venosa, Jeffrey T. R. Evans, Antonio Gomez-escobar
    Abstract:

    Abstract Background Serous chorioretinopathy has been associated with MEK inhibitors, including Cobimetinib. We describe the clinical features of serous retinopathy observed with Cobimetinib in patients with BRAF V600-mutated melanoma treated in the Phase III coBRIM study. Methods In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: Cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms. Results Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 Cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during Cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of Cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014). Conclusions Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600-mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking Cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 201

  • Cobimetinib combined with vemurafenib in advanced braf v600 mutant melanoma cobrim updated efficacy results from a randomised double blind phase 3 trial
    Lancet Oncology, 2016
    Co-Authors: Paolo A Ascierto, Brigitte Dréno, Grant A. Mcarthur, Victoria Atkinson, G Liszkay, Anna Maria Di Giacomo, Mario Mandala, Lev V Demidov, Daniil Stroyakovskiy
    Abstract:

    Summary Background The combination of Cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF V600 -mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. Methods In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF V600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive Cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. Findings Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the Cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5–17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5–13·4) for Cobimetinib and vemurafenib versus 7·2 months (5·6–7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46–0·72], p vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [ vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the Cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the Cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the Cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the Cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. Interpretation These data confirm the clinical benefit of Cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF V600 -mutant melanoma. Funding F Hoffmann-La Roche–Genentech.

Daniil Stroyakovskiy - One of the best experts on this subject based on the ideXlab platform.

  • Cobimetinib plus atezolizumab in brafv600 wild type melanoma primary results from the randomized phase iii imspire170 study
    Annals of Oncology, 2021
    Co-Authors: Helen Gogas, Brigitte Dréno, Lev V Demidov, Daniil Stroyakovskiy, Piotr Rutkowski, J Larkin, Zeynep Eroglu, Francesco P Ferrucci, Jacopo Pigozzo, Jacek Mackiewicz
    Abstract:

    Background Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. Patients and methods IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive Cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive Cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for Cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with Cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with Cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with Cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

  • atezolizumab vemurafenib and Cobimetinib as first line treatment for unresectable advanced brafv600 mutation positive melanoma imspire150 primary analysis of the randomised double blind placebo controlled phase 3 trial
    The Lancet, 2020
    Co-Authors: Ralf Gutzmer, Thomas K. Eigentler, Karl D. Lewis, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Svetlana Protsenko, Rodrigo Perez Pereira, Piotr Rutkowski, Lev V Demidov
    Abstract:

    Summary Background IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. Methods IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc–IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and Cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and Cobimetinib (control group). In cycle 1, all patients received vemurafenib and Cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial ( ClinicalTrials.gov , NCT02908672 ) is ongoing but no longer recruiting patients. Findings Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4–23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63–0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. Interpretation The addition of atezolizumab to targeted therapy with vemurafenib and Cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. Funding F Hoffmann–La Roche and Genentech.

  • Cobimetinib combined with vemurafenib in advanced braf v600 mutant melanoma cobrim updated efficacy results from a randomised double blind phase 3 trial
    Lancet Oncology, 2016
    Co-Authors: Paolo A Ascierto, Brigitte Dréno, Grant A. Mcarthur, Victoria Atkinson, G Liszkay, Anna Maria Di Giacomo, Mario Mandala, Lev V Demidov, Daniil Stroyakovskiy
    Abstract:

    Summary Background The combination of Cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF V600 -mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. Methods In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF V600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive Cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. Findings Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the Cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5–17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5–13·4) for Cobimetinib and vemurafenib versus 7·2 months (5·6–7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46–0·72], p vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [ vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the Cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the Cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the Cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the Cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. Interpretation These data confirm the clinical benefit of Cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF V600 -mutant melanoma. Funding F Hoffmann-La Roche–Genentech.

  • combined vemurafenib and Cobimetinib in braf mutated melanoma
    The New England Journal of Medicine, 2014
    Co-Authors: James Larkin, Brigitte Dréno, Paolo A Ascierto, Victoria Atkinson, G Liszkay, Mario Mandala, Lev V Demidov, Daniil Stroyakovskiy, Michele Maio, L Thomas
    Abstract:

    BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor Cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation–positive melanoma to receive vemurafenib and Cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and Cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of Cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann– La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)

  • combined vemurafenib and Cobimetinib in braf mutated melanoma
    The New England Journal of Medicine, 2014
    Co-Authors: James Larkin, Brigitte Dréno, Paolo A Ascierto, Victoria Atkinson, G Liszkay, Mario Mandala, Lev V Demidov, Daniil Stroyakovskiy, Michele Maio, L Thomas
    Abstract:

    BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor Cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation–positive melanoma to receive vemurafenib and Cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and Cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of Cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann– La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)

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  • atezolizumab vemurafenib and Cobimetinib as first line treatment for unresectable advanced brafv600 mutation positive melanoma imspire150 primary analysis of the randomised double blind placebo controlled phase 3 trial
    The Lancet, 2020
    Co-Authors: Ralf Gutzmer, Thomas K. Eigentler, Karl D. Lewis, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Svetlana Protsenko, Rodrigo Perez Pereira, Piotr Rutkowski, Lev V Demidov
    Abstract:

    Summary Background IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. Methods IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc–IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and Cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and Cobimetinib (control group). In cycle 1, all patients received vemurafenib and Cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial ( ClinicalTrials.gov , NCT02908672 ) is ongoing but no longer recruiting patients. Findings Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4–23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63–0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. Interpretation The addition of atezolizumab to targeted therapy with vemurafenib and Cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. Funding F Hoffmann–La Roche and Genentech.

  • extended 5 year follow up results of a phase ib study brim7 of vemurafenib and Cobimetinib in braf mutant melanoma
    Clinical Cancer Research, 2020
    Co-Authors: Antoni Ribas, Adil Daud, Karl D. Lewis, Matthew Wongchenko, Omid Hamid, Rene Gonzalez, Anna C Pavlick, Thomas F Gajewski, Igor Puzanov, Isabelle Rooney
    Abstract:

    Purpose: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus Cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. Patients and Methods: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and Cobimetinib in two cohorts of patients with advanced BRAFV600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naive (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy–progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with Cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and Cobimetinib (60 mg/d 21/7). Results: Median OS was 31.8 months [95% confidence interval (CI), 24.5–not estimable] in the BRAFi-naive cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, the median OS was 8.5 months (95% CI, 6.7–11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. Conclusions: A subset of patients with advanced BRAFV600-mutated melanoma treated with a combination regimen of vemurafenib and Cobimetinib achieve favorable long-term outcomes.

  • 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, 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Paolo A Ascierto, Antoni Ribas, Yibing Yan, Matthew Wongchenko
    Abstract:

    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: BackgroundThis 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.MethodsThe 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.ResultsGreater 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.ConclusionsGreater 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.

  • 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), 2019
    Co-Authors: Karl D. Lewis, Brigitte Dréno, Axel Hauschild, James Larkin, Keith T. Flaherty, Grant A. Mcarthur, Edward Mckenna, Qian Zhu, Yeung-chul Mun
    Abstract:

    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.

  • atezolizumab plus Cobimetinib and vemurafenib in braf mutated melanoma patients
    Nature Medicine, 2019
    Co-Authors: Ryan J Sullivan, Karl D. Lewis, Omid Hamid, Rene Gonzalez, Jeffrey R Infante, Manish R Patel, Stephen F Hodi, Hussein Abdulhassan Tawbi, Genevive Hernandez, Matthew Wongchenko
    Abstract:

    Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1–9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10–20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or Cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + Cobimetinib + vemurafenib, after a 28-d run-in period with Cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the Cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1–85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6–25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway. Treatment with BRAF and/or MEK inhibitors followed by addition of anti-PD-L1 in BRAF-mutant melanoma patients is safe and shows promising anti-tumor activity.