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LESSONS LEARNT Melanoma Academic Perspective · PDF file LESSONS LEARNT Melanoma Academic Perspective Paolo A. Ascierto, MD. Unit Melanoma, Cancer Immunotherapy and Innovative Therapies

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  • LESSONS LEARNT Melanoma

    Academic Perspective

    Paolo A. Ascierto, MD Unit Melanoma, Cancer Immunotherapy and Innovative Therapies Istituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy

  • Disclosures • Employment or Leadership Position: None • Consultant/Advisory Role: Bristol-Meyers Squibb,

    Merck Sharp & Dohme, Roche-Genentech, Ventana, Novartis, Amgen, Array

    • Stock Ownership: None • Honoraria: None • Research Funding: Bristol-Meyers Squibb, Roche-

    Genentech, Ventana

    • Expert Testimony: None • Other Remuneration: None

  • Meta-analysis of Phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future Phase II trials

    Korn E , et al. J Clin Oncol 2008;26:527–34. Reprinted with permission©2008, American Society of Clinical Oncology. All rights reserved

     Median survival time 6.2 months

     Alive at 1 year 25.5%

     Median PFS 1.7 months

     Progression free at 6 months 14.5%

    This metanalysis summarises the outcome of advanced melanoma patients before 2011

  • Treatment for advanced melanoma approved by EMA after 2011

    2011 ipilimumab

    2013 dabrafenib

    2014 trametinib

    2015 nivolumab

    pembrolizumab combo dabrafenib-trametinib

    combo vemurafenib-cobimetinib talimogene laherparepvec

    pending combo ipilimumab-

    nivolumab

    2012 vemurafenib

    Agent Company Indication

    Nivolumab BMS Unresectable or metastatic melanoma

    Ipilimumab BMS Unresectable or metastatic melanoma

    Vemurafenib Roche/Genentech Unresectable or metastatic melanoma with BRAF V600E mutation

    Dabrafenib Novartis Unresectable or metastatic melanoma with BRAF V600E mutation

    Trametinib Novartis Unresectable or metastatic melanoma with BRAF V600E/K mutation

    Talimogene laherparepvec Amgen

    Unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other

    visceral disease.

  • Advanced melanoma: different approaches according to mutational status

    BRAFV600E/K Q61NRAS

    c-KIT

    BRAF wt NRAS wt

    Ascierto P, et al. J Transl Med. 2012 May 2;10(1):83

  • Oct-2010 Jun-2011

    Ipilimumab slow action, but it’s able to make

    chronic the disease

    Vemurafenib quick action, rapid metabolic

    shutdown, unfortunately resistance after a median of 6-8 months

    Day 15 Day 0

    Two different drugs ... Two different concepts

  • Target Therapy

  • Day 0 Day 7

    VEMU-PET study Patient # 18V600EBRAF mutated

    Istituto Nazionale Tumori Napoli

  • Experience Patients sample (n)

    % of patients with a rapid disease

    progression kinetics BRIM-2 39 41%

    BRIM-3 42 52%

    Ascierto et al. 28 43%

    Ackerman et al. 32 50%

    Italian ipilimumab EAP 54 41%

    Fisher et al. 42 38%

    Different evidences of rapid progression disease after BRAF inhibitors treatment

    Ascierto et al. J Trans Med 2013

  • BRIM-3: OS Without Censoring at Crossover (ITT Population)

    10 Data cutoff: August 14, 2015. DTIC, dacarbazine; ITT, intention-to-treat.

    DTIC 338 254 210 171 140 117 103 83 73 65 58 57 53 47 45 40 27 17 1 0 0

    46.0% 24.5% 18.9% 15.6%

    DTIC (n = 338) 10.3 (9.1-12.8)

    Ascierto P, et al. Bridge meeting 2015.

  • BRIM-3: OS Was Better for ECOG PS 0 in Vemurafenib Arm

    Data cutoff: August 14, 2015. ECOG PS, Eastern Cooperative Oncology Group performance status.

    9 Ascierto P, et al. Bridge meeting 2015.

  • BRIM-3: OS Was Better for Normal Baseline LDH in Vemurafenib Arm

    12

    Data cutoff: August 14, 2015. LDH, lactate dehydrogenase. Ascierto P, et al. Bridge meeting 2015.

  • Effect of BRAF inhibitors on the immune system

    CD4+ and CD8+ increase in responder lesion and decrease in lesions which progressed

    Wilmott JS, et al. Clin Cancer Res 2011;18:1386–94, Reprinted from Clinical Cancer Research 2012, with permission from AACR Frederick DT, et al. Clin Cancer Res 2013;19:1225–31, Reprinted from Clinical Cancer Research 2013, with permission from AACR 3. From Hu-Lieskovan S et al. Sci Transl Med 2015;7:279ra41., Reprinted with permission from AAAS

    BRAF inhibition is associated with increased melanoma antigen expression in tumours of patients with metastatic melanoma

    ↑ MHC and melanoma antigen expression3

    Antitumour activity of combined BRAFi+MEKi

    plus anti-PD-13 BRAF inhibition is associated with increased CD8+ T-cell infiltrate in tumours of patients with metastatic melanoma

  • Resistance BRAF-mutant melanomas acquire BRAF inhibitor resistance via upregulation of both MAPK and PI3K– AKT pathways. However, MAPK reactivation is the major pathway of acquired BRAF inhibitor resistance in melanoma. Among MAPK-reactivating mechanisms associated with acquired BRAF inhibitor resistance the most frequents are NRAS mutations, mutant BRAF amplification and alternative splice variants, MAP2K1 and CDKN2A mutations

    Day 0 Day 7 Day 30 Day 15 Shi H et al. Cancer Discovery 2014; 4:80-93

    Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy

  • Rationale for the combination of BRAF and MEK inhibitors

    1. Shi H et al. Cancer Discov. 2014. 2. Trunzer K et al. J Clin Oncol. 2013 3. Paraiso K et al. Br J Cancer. 2010 4. Long GV et al. J Clin Oncol. 2014. 5. Ribas A et al. Lancet Oncol. 2014. 6. Su F et al. New Engl J Med 2012.

    Rationale  Most common mechanism of acquired

    resistance to vemurafenib is MAPK reactivation through MEK1,2

     MEK + BRAF inhibition prevents the development of acquired resistance in preclinical models3

     MEK + BRAF inhibition (dabrafenib + trametinib4 phase 3 and vemurafenib + cobimetinib phase 1/2)5 improved response rates and PFS in BRAF inhibitor–naive melanoma patients

     Reduced incidence of hyperproliferative lesions by blocking paradoxical activation of the MAPK pathway from RAF inhibition6

    © 2013 Gowrishankar et al.; licensee InTech. ISBN: 978-953-51-0961-7, DOI: 10.5772/53629. Available from: http://www.intechopen.com/books/melanoma-from-early- detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma. Open access article distributed under the terms of the Creative Commons Attribution License 3.0

    BRAF inhibitors vemurafenib dabrafenib encorafenib

    MEK inhibitors trametinib

    cobimetinib binimetinib

    http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/acquired-resistance-to-targeted-mapk-inhibition-in-melanoma http://www.intechopen.

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