DOCSLIB.ORG

Improvements in Clinical Outcomes for BRAFV600E-Mutant Colorectal Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Improvements in Clinical Outcomes for BRAFV600E-Mutant Colorectal Cancer Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Improvements in Clinical Outcomes for BRAFV600E-mutant Metastatic Colorectal Cancer Authors: Van K Morris,1 Tanios Bekaii-Saab2 Affiliations: 1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Mayo Clinic College of Medicine and Science, Phoenix, Arizona Corresponding author: Name: Tanios Bekaii Saab Address: Mayo Clinic, 5881 E Mayo Blvd, Phoenix, Arizona, 85054 Tel: +014803422501 Email: [email protected] Running title: BRAFV600E-mutant metastatic colorectal cancer Acknowledgments Publication of this article was supported by Pfizer Inc (formerly Array BioPharma), who were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion. All authors meet the authorship criteria of the International Committee of Medical Journal Editors, take responsibility for the integrity of the work and provided final approval of the version to be published. Medical writing support was provided by Alex Lowe, PhD of Touch Medical Communications and subsequently by JD Cox, PhD of Mayville Medical Communications (funded by Pfizer Inc). 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Conflicts of interests TBS is a paid consultant for Imugen and a paid IDMC member for Exelixis, Astra Zeneca, Silajen and Armo. He is also a consultant for Array Biopharma, Bayer, Amgen, Incyte, Ipsen, Merck and Seattle Genetics. VKM is a consultant for Array Biopharma and Incyte, and has research support from EMD Serono, Astra Zeneca, Bristol Myers Squibb, and Array Biopharma. Max word count; current word count: 2000–10,000; Current: 4147 Max no. tables/figures: 0 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Abstract Although the last two decades have seen a broad improvement in overall survival, colorectal cancer (CRC) is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their CRC. Consequently, many patients present with metastatic CRC, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of CRC tumors and are associated with uninhibited cell proliferation, reduced apoptosis and resistance to standard therapeutic options. In CRC, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared to tumors with wildtype BRAF. Success in treating other BRAF V600E- mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic CRC. Consequently, combination therapy with inhibitors of BRAF, MEK, and epidermal growth factor receptor, which overcomes the innate treatment-resistant characteristics of BRAF V600E-mutant CRC, is now recommended by treatment guidelines. Keywords (Max 5): Colorectal cancer, biomarker, metastasis, MAPK signaling, BRAFV600E 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Introduction Colorectal cancer (CRC) is a common cause of morbidity and mortality, and currently the second and third most common cancer worldwide in women and men respectively, accounting for 1.8 million new diagnoses and approximately 880,800 deaths in 2018.(1),(2),(3),(4) Given the inherent clinical challenges in diagnosing CRC including variable symptomatic presentation, natural history, rate of progression and tumor mutations, there is now a focus on the role of biomarkers in disease identification and predicting treatment responses.(5) Promising new treatments being explored for the treatment of CRC include inhibitors of critical oncoproteins in the MAPK signaling pathway, including MEK, BRAF and epidermal growth factor receptor (EGFR).(6) A key pathway in the pathogenesis of CRC is the mitogen-activated protein kinase (MAPK) signaling pathway.(7) Dysfunction of this pathway, including the RAS, RAF, and MEK kinases leads to increased cell proliferation and survival by the disruption of apoptosis.(7) Activating point mutations of the RAS family genes (H-RAS, K-RAS, and N-RAS) are common and comprise up to 30% of all human cancers.14 In this pathway, BRAF is a serine/threonine kinase downstream of EGFR and RAS.(7) Mutations in the BRAF gene most commonly result in a substitution of valine to glutamic acid at the 600th amino acid (BRAFV600; approximately 90% of BRAF mutations) and are mutually exclusive from KRAS/NRAS mutations.(6, 8, 9) BRAF mutations lead to a conformational change of RAF kinase, leading to the activation of BRAF kinase and the downstream MAPK pathway, subsequently driving increased tumor cell proliferation and anti-apoptotic behavior.(6) BRAFV600E mutations occur in approximately 10% of cases of CRC (estimates range from 5% to 21%),(6, 9-17) as well as being present in 51% of papillary thyroid cancers, 7% of non-small cell lung cancers and 40 to 60% of melanoma cases.(6, 8, 9, 14, 18-20) In recognition of the importance of BRAF V600E mutations in CRC, screening is recommended in the National Comprehensive Cancer Network (NCCN) guidelines.(21, 22) However, despite these recommendations, testing rates for BRAFV600E mutations may be as low 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer as 11.5% before first-line treatment initiation, once again highlighting the need for a more comprehensive screening effort.(23) Understanding the clinical impact of BRAFV600E mutations Due to their association with dysregulation of the MAPK pathway, the BRAFV600E mutation is an important prognostic biomarker and has predictive implications for patients with metastatic CRC.(6, 24, 25) In contrast, the less-common BRAFnon-V600 mutations, which are found in approximately 2% of patients with metastatic CRC, are associated with an improved disease prognosis compared with patients with BRAFV600E-mutant metastatic CRC.(26) The increasing incidence of BRAFV600E mutations with age in CRC may be a contributing factor to worse overall prognosis of patients with this mutation.(8) Additionally, mutations in BRAFV600E are associated with higher rates of bone, brain, and peritoneal involvement, a unique pattern of metastatic spread and worse health-related quality of life (HRQoL), relative to their BRAFV600E wildtype counterparts.(27-29) A number of studies have demonstrated worse prognosis with BRAF V600E-mutant compared with BRAF V600 wildtype CRC.(8, 30-33) In one study (n=229), patients with BRAF V600E-mutant/KRAS- wildtype CRC demonstrated significantly reduced overall survival (OS) compared with patients with BRAF V600-wildtype/KRAS-wildtype tumors (11.0 months vs 40.6 months; HR 4.25, 95% confidence interval [CI]: 2.08–8.67; p<0.001).(30) Similarly, a separate study (n=504) evaluating the detection of mutant BRAF V600E as part of daily clinical practice found that regardless of time of first-line intervention, there was a significant reduction in OS (14.0 months vs 34.6 months; HR: 5.43; 95% CI: 3.60–8.18; p<0.001), in addition to worsened progression-free survival (PFS) (4.1 months vs 11.6 months; HR: 4.07; 95% CI: 2.66–6.20; p<0.001) with BRAF V600E-mutant compared with BRAF V600- wildtype CRC.(31) Additionally, 5-year OS of patients with stage I–IV BRAFV600E-mutant CRC has been reported to be 47.5% compared with 60.7% in patients with wildtype tumors.(32) These findings are 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer supported by a recent real-world analysis (n=503) that observed a median OS of 18.2 months for BRAF V600E-mutant metastatic CRC compared with an OS of 41.1
Load more

Recommended publications
  • RP - HPLC Method Development & Validation for the Simultaneous Estimation of Encorafenib and Binimetinib in API & Tablet Dosage Form
    International Journal of Science and Research (IJSR) ISSN: 2319-7064 ResearchGate Impact Factor (2018): 0.28 | SJIF (2018): 7.426 RP - HPLC Method Development & Validation for the Simultaneous Estimation of Encorafenib and Binimetinib in API & Tablet Dosage Form Kafiya Suroor1, Kudaravalli Sreedevi2 Department of Quality Assurance, Sultan –ul-Uloom College of Pharmacy, Hyderabad, India Abstract: A new RP-HPLC method was developed, validated and adapted for the estimation of encorafenib and binimetinib in bulk and tablet formulation. In this method, separation and assay of encorafenib and binimetinib was done in stationary phase using Agilent C18 column with mobile phase of 0.1M dipotassium hydrogen phosphate (pH 4.0) and methanol in 50:50 vol/vol ratio. The Binimetinib was eluted at 3.448 min and encorafenib at 5.795 min. Linearity ranges are 7.5-22.5 μg/ml and 37.5-112.50 μg/ml with regression coefficient values of 0.9996 and 0.9997 for binimetinib and encorafenib respectively. The LOD values found were binimetinib – 0.017 µg/ml and encorafenib – 0.114 µg/ml, and the LOQ values of binimetinib – 0.058 µg/ml and encorafenib – 0.381 µg/ml. Validation parameters examined following suggestions of ICH are accurate ample for the supposed assay. The approach is confirmed as splendid method for assay of encorafenib and binimetinib in tablet formula with excellent assay percentage values. Keywords: RP-HPLC, Encorafenib, Binimetinib, Antineoplastic drugs 1. Introduction dose of binimetinib is 45 mg orally twice daily and of encorafenib is 450 mg orally once daily. Approval by FDA Encorafenib and Binimetanib belong to the class of was based on a randomized, active-controlled, open-label, antineoplastic agents.
    [Show full text]
  • FOI Reference: FOI 414 - 2021
    FOI Reference: FOI 414 - 2021 Title: Researching the Incidence and Treatment of Melanoma and Breast Cancer Date: February 2021 FOI Category: Pharmacy FOI Request: 1. How many patients are currently (in the past 3 months) undergoing treatment for melanoma, and how many of these are BRAF+? 2. In the past 3 months, how many melanoma patients (any stage) were treated with the following: • Cobimetinib • Dabrafenib • Dabrafenib AND Trametinib • Encorafenib AND Binimetinib • Ipilimumab • Ipilimumab AND Nivolumab • Nivolumab • Pembrolizumab • Trametinib • Vemurafenib • Vemurafenib AND Cobimetinib • Other active systemic anti-cancer therapy • Palliative care only 3. If possible, could you please provide the patients treated in the past 3 months with the following therapies for metastatic melanoma ONLY: • Ipilimumab • Ipilimumab AND Nivolumab • Nivolumab • Pembrolizumab • Any other therapies 4. In the past 3 months how many patients were treated with the following for breast cancer? • Abemaciclib + Anastrozole/Exemestane/Letrozole • Abemaciclib + Fulvestrant • Alpelisib + Fulvestrant • Atezolizumab • Bevacizumab [Type text] • Eribulin • Everolimus + Exemestane • Fulvestrant as a single agent • Gemcitabine + Paclitaxel • Lapatinib • Neratinib • Olaparib • Palbociclib + Anastrozole/Exemestane/Letrozole • Palbociclib + Fulvestrant • Pertuzumab + Trastuzumab + Docetaxel • Ribociclib + Anastrozole/Exemestane/Letrozole • Ribociclib + Fulvestrant • Talazoparib • Transtuzumab + Paclitaxel • Transtuzumab as a single agent • Trastuzumab emtansine • Any other
    [Show full text]
  • Summary Risk Management Plan for Braftovi
    Summary of the risk management plan Summary of the risk management plan for BRAFTOVI This is a summary of the risk management plan (RMP) for BRAFTOVI when administered in combination with MEKTOVI or cetuximab. The RMP details important risks of BRAFTOVI in combination with MEKTOVI or cetuximab, how these risks can be minimised, and how more information will be obtained about BRAFTOVI in combination with MEKTOVI or cetuximab risks and uncertainties (missing information). Summary of product characteristics (SmPC) for BRAFTOVI and its package leaflets give essential information to healthcare professionals and patients on how BRAFTOVI should be used. This summary of the RMP for BRAFTOVI when administered in combination with MEKTOVI or cetuximab should be read in the context of all this information including the assessment reports of the evaluation and the plain-language summary, all of which are part of the European Public Assessment Report (EPAR). Important new concerns or changes to current concerns will be included in future updates of the RMP for BRAFTOVI. I. The medicine and what it is used for BRAFTOVI is authorised in combination with MEKTOVI for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see SmPC for the full indication). The active substance of BRAFTOVI is encorafenib and of MEKTOVI is binimetinib and both are given by the oral route of administration. BRAFTOVI in combination with cetuximab is authorised for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy. Cetuximab is given by intravenous infusion.
    [Show full text]
  • New Century Health Policy Changes April 2021
    Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a n/a new Fotivda (tivozanib) n/a n/a new Cosela (trilaciclib) n/a n/a Add inclusion criteria: NSCLC UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for actionable molecular markers (ALK, EGFR, or ROS‐1) Add inclusion criteria: a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a UM ONC_1133 Erbitux (Cetuximab) Positive change contraindication and/or intolerance to cisplatin use OR B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. Add inclusion criteria: UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for BRAFV600E positive colorectal cancer.. Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic confirmation of ipsilateral (same side) axillary nodal involvement.
    [Show full text]
  • The Role of BRAF-Targeted Therapy for Advanced Melanoma in the Immunotherapy Era
    Current Oncology Reports (2019) 21: 76 https://doi.org/10.1007/s11912-019-0827-x MELANOMA (RJ SULLIVAN, SECTION EDITOR) The Role of BRAF-Targeted Therapy for Advanced Melanoma in the Immunotherapy Era Vito Vanella1 & Lucia Festino 1 & Claudia Trojaniello1 & Maria Grazia Vitale1,2 & Antonio Sorrentino1 & Miriam Paone1 & Paolo A. Ascierto 1 Published online: 29 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The treatment of advanced melanoma has changed dramatically in recent years with several new drugs having been approved for the treatment of melanoma since 2011. This review aims to evaluate the role of BRAF-targeted therapy for advanced melanoma in the immunotherapy era. Recent Findings Currently, in patients with BRAF wild-type advanced melanoma, anti-PD-1 (nivolumab or pembrolizumab) is the main treatment. The combination of nivolumab and ipilimumab (anti-CTLA-4) is also an important option for these patients, resulting in a better outcome, but with less favorable toxicity profile. In patients with BRAF mutations, three regimens of BRAF plus MEK inhibitors are now approved (vemurafenib plus cobimetinib, dabrafenib plus trametinib, and encorafenib plus binimetinib), which achieve rapid antitumor responses and a significant survival benefit. In these patients, as well as in BRAF wild-type patients, immunotherapy can be also effective and is regularly used. Summary Immunotherapy and targeted therapy have become the new standards of care, substantially improving survival rates. However, many questions still remain unanswered, such as what is the best first- and second-line treatment and the best treatment sequence. New combinations of drugs, targeted therapy combined with immunotherapy, and sequencing approaches are now underway in many ongoing clinical trials.
    [Show full text]
  • Braftovi, INN-Encorafenib
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Braftovi 50 mg hard capsules Braftovi 75 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Braftovi 50 mg hard capsules Each hard capsule contains 50 mg of encorafenib. Braftovi 75 mg hard capsules Each hard capsule contains 75 mg of encorafenib. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule (capsule). Braftovi 50 mg hard capsules Orange opaque cap and flesh opaque body, printed with a stylised “A” on the cap and “LGX 50mg” on the body. The length of the capsule is approximately 22 mm. Braftovi 75 mg hard capsules Flesh coloured opaque cap and white opaque body, printed with a stylised “A” on the cap and “LGX 75mg” on the body. The length of the capsule is approximately 23 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Encorafenib is indicated: - in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1). - in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy (see sections 4.4 and 5.1). 4.2 Posology and method of administration Encorafenib treatment should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products.
    [Show full text]
  • In This Issue
    IN THIS ISSUE The HER2T798I Mutation Promotes Acquired Resistance to Neratinib • A patient with breast cancer • HER2T798I acquisition promoted • Patients with HER2L869R/T798I tumors harboring the HER2L869R mutation neratinib resistance, but cells remained may respond to afatinib even after initially responded to neratinib. sensitive to afatinib in vitro. neratinib resistance develops. The receptor tyrosine kinase Consistent with these findings, HER2L869R expression trans- HER2 (also known as ERBB2) is formed MCF10A breast epithelial cells, and neratinib blocked subject to activating mutations the activity of HER2L869R. Based on these findings, the patient in a subset of breast cancers. was enrolled in a clinical trial to receive single-agent neratinib Irreversible EGFR/HER2 tyros- and exhibited an excellent clinical response. The patient even- ine kinase inhibitors includ- tually progressed on neratinib, and NGS detected an acquired ing neratinib and afatinib have HER2T798I mutation. Computational models predicted that demonstrated preclinical activity this mutation would result in steric hindrance to reduce ner- against HER2-mutant tumors atinib binding. Indeed, the T798I mutation reduced HER2 and clinical trials are ongoing. stability and rendered HER2L869R-transformed cells refrac- Hanker and colleagues identified aHER2 kinase domain tory to neratinib, suggesting that neratinib treatment selects mutation (HER2L869R) in a patient with estrogen receptor– for the HER2T798I mutation to promote neratinib resistance. positive, progesterone receptor–positive lobular breast carci- HER2L869R/T798I cells that had developed resistance to ner- noma through targeted capture next-generation sequencing atinib showed sensitivity to afatinib. In addition to identify- (NGS) of DNA from a skin metastasis. Structural modeling ing HER2T798I as an acquired neratinib-resistant mutation, predicted that the HER2L869R mutation would destabilize the these results suggest that patients with this mutation may inactive kinase conformation to activate HER2.
    [Show full text]
  • Comparator Report on Cancer in Europe 2019 −Disease Burden, Costs and Access to Medicines
    COMPARATOR REPORT ON CANCER IN EUROPE 2019 −DISEASE BURDEN, COSTS AND ACCESS TO MEDICINES THOMAS HOFMARCHER GUNNAR BRÅDVIK CHRISTER SVEDMAN PETER LINDGREN BENGT JÖNSSON IHE REPORT NILS WILKING 2019:7 COMPARATOR REPORT ON CANCER IN EUROPE 2019 – DISEASE BURDEN, COSTS AND ACCESS TO MEDICINES Thomas Hofmarcher Gunnar Brådvik Christer Svedman Peter Lindgren Bengt Jönsson Nils Wilking IHE - The Swedish Institute for Health Economics Updated version: October 2020 Please cite this report as: Hofmarcher, T., Brådvik, G., Svedman, C., Lindgren, P., Jönsson, B., Wilking, N. Comparator Report on Cancer in Europe 2019 – Disease Burden, Costs and Access to Medicines. IHE Report 2019:7. IHE: Lund, Sweden. This report was commissioned and funded by EFPIA - the European Federation of Pharmaceutical Industries and Associations and based on independent research delivered by IHE. EFPIA has had no influence or editorial control over the content of this report, and the views and opinions of the authors are not necessarily those of EFPIA. IHE REPORT 2019:7 e-ISSN: 1651-8187 ISSN: 1651-7628 The report can be downloaded from IHE’s website. www.ihe.se | [email protected] COMPARATOR REPORT ON CANCER IN EUROPE 2019 Foreword Cancer care remains one of the most intensely discussed health policy issues in Europe. Demographic factors such as an ageing population, in part driven by advancements in other medical fields, have led to an increased disease burden caused by cancer, both to patients and to the health care system as a whole. At the same time, there has been significant scientific advancements made, in some cases transforming cancer from a fatal to a chronic disease which in turn introduces new challenges that need to be addressed.
    [Show full text]
  • BRAF Gene and Melanoma: Back to the Future
    International Journal of Molecular Sciences Review BRAF Gene and Melanoma: Back to the Future Margaret Ottaviano 1,2,3,*,† , Emilio Francesco Giunta 4,† , Marianna Tortora 3 , Marcello Curvietto 5, Laura Attademo 2, Davide Bosso 2, Cinzia Cardalesi 2, Mario Rosanova 2, Pietro De Placido 1, Erica Pietroluongo 1 , Vittorio Riccio 1, Brigitta Mucci 1, Sara Parola 1, Maria Grazia Vitale 5, Giovannella Palmieri 3 , Bruno Daniele 2 , Ester Simeone 5 and on behalf of SCITO YOUTH ‡ 1 Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; [email protected] (P.D.P.); [email protected] (E.P.); [email protected] (V.R.); [email protected] (B.M.); [email protected] (S.P.) 2 Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; [email protected] (L.A.); [email protected] (D.B.); [email protected] (C.C.); [email protected] (M.R.); [email protected] (B.D.) 3 CRCTR Coordinating Rare Tumors Reference Center of Campania Region, 80131 Naples, Italy; [email protected] (M.T.); [email protected] (G.P.) 4 Department of Precision Medicine, Università Degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy; [email protected] 5 Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy; [email protected] (M.C.); [email protected] (M.G.V.); [email protected] (E.S.) * Correspondence: [email protected] † These authors contributed equally to this work. ‡ Membership of the SCITO YOUTH is provided in the Acknowledgments. Citation: Ottaviano, M.; Giunta, E.F.; Tortora, M.; Curvietto, M.; Attademo, Abstract: As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF L.; Bosso, D.; Cardalesi, C.; Rosanova, mutation (mostly BRAF V600E).
    [Show full text]
  • BRAFTOVI (Encorafenib) RATIONALE for INCLUSION in PA PROGRAM
    BRAFTOVI (encorafenib) RATIONALE FOR INCLUSION IN PA PROGRAM Background Braftovi (encorafenib) is a kinase inhibitor indicated for the treatment of patients with certain cancers with BRAF mutations. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Braftovi targets BRAF V600E as well as other kinases and inhibits the activity of these kinases, thereby inhibiting tumor growth and proliferation (1). Regulatory Status FDA approved indications: Braftovi is a kinase inhibitor indicated: (1) • In combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test • In combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy Limitations of use: (1) Braftovi is not indicated for treatment of patients with wild-type BRAF melanoma or wild-type BRAF CRC. Confirmation of the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of Braftovi. New primary malignancies, cutaneous and non-cutaneous can occur during therapy as well as major hemorrhagic events, uveitis, embryo-fetal toxicity, and QT prolongation. Prescribers must monitor for these adverse events and adjust the dosage, interrupt, or discontinue therapy as indicated (1). Safety and effectiveness of Braftovi in pediatric patients have not been established (1). Summary Braftovi (encorafenib) is a kinase inhibitor indicated for the treatment of patients with certain cancers with BRAF mutations. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of Braftovi.
    [Show full text]
  • New Insights and Therapeutıc Implicatıons in Cutaneous Melanoma Pinar Ozuguz*, Serap Karatas and Seval Dogruk Kacar
    Ozuguz et al. J Dermatol Res Ther 2016, 2:020 Volume 2 | Issue 2 ISSN: 2469-5750 Journal of DOI: 10.23937/2469-5750/1510020 Dermatology Research and Therapy Review Article: Open Access New Insights and Therapeutıc Implicatıons in Cutaneous Melanoma Pinar Ozuguz*, Serap Karatas and Seval Dogruk Kacar Check for Department of Dermatology, Afyon Kocatepe University, Afyon, Turkey updates *Corresponding author: Pinar Ozuguz, Department of Dermatology, Afyon Kocatepe University, Izmir Yolu 8 km Afyon, Turkey, Tel: +905055210335, E-mail: [email protected] adolescents and young adults between the ages of 15-29 [5]. Abstract Melanoma is a highly aggressive tumour with poor prognosis in By the time, the increase in the incidence of MM has necessitated the metastatic stage that arises and evolves due to a myriad of new treatment approaches. As factors in the pathogenesis were genetic and epigenetic events. Among these, the interaction understood more clearly, targeted therapies have been raised and the between epigenetic alterations (i.e., DNA methylation, histone studies have increased [3,5]. Although a new viewpoint does not modifications, mRNA silencing by miRNAs and nucleosome mean an increase in survival, it may shed light on treatment desicion repositioning) has been recently identified as playing an important and better treatment alternatives. role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, DNA repair, Traditional therapeutics and immunomodulatory agents have apoptosis, invasion and immune recognition. A number of new not shown much efficacy against metastatic melanoma. Agents that oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, target the RAS/RAF/MEK/ERK (MAPK) signaling pathway - the GRM3, RAC1, and PREX2 were identified.
    [Show full text]
  • Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy
    PERSPECTIVE published: 16 April 2019 doi: 10.3389/fonc.2019.00263 Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy Jing Jin 1†, Xu Wu 2,3†, Jianhua Yin 2,3, Mingxing Li 2,3, Jing Shen 2,3, Jing Li 4, Yueshui Zhao 2,3, Qijie Zhao 2,3, Jingbo Wu 1, Qinglian Wen 1, Chi Hin Cho 2,3, Tao Yi 5*, Zhangang Xiao 2* and Liping Qu 6 1 Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China, 2 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China, 3 South Sichuan Institute of Translational Medicine, Luzhou, China, 4 Department of Oncology and Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, China, 5 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China, 6 College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Edited by: Chengdu, China Yan-yan Yan, Shanxi Datong University, China The introduction of targeted therapy is the biggest success in the treatment of Reviewed by: Shengpeng Wang, cancer in the past few decades. However, heterogeneous cancer is characterized University of Macau, China by diverse molecular alterations as well as multiple clinical profiles. Specific genetic Maria Munoz Caffarel, mutations in cancer therapy targets may increase drug sensitivity, or more frequently Biodonostia Health Research Institute, Spain result in therapeutic resistance. In the past 3 years, several novel targeted therapies Tinghong Ye, have been approved for cancer treatment, including drugs with new targets (i.e., Sichuan University, China anti-PD1/PDL1 therapies and CDK4/6 inhibitors), mutation targeting drugs (i.e., the *Correspondence: Tao Yi EGFR T790M targeting osimertinib), drugs with multiple targets (i.e., the EGFR/HER2 [email protected] dual inhibitor neratinib) and drug combinations (i.e., encorafenib/binimetinib and Zhangang Xiao dabrafenib/trametinib).
    [Show full text]