DOCSLIB.ORG

2020 Master Class Course Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas Including GIST George D

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

2020 Master Class Course Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas including GIST George D. Demetri, MD FACP FASCO 1 George D. Demetri, MD Faculty Disclosure • Scientific consultant with sponsored research to Dana-Farber: Bayer, Pfizer, Novartis, Epizyme, Roche/Genentech, Epizyme, LOXO Oncology, AbbVie, GlaxoSmithKline, Janssen, PharmaMar, Daiichi-Sankyo, AdaptImmune • Scientific consultant: GlaxoSmithKline, EMD-Serono, Sanofi, ICON plc, MEDSCAPE, Mirati, WCG/Arsenal Capital, Polaris, MJ Hennessey/OncLive, C4 Therapeutics, Synlogic, McCann Health • Consultant/SAB member with minor equity holding: G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, Champions Biotechnology, Caprion/HistoGeneX • Board of Directors member and Scientific Advisory Board Consultant with minor equity holding: Blueprint Medicines, Translate BIO • Patents/Royalties: Novartis royalty to Dana-Farber for use patent of imatinib in GIST • Non-Financial Interests: AACR Science Policy and Government Affairs Committee Chair, Alexandria Real Estate Equities, Faculty of this CE activity may include discussions of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off label or investigational uses (any uses not approved by the FDA) of products or devices. 2 Soft Tissue Sarcomas: Approximate Anatomic Distribution Head and Neck 10% Upper extremities 15% Trunk 10% Retroperitoneal, pelvic and visceral Lower extremities 15% 50% (includes GIST and GYN sarcomas) Modified from Clark MA et al. NEJM 2005;353:701-11 3 Sarcomas represent an exceedingly diverse set of diseases Bone Sarcomas 10% GIST Un- differentiated Liposarcomas Leiomyo- Sarcomas 4 Ducimetiere et al. PLoS ONE 6(8): e20294. doi:10.1371/journal.pone.0020294. What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation KIT exon 11 point mutations (80%) confer overall favorable prognosis KIT exon 9 mutations associated with worse prognosis GIST Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation (80%) PDGFRA D842V mutation = PDGFRA mutation good risk in primary GIST. (10% in met, 25% in gastric primary) GIST Imatinib not effective. 2020 FDA approved new selective inhibitor avapritinib Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 Activity of Avapritinib in PDGFRA D842-mutant GIST 49 of 56 (88%) patients with confirmed objective response by central radiology review Heinrich M. et al. 7 What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation (80%) PDGFRA mutation (10% in met, 25% in gastric primary) Most common pediatric type SDH GIST mutation or deficiency by IHC Epithelioid+spindle cells (either SDHA, SDHB, or SDHC) (approx. 10%) Gastric primaries, often multifocal DIFFERENT MOLECULAR MECHANISM! Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 Novel Epigenetic Mechanism for Oncogene Activation in SDH-Deficient GIST Brad Bernstein MD PhD Genetic Epigenetic TAD boundary FGF/KIT (disrupted) KIT mutation insulator losses GIST Oncogene Oncogene Suzanne George, MD Activation Flavahan W. et al, Nature 2019 CTEP 10411: Trial to Target FGFR in SDH-deficient GIST 9 What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation (80%) PDGFRA mutation (10% in met, 25% in gastric primary) GIST SDH mutation or deficiency by IHC (either SDHA, SDHB, or SDHC) Require therapy with specific Rx: (approx. 10%) TRK-fusion inhibitor, NTRK fusions; BRAF or NF1 mutations; BRAF inhibitor, (<2%) MEK pathway inhibitor Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 Adjuvant therapy after resection for PRIMARY localized GIST at moderate/high risk of recurrence • Standard is post-operative adjuvant imatinib for at least 3 years • For high risk of recurrence, 5 years or longer may be better if patient tolerates imatinib well since risk of recurrence increases once imatinib therapy is stopped 11 Managing Recurrent or Metastatic GIST • Standard sequence remains imatinib sunitinib regorafenib • At each point of progression, assess for potential to resect clonal site of solitary or limited progressive disease and continue same Rx • New option for unresectable metastatic disease after failure of all three of these standard kinase inhibitors = RIPRETINIB • FDA approved for > 4th line GIST therapy, May 2020 12 85% Risk Reduction of Disease Progression or Death with Ripretinib Compared to Placebo in > 4th Line GIST 100 Median PFS 6.3 months vs 1.0 month* HR=0.15 (95% CI, 0.09–0.25) Ripretinib Placebo (n=85) (n=44) P<0.0001 80 Events, n (%) 51 (60.0%) 37 (84.1%) Censored, n (%) 34 (40.0%) 7 (15.9%) 60 PFS 6 months, % (95% 51.0% (39.4– 3.2% (0.2–13.8) CI) 61.4) 40 20 Survival probability (%) probability Survival Ripretinib 150 mg QD Censored 0 Placebo 0 2 4 6 8 10 12 14 Months Number of patients at risk: Ripretinib 150 mg QD 85 64 52 37 18 8 1 0 Placebo 44 7 4 1 1 0 *Double-blind period. Blay JY, CTOS Presentation, Tokyo Nov 2019 13 OS Benefit: 64% Risk Reduction of Death with Ripretinib Compared to Placebo in > 4th Line GIST Median OS 15.1 vs 6.6 months HR=0.36 (95% CI, 0.20–0.62) Nominal Ripretinib Placebo (n=85) (n=44) 100 P=0.0004* Events, n (%) 26 (30.6%) 26 (59.1%) Censored, n (%) 59 (69.4%) 18 (40.9%) 80 OS 6 months, % (95% CI) 84.3% (74.5– 55.9% (39.9–69.2) 90.6) OS 12 months, % (95% CI) 65.4% (51.6– 25.9% (7.2–49.9) 60 76.1) 40 20 Survival probability (%) probability Survival Ripretinib 150 mg QD Censored 0 Placebo 0 2 4 6 8 10 12 14 16 Months Number of patients at risk: Ripretinib 150 mg QD 85 81 76 67 42 24 10 2 0 Placebo 44 34 29 24 14 8 1 1 0 *Due to hierarchal testing procedures of the end points, the OS end point could not be formally tested because the ORR was not statistically significant. Blay JY, CTOS Presentation, Tokyo Nov 2019 14 Advances in Management of Other Sarcoma Subtypes • Undifferentiated Pleomorphic Sarcoma • This term is pathologist-dependent, as many cancers can mistakenly be placed into this diagnostic rubric, including • Poorly differentiated sarcomatoid carcinomas • Many other sarcomas or even some melanomas 15 Immune Checkpoint Inhibitors: Activity in Sarcoma Subtypes Objective Responses 4/10 Undiff Pleomorphic Sarcs 2/9 Liposarcomas (De-Diff) 16 NTRK gene fusions are rare but relevant to sarcomas in both adults and children Brain tumors (glioma, GBM, astrocytoma) Salivary gland carcinoma (MASC) Thyroid cancer Lung cancer Breast carcinoma (secretory) Pancreatic Cholangiocarcinoma Gliomas Colon GIST with Thyroid cancer Infantile fibrosarcoma Melanoma normal KIT, PDGFRA, SDH, BRAF Congenital nephroma Spitz nevi Sarcomas (undifferentiated and Sarcoma (multiple subtypes) multiple other subtypes) Amatu. ESMO Open. 2016;1:e000023. Urano. Hum Pathol. 2015;46:94. Knezevich. Nat Gen. 1998;18:184. Watanabe. Cancer Genet Cytogenet. 2002;136:10. Hyman. ASCO 2017. Abstr LBA2501. Gatalica. AACR-NCI-EORTC 2017. Abstr A047. Frequent and Durable Responses in TRK-FUSION+ Sarcomas and other cancers with either Larotrectinib vs Entrectinib Larotrectinib Entrectinib Lassen. ESMO 2018. Abstr 279. Drilon. NEJM. 2018;378:731. Demetri. ESMO 2018. Abstr LBA17. Doebele. Lancet Oncol. 2020;21:271. Epithelioid Sarcoma is characterized by loss of INI1 LOSS OF INI1 CREATES AN ONCOGENIC Tazemetostat: first-in-class, DEPENDENCY ON EZH2 selective oral inhibitor of EZH2 SWI/SNF SWI/SNF NORMAL PRC2 INI1 PRC2 INI1 loss EZH2 EZH2 • Coordinated gene transcription Enhanced EZH2 activity • Appropriate cell differentiation and growth Repressed cell differentiation • Tumor suppression Promotion of tumor growth Adapted from Stacciotti S, et al. ASCO June 2019 19 Tazemetostat (FDA accelerated approval, Jan 2020): Activity in Epithelioid Sarcoma Patients Best percent change in sum of diameters of target lesions Durability of disease control Gounder M. et al. Lancet Oncology (online October 6, 2020) 20 Pexidartinib for Tenosynovial Giant Cell Tumor: Phase 3 placebo-controlled trial. (FDA approval Aug 2019) Durable Responses: Median Duration still not met after median 22 months of follow-up Tap WD, et al. 21 Variable Efficacy of Genetically Engineered Autologous T-cells with an optimized T-Cell Receptor Targeting NY-ESO1 (and different pre-cell-infusion chemotherapy regimen intensity) 50% Response Rate 27% Response Rate Modified from Van Tine et al. ESMO 2019 presentation, 2019 Clinical Responses in MAGE-A4+ Sarcomas with ADP-A2M4 Genetically Engineered Autologous T-Cells Modified from Van Tine et al. ESMO 2019 presentation, 2019 Changes in Management Approach to Desmoid Tumor • Up to 1500 cases per year in USA • FAP associated (15%) with loss of function of APC gene product and subsequent accumulation of β-cateinin • Sporadic (85%): point mutations in the β-cateinin gene with aberrant stability and accumulation • Least aggressive surgical intervention is advised • Medical therapies preferred (e.g. anti-inflammatory agents, low dose anthracyclines, vinca alkaloids, methotrexate, or TKI) 25 Sorafenib improves PFS in Desmoid – but responses are seen with placebo as well as sorafenib Changes from baseline in Tumor Size Placebo Sorafenib Gounder MM, et al. 26 Summary: New Approaches to Sarcomas and GIST • The most expert and detailed diagnosis is key to management • Referral to centers with expertise in all disciplines is helpful • New trials and new approaches change management • It is hard to keep up – lots of new therapies! • Expert centers are here to help you care for your patients 27 THANK YOU for your attention George D. Demetri, M.D. Sarcoma Center Dana-Farber Cancer Institute Professor of Medicine, Harvard Medical School Boston, Massachusetts [email protected] @DrSarcoma 28.
Recommended publications
  • Ripretinib Demonstrated Activity Across All KIT/PDGFRA Mutations In

    Ripretinib Demonstrated Activity Across All KIT/PDGFRA Mutations In

    Ripretinib demonstrated activity across all KIT/PDGFRA mutations in patients with fourth-line advanced gastrointestinal stromal tumor: Analysis from the phase 3 INVICTUS study Patrick Schöffski1, Sebastian Bauer2, Michael Heinrich3, Suzanne George4, John Zalcberg5, Hans Gelderblom6, Cesar Serrano Garcia7, Robin L Jones8, Steven Attia9, Gina D’Amato10, Ping Chi11, Peter Reichardt12, Julie Meade13, Kelvin Shi13, Ying Su13, Rodrigo Ruiz-Soto13, Margaret von Mehren14, Jean-Yves Blay15 1University Hospitals Leuven, Leuven, Belgium; 2West German Cancer Center, Essen, Germany; 3OHSU Knight Cancer Institute, Portland, OR, USA; 4Dana-Farber Cancer Institute, Boston, MA, USA; 5Monash University, Melbourne, VIC, Australia; 6Leiden University Medical Center, Leiden, Netherlands; 7Vall d’Hebron Institute of Oncology, Barcelona, Spain; 8Royal Marsden and Institute of Cancer Research, London, UK; 9Mayo Clinic, Jacksonville, FL, USA; 10Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; 11Memorial Sloan Kettering Cancer Center, New York, NY, USA; 12Sarcoma Center, Helios Klinikum Berlin-Buch, Berlin, Germany; 13Deciphera Pharmaceuticals, LLC, Waltham, MA, USA; 14Fox Chase Cancer Center, Philadelphia, PA, USA; 15Centre Leon Berard, Lyon, France KIT mutation analysis by combined tumor and liquid biopsy INTRODUCTION RESULTS Figure 7. Hazard ratio of PFS with different mutation groups by combined • Patients were grouped into 4 subsets: any KIT exon 9, any KIT exon 11, any KIT exon 13, and any KIT exon 17 tumor and liquid biopsy • Patients
  • Australian Public Assessment Report for Larotrectinib

    Australian Public Assessment Report for Larotrectinib

    Australian Public Assessment Report for Larotrectinib Proprietary Product Name: Vitrakvi Sponsor: Bayer Australia Limited December 2020 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
  • Entrectinib (Interim Monograph)

    Entrectinib (Interim Monograph)

    Entrectinib (interim monograph) DRUG NAME: Entrectinib SYNONYM(S): RXDX-1011, NMS-E6282 COMMON TRADE NAME(S): ROZLYTREK® CLASSIFICATION: molecular targeted therapy Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Entrectinib is an orally administered, small molecule, multi-target tyrosine kinase inhibitor which targets tropomyosin- related kinase (Trk) proteins TrkA, TrkB, and TrkC, proto-oncogene tyrosine-protein kinase ROS (ROS1) and anaplastic lymphoma kinase (ALK). TrkA, TrkB, and TrkC are receptor tyrosine kinases encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Fusion proteins that include Trk, ROS1, or ALK kinase domains drive tumorigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. By potently inhibiting the Trk kinases, ROS1, and ALK, entrectinib inhibits downstream signalling pathways, cell proliferation and induces tumour cell apoptosis.3-5 PHARMACOKINETICS: Oral Absorption bioavailability = 55%; Tmax = 4-6 hours; Tmax delayed 2 h by high-fat, high-calorie food intake Distribution highly bound to human plasma proteins cross blood brain barrier? yes volume of distribution 551 L (entrectinib); 81.1 L (M5) plasma protein binding >99% (entrectinib and M5) Metabolism primarily metabolized by CYP 3A4 active metabolite(s) M5 inactive metabolite(s) M11 Excretion primarily via hepatic clearance urine 3.06% feces 82.9% (36% as unchanged entrectinib, 22% as M5) terminal half life 20 h (entrectinib); 40 h (M5) clearance 19.6 L/h (entrectinib); 52.4 L/h (M5) Elderly no clinically significant difference Children comparable pharmacokinetics of entrectinib and M5 in adults and children Ethnicity no clinically significant difference Adapted from standard reference3,4 unless specified otherwise.
  • 07052020 MR ASCO20 Curtain Raiser

    07052020 MR ASCO20 Curtain Raiser

    Media Release New data at the ASCO20 Virtual Scientific Program reflects Roche’s commitment to accelerating progress in cancer care First clinical data from tiragolumab, Roche’s novel anti-TIGIT cancer immunotherapy, in combination with Tecentriq® (atezolizumab) in patients with PD-L1-positive metastatic non- small cell lung cancer (NSCLC) Updated overall survival data for Alecensa® (alectinib), in people living with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC Key highlights to be shared on Roche’s ASCO virtual newsroom, 29 May 2020, 08:00 CEST Basel, 7 May 2020 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that new data from clinical trials of 19 approved and investigational medicines across 21 cancer types, will be presented at the ASCO20 Virtual Scientific Program organised by the American Society of Clinical Oncology (ASCO), which will be held 29-31 May, 2020. A total of 120 abstracts that include a Roche medicine will be presented at this year's meeting. "At ASCO, we will present new data from many investigational and approved medicines across our broad oncology portfolio," said Levi Garraway, M.D., Ph.D., Roche's Chief Medical Officer and Head of Global Product Development. “These efforts exemplify our long-standing commitment to improving outcomes for people with cancer, even during these unprecedented times. By integrating our medicines and diagnostics together with advanced insights and novel platforms, Roche is uniquely positioned to deliver the healthcare solutions of the future." Together with its partners, Roche is pioneering a comprehensive approach to cancer care, combining new diagnostics and treatments with innovative, integrated data and access solutions for approved medicines that will both personalise and transform the outcomes of people affected by this deadly disease.
  • Clinical Policy: Sorafenib (Nexavar)

    Clinical Policy: Sorafenib (Nexavar)

    Clinical Policy: Sorafenib (Nexavar) Reference Number: CP.PHAR.69 Effective Date: 07.01.11 Last Review Date: 05.21 Line of Business: Commercial, HIM, Medicaid Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Sorafenib (Nexavar®) is a kinase inhibitor. FDA Approved Indication(s) Nexavar (sorafenib) is indicated for the treatment of: Unresectable hepatocellular carcinoma (HCC); Advanced renal cell carcinoma (RCC); Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Nexavar is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Hepatocellular Carcinoma (must meet all): 1. Diagnosis of HCC; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Confirmation of Child-Pugh class A or B7 status; 5. Request meets one of the following (a or b):* a. Dose does not exceed 800 mg per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration: Medicaid/HIM – 6 months Commercial – Length of Benefit B. Renal Cell Carcinoma (must meet all): 1. Diagnosis of advanced RCC; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Request meets one of the following (a or b):* Page 1 of 8 CLINICAL POLICY Sorafenib a.
  • Cogent Biosciences Announces Creation of Cogent Research Team

    Cogent Biosciences Announces Creation of Cogent Research Team

    Cogent Biosciences Announces Creation of Cogent Research Team April 6, 2021 Names industry veteran John Robinson, PhD as Chief Scientific Officer New Boulder-based team with exceptional track record of drug discovery and development focused on creating novel small molecule therapies for rare, genetically driven diseases Strong year-end cash position of $242.2 million supports company goals into 2024, including three CGT9486 clinical trials on-track to start this year, beginning with ASM in 1H21 BOULDER, Colo. and CAMBRIDGE, Mass., April 6, 2021 /PRNewswire/ -- Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today announced the formation of the Cogent Research Team led by newly appointed Chief Scientific Officer, John Robinson, PhD. "Today marks an important step forward for Cogent Biosciences as we announce the formation of the Cogent Research Team with a focus on discovering and developing new small molecule therapies for patients fighting rare, genetically driven diseases," said Andrew Robbins, President and Chief Executive Officer of Cogent Biosciences. "I am thrilled to welcome John onboard as Cogent Biosciences' Chief Scientific Officer. John's expertise and seasoned leadership make him ideally suited to lead this new team of world class scientists. Given the team's impressive experience and accomplishments, we are excited for Cogent Biosciences' future and the opportunity to expand our pipeline and deliver novel precision therapies for patients." With an exceptional track record of innovation, the Cogent Research Team will focus on pioneering best-in-class, small molecule therapeutics to both improve upon existing drugs with clear limitations, as well as create new breakthroughs for diseases where others have been unable to find solutions.
  • Phase II Study of Selumetinib, an Orally Active Inhibitor of MEK1 and MEK2 Kinases, in KRASG12R-Mutant Pancreatic Ductal Adenocarcinoma

    Phase II Study of Selumetinib, an Orally Active Inhibitor of MEK1 and MEK2 Kinases, in KRASG12R-Mutant Pancreatic Ductal Adenocarcinoma

    UC Davis UC Davis Previously Published Works Title Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma. Permalink https://escholarship.org/uc/item/3520819s Journal Investigational new drugs, 39(3) ISSN 0167-6997 Authors Kenney, Cara Kunst, Tricia Webb, Santhana et al. Publication Date 2021-06-01 DOI 10.1007/s10637-020-01044-8 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Investigational New Drugs (2021) 39:821–828 https://doi.org/10.1007/s10637-020-01044-8 SHORT REPORT Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma Cara Kenney1 & Tricia Kunst1 & Santhana Webb1 & Devisser Christina Jr2 & Christy Arrowood3 & Seth M. Steinberg4 & Niharika B. Mettu3 & Edward J. Kim2 & Udo Rudloff1,5 Received: 5 November 2020 /Accepted: 3 December 2020 / Published online: 6 January 2021 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020 Summary Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We con- ducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two- stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred.
  • Patient Group Input Submissions

    Patient Group Input Submissions

    CBCN’s 2012 Metastatic Breast Cancer Patient and Caregiver Survey Report: An online survey was distributed to patients living with metastatic breast cancer and their caregivers. No patients surveyed had experience with the treatment under review. Survey questions comprised of a combination of scoring options and free form commentary. Patients were contacted through the membership databases of CBCN and other patient organizations. -71 patients participated in the survey -16 caregivers participated in the survey Printed sources: A review was conducted of current studies and grey literature to identify issues and experiences that are commonly shared among many women living with metastatic breast cancer. 3. Disease Experience Metastatic breast cancer is the spread of cancerous cell growth to areas of the body other than where the cancer first formed. It is most commonly spread to the bones, but can include the lungs, liver, brain and skin. Triple-negative breast cancer (TNBC) is breast cancer that is estrogen-receptor-negative, progesterone-receptor-negative and HER2-negative. Accounting for 12-17% of breast cancers, TNBC’s have been shown to be relatively aggressive and display a high risk of metastasis and death within 5 years after diagnosis. TNBC is considered to be vastly heterogeneous and is often used as an umbrella term, encompassing a wide spectrum of entities with marked genetic, transcriptional, histological, and clinical differences. 1 A rare cancer that is more commonly associated with TNBC, is secretory breast carcinomas- a cancer that occurs due to an over secretion of mucin in the tumor. It is considered a subtype of invasive ductal carcinoma but is prone to metastasis and local recurrence.
  • CDER Breakthrough Therapy Designation Approvals Data As of December 31, 2020 Total of 190 Approvals

    CDER Breakthrough Therapy Designation Approvals Data As of December 31, 2020 Total of 190 Approvals

    CDER Breakthrough Therapy Designation Approvals Data as of December 31, 2020 Total of 190 Approvals Submission Application Type and Proprietary Approval Use Number Number Name Established Name Applicant Date Treatment of patients with previously BLA 125486 ORIGINAL-1 GAZYVA OBINUTUZUMAB GENENTECH INC 01-Nov-2013 untreated chronic lymphocytic leukemia in combination with chlorambucil Treatment of patients with mantle cell NDA 205552 ORIGINAL-1 IMBRUVICA IBRUTINIB PHARMACYCLICS LLC 13-Nov-2013 lymphoma (MCL) Treatment of chronic hepatitis C NDA 204671 ORIGINAL-1 SOVALDI SOFOSBUVIR GILEAD SCIENCES INC 06-Dec-2013 infection Treatment of cystic fibrosis patients age VERTEX PHARMACEUTICALS NDA 203188 SUPPLEMENT-4 KALYDECO IVACAFTOR 21-Feb-2014 6 years and older who have mutations INC in the CFTR gene Treatment of previously untreated NOVARTIS patients with chronic lymphocytic BLA 125326 SUPPLEMENT-60 ARZERRA OFATUMUMAB PHARMACEUTICALS 17-Apr-2014 leukemia (CLL) for whom fludarabine- CORPORATION based therapy is considered inappropriate Treatment of patients with anaplastic NOVARTIS lymphoma kinase (ALK)-positive NDA 205755 ORIGINAL-1 ZYKADIA CERITINIB 29-Apr-2014 PHARMACEUTICALS CORP metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients NDA 206545 ORIGINAL-1 ZYDELIG IDELALISIB GILEAD SCIENCES INC 23-Jul-2014 for whom rituximab alone would be considered appropriate therapy due to other co-morbidities
  • Rxoutlook® 1St Quarter 2019

    Rxoutlook® 1St Quarter 2019

    ® RxOutlook 1st Quarter 2020 optum.com/optumrx a RxOutlook 1st Quarter 2020 Orphan drugs continue to feature prominently in the drug development pipeline In 1983 the Orphan Drug Act was signed into law. Thirty seven years later, what was initially envisioned as a minor category of drugs has become a major part of the drug development pipeline. The Orphan Drug Act was passed by the United States Congress in 1983 in order to spur drug development for rare conditions with high unmet need. The legislation provided financial incentives to manufacturers if they could demonstrate that the target population for their drug consisted of fewer than 200,000 persons in the United States, or that there was no reasonable expectation that commercial sales would be sufficient to recoup the developmental costs associated with the drug. These “Orphan Drug” approvals have become increasingly common over the last two decades. In 2000, two of the 27 (7%) new drugs approved by the FDA had Orphan Designation, whereas in 2019, 20 of the 48 new drugs (42%) approved by the FDA had Orphan Designation. Since the passage of the Orphan Drug Act, 37 years ago, additional regulations and FDA designations have been implemented in an attempt to further expedite drug development for certain serious and life threatening conditions. Drugs with a Fast Track designation can use Phase 2 clinical trials to support FDA approval. Drugs with Breakthrough Therapy designation can use alternative clinical trial designs instead of the traditional randomized, double-blind, placebo-controlled trial. Additionally, drugs may be approved via the Accelerated Approval pathway using surrogate endpoints in clinical trials rather than clinical outcomes.
  • And Salivary Gland Cancers

    And Salivary Gland Cancers

    Larotrectinib is highly active in patients with advanced recurrent TRK fusion thyroid (TC) and salivary gland cancers (SGC) Wirth L, 1 Drilon A, 2 Albert CM, 3 Farago A, 1 el-Diery W, 4 Ma P, 5 Sohal D, 6 Raez L, 7 Baik C, 8 Brose MS, 9 Doebele R, 10 Cox MC, 11 Ku N, 11 Hong D 12 1Massachusetts General Hospital, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Seattle Children’s Hospital, Seattle, WA; 4Fox Chase Cancer Center, Philadelphia, PA; 5West Virginia University, Morgantown, WV; 6Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 7Memorial Cancer Institute, Pembroke Pines, FL; 8University of Washington/Seattle Cancer Care Alliance, Seattle, WA; 9University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA; 10 University of Colorado, Aurora, CO; 11 Loxo Oncology, South San Francisco, CA; 12 M.D. Anderson Cancer Center, Houston, TX Abstract # 20570 Introduction Patient and disease characteristics Adverse events with larotrectinib: ≥15% in safety database (n=125) n TRK fusions, involving the genes NTRK1, NTRK2, and NTRK3 , occur in a broad range of solid Characteristic Total N=19 Treatment-emergent AEs (%) Treatment-related AEs (%) tumors and are oncogenic: Median age (range), years 59 (15 –75) Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total – Targeted inhibition of TRK can be an effective antitumor approach Female, n 7 (37%) Fatigue 15 18 5–38 1–18 ECOG 0 –1 19 (100%) n Larotrectinib is the first selective pan-TRK inhibitor in clinical development and has demonstrated Dizziness 22 42–27
  • Ripretinib Turns Off the Switch in GIST

    Ripretinib Turns Off the Switch in GIST

    RESEARCH HIGHLIGHTS TARGETED THERAPY Ripretinib turns off the switch in GIST More than 85% of cases of type II kinase inhibitors such as gastrointestinal stromal tumour imatinib, regorafenib and sunitinib. (GIST) harbour mutations in the To develop a novel KIT and genes encoding the receptor tyrosine PDGFRα inhibitor that is designed kinases KIT and platelet-derived to inhibit activating mutations in growth factor receptor α (PDGFRα). all relevant known exons, including Treatment of metastatic GIST has in the activation loop, Flynn and been transformed by kinase inhibitors colleagues used structure-based drug such as imatinib, which is considered design to create an inhibitor that to be one of the most successful could bind to key amino acid residues targeted agents ever developed. within the KIT switching mechanism. Plus Images Bank/Getty Image Rosario/The M. Antonio Credit: However, this type of inhibitor In vitro, ripretinib and other only blocks a limited number analogues both prevented KIT from conducted a first-in-human study to of KIT mutants, and secondary adopting a type I active conformation evaluate the safety and tolerability resistance mutations eventually and locked it in the inactive of ripretinib (NCT02571036). emerge. Now, Daniel Flynn, from conformation. The authors showed Patients with drug-resistant GIST Deciphera Pharmaceuticals, that ripretinib inhibited mutations harbouring a broad spectrum of and collaborators have designed across all six exons known to be KIT mutations were enrolled during ripretinib, an investigational mutated in KIT-driven GIST as well the dose-escalation phase of study. tyrosine kinase inhibitor that targets as mutations in PDGFRα in a panel At first assessment, two representative a broad spectrum of KIT and of GIST cell lines and cells expressing patients in this phase I study showed PDGFRα mutants.