The Use of Superlatives in Cancer Research

Total Page:16

File Type:pdf, Size:1020Kb

The Use of Superlatives in Cancer Research Letters from work, child care, and transportation could also improve 4. Unger JM, Coltman CA Jr, Crowley JJ, et al. Impact of the year 2000 access to clinical trials for lower-income patients. Future Medicare policy change on older patient enrollment to cancer clinical trials. J Clin Oncol. 2006;24(1):141-144. research should investigate how to overcome financial barri- 5. Zafar SY, Peppercorn JM, Schrag D, et al. The financial toxicity of cancer ers to clinical trial participation. treatment: a pilot study assessing out-of-pocket expenses and the insured The identification of patient income level as an indepen- cancer patient’s experience. Oncologist. 2013;18(4):381-390. dent predictor of trial participation is important for multiple 6. Dickert N, Grady C. What’s the price of a research subject? approaches to reasons. If income is associated with health status, then im- payment for research participation. N Engl J Med. 1999;341(3):198-203. proving representativeness of lower-income patients in trials would improve the generalizability of study outcomes. Also, The Use of Superlatives in Cancer Research greater participation of lower-income patients would allow The language used in oncology practice and research may elicit trials to be conducted more quickly, speeding the develop- important connotations.1 Whereas most new cancer drugs af- ment of new treatments. Crucially, since clinical trial treat- ford modest benefits,2 approved drugs or those in develop- ments represent the newest available treatments, access to this ment may be heralded as “game changers” or “break- vital resource should be available to individuals of all income throughs” in the lay press. These news articles may be important levels. sources of information to patients, the public, and investors— with a broader reach than medical journal articles. However, Joseph M. Unger, PhD omission of medical context or use of inflated descriptors may 3 Julie R. Gralow, MD lead to misunderstandings among readers. Kathy S. Albain, MD We sought to investigate the use of modest and superla- Scott D. Ramsey, MD tive descriptors in contemporary news articles regarding can- Dawn L. Hershman, MD cer drugs. We sought to determine who uses this inflated lan- guage and what classes of drugs were most heralded. Author Affiliations: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington (Unger); Seattle Cancer Care Alliance, University of Methods | We searched 10 superlative terms in conjunction with Washington, Seattle (Gralow); Loyola University, Chicago Stritch School of “cancer drug” in Google’s news search (http://news.google Medicine, Maywood, Illinois (Albain); University of Washington Medical Center, .com) between June 21, 2015, and June 25, 2015. Superlative Seattle (Ramsey); Fred Hutchinson Cancer Research Center, Seattle, Washington (Ramsey); Columbia University, New York, terms included “breakthrough,” “game changer,” “miracle,” New York (Hershman). “cure,” “home run,” “revolutionary,” “transformative,” “life Corresponding Author: Joseph M. Unger, PhD, SWOG Statistical Center, saver,”“groundbreaking,”and “marvel.”Terms were prespeci- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M3-C102, fied and identified through discussion. PO Box 19024, Seattle, WA 98109-1024 ([email protected]). All articles resulted were read in full by one reviewer Published Online: October 15, 2015. doi:10.1001/jamaoncol.2015.3924. (M.V.A.). The following information was extracted: drug de- Author Contributions: Dr Unger had full access to all of the data in the study scribed, mechanism of action, class of medication, whether the and takes responsibility for the integrity of the data and the accuracy of the data agent described had already received US Food and Drug Ad- analysis. Study concept and design: Unger, Ramsey, Hershman. ministration approval, whether the data described con- Acquisition, analysis, or interpretation of data: Unger, Gralow, Albain, Ramsey, cerned human trial results or preclinical (eg, mouse or cell cul- Hershman. ture) data, and the quoted individual (physician, journalist, Drafting of the manuscript: Unger, Hershman. industry expert, or patient). An academic hematologist- Critical revision of the manuscript for important intellectual content: Unger, Gralow, Albain, Ramsey, Hershman. oncologist (V.P.) researched mechanism of action of all drugs Statistical analysis: Unger. and coded their class as cytotoxic, targeted, immunotherapy— Obtained funding: Gralow, Ramsey. checkpoint inhibitor, immunotherapy—therapeutic vaccine, ra- Administrative, technical, or material support: Gralow. Study supervision: Ramsey, Hershman. diotherapy, gene therapy, or other. Conflict of Interest Disclosures: None reported. Results | We found 94 news articles from 66 distinct news out- Funding/Support: This work was supported by a Breast Cancer Research Foundation grant and by the National Institutes of Health, National Cancer lets that made 97 superlative mentions that fit our criteria, re- Institute (NCI) Community Oncology Research Program Research Base grant ferring to 36 specific drugs, with 3 articles not naming the drug. 5UG1CA189974-01. The most common class of drugs referenced was targeted therapy Role of the Funder/Sponsor: The funding organizations had a role in the design (17 of 36 [47%]). Nine (25%) cytotoxic drugs were discussed, fol- and conduct of the study and in the collection and management of the data but lowed by 5 (14%) immunotherapy checkpoint inhibitors, 3 (8%) had no role in the analysis and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit for publication. cancer vaccines, 1 radiotherapy, and 1 gene therapy. 1. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: Among 97 superlatives used, 39 (40%) referred to a tar- race-, sex-, and age-based disparities. JAMA. 2004;291(22): geted therapy, 37 (38%) referred to an immunologic check- 2720-2726. point inhibitor, 10 (10%) referenced a cytotoxic drug, 5 (5%) 2. Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer discussed a therapeutic cancer vaccine, 3 (3%) did not name clinical trial participation. J Clin Oncol. 2013;31(5):536-542. the drug, 2 (2%) referred to a radiotherapy, and 1 (1%) referred 3. Javid SH, Unger JM, Gralow JR, et al. A prospective analysis of the influence to gene therapy. of older age on physician and patient decision-making when considering enrollment in breast cancer clinical trials (SWOG S0316). Oncologist. 2012;17(9): Precisely half (18 of 36) of drugs described had not re- 1180-1190. ceived Food and Drug Administration approval (as of July 15, jamaoncology.com (Reprinted) JAMA Oncology January 2016 Volume 2, Number 1 139 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Letters Table. Frequency and Characteristics of Cancer Drugs Described With Superlatives Superlative Frequency, No. (%)a Superlative(s) Drug FDA-Approved Clinical Drug (N = 97) Used (Frequency) Classification Drug(s) Data? Ipilimumab and 20 (21) Breakthrough (7), Immunotherapy— Yes Yes nivolumab miracle (5), game checkpoint inhibitor (Yervoy-Opdivo changer (5), combination) revolutionary (2), groundbreaking (1) Pembrolizumab 12 (12) Revolutionary (5), Immunotherapy— Yes Yes (Keytruda) game changer (2), checkpoint inhibitor groundbreaking (2), cure (2), miracle (1) Palbociclib (Ibrance) 10 (10) Groundbreaking (6), Targeted therapy Yes Yes game changer (2), revolutionary (1), miracle (1) Trastuzumab 7 (7) Revolutionary (4), Targeted therapy Yes Yes emtansine (Kadcyla) miracle (3) Dinutuximab 4 (4) Game changer (1), Targeted therapy Yes Yes (Unituxin) groundbreaking (1), Abbreviation: FDA, Food and Drug breakthrough (1), Administration. miracle (1) a MPDL3280A 3 (3) Game changer (2), Immunotherapy— No Yes Drugs with 1 (1%) superlative: revolutionary (1) checkpoint inhibitor ABT-199, acelarin, ALM201, Olaparib (Lynparza) 3 (3) Revolutionary (2), Targeted therapy Yes Yes bortezomib (Velcade), brentuximab breakthrough (1) vedotin (Adcetris), Cimavax, T-VEC 3 (3) Breakthrough (3) Immunotherapy— No Yes docetaxel (Taxotere), doxorubicin vaccine with vinorelbine, epidaza (Chidamide), eribulin (Halaven), Pertuzumab (Perjeta) 3 (3) Groundbreaking (3) Targeted therapy Yes Yes figitumumab, G1 T-28, ibrutinib Unnamed 3 (3) Breakthrough (1), ………(Imbruvica), ipilimumab, NeuVax, miracle (1), nivolumab (Opdivo), OH14 game changer (1) compound, OTS964, PENAO, Radium-223 2 (2) Game changer (2) Radiotherapeutic drug Yes Yes protein-bound paclitaxel dichloride (Alpharadin or Xofigo) (Abraxane), rociletinib, TargomiRs, TRXE-009, vemurafenib (Zelboraf), BPM31510 2 (2) Revolutionary (2) Cytotoxic therapy No Yes ZL105. 2015) for at least 1 indication. For 5 of 36 (14%) drugs, super- cology conference; as such, it may not reflect the use of these latives were used in the absence of clinical data (ie, based solely terms at other times, as well as in other years. on mouse, cell culture, and/or preclinical work). The specific A range of speakers used superlatives, but the majority drug mentioned, superlative used, and other characteristics were journalists (55%), who may not have the expertise to iden- are described in the Table. tify the most promising medical therapies, or what magni- A variety of speakers were credited with using the super- tude of benefit warrants a superlative. The use of superla- lative (53 journalists [55%], 26 physicians
Recommended publications
  • The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients
    biomedicines Review The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients Alessandro Allegra 1,* , Eleonora Di Salvo 2 , Marco Casciaro 3,4, Caterina Musolino 1, Giovanni Pioggia 5 and Sebastiano Gangemi 3,4 1 Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; [email protected] 2 Department of Veterinary Sciences, University of Messina, 98125 Messina, Italy; [email protected] 3 School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (M.C.); [email protected] (S.G.) 4 Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy 5 Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-090-221-2364 Abstract: Although pruritus may sometimes be a consequential situation to neoplasms, it more frequently emerges after commencing chemotherapy. In this review, we present our analysis of the chemotherapy treatments that most often induce skin changes and itching. After discussing conventional chemotherapies capable of inducing pruritus, we present our evaluation of new drugs such as immunological checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and monoclonal antibodies. Although ICIs and targeted therapy are thought to damage tumor cells, these therapies can modify homeostatic events of the epidermis and dermis, causing the occurrence of cutaneous toxicities in treated subjects. In the face of greater efficacy, greater skin toxicity has been reported for most of these drugs.
    [Show full text]
  • MET Or NRAS Amplification Is an Acquired Resistance Mechanism to the Third-Generation EGFR Inhibitor Naquotinib
    www.nature.com/scientificreports OPEN MET or NRAS amplifcation is an acquired resistance mechanism to the third-generation EGFR inhibitor Received: 5 October 2017 Accepted: 16 January 2018 naquotinib Published: xx xx xxxx Kiichiro Ninomiya1, Kadoaki Ohashi1,2, Go Makimoto1, Shuta Tomida3, Hisao Higo1, Hiroe Kayatani1, Takashi Ninomiya1, Toshio Kubo4, Eiki Ichihara2, Katsuyuki Hotta5, Masahiro Tabata4, Yoshinobu Maeda1 & Katsuyuki Kiura2 As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from geftinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplifcation was detected in naquotinib-resistant cells derived from geftinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly benefcial efect in resistant cells with NRAS amplifcation, but the combination of MEK inhibitors and osimertinib had limited efects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little efect on osimertinib-resistant cells.
    [Show full text]
  • The Role of Single Arm Trials in Oncology Drug Development EMA-ESMO Workshop on Single-Arm Trials for Cancer Drug Market Access 30Th June 2016
    The role of Single Arm Trials in Oncology Drug Development EMA-ESMO Workshop on single-arm trials for cancer drug market access 30th June 2016 Gideon Blumenthal, MD Office of Hematology and Oncology Products U.S. Food and Drug Administration Challenges with “newparadigm” with Challenges Challenges ROS1 MET PTEN+ PTEN+ Targeted KRAS Therapy N=50 p53 with “oldparadigm” - 200 LKB1 ??? ORR Magnitude, Durable Large EGFR ALK N=800 R - 1200 1. Feasibility of screening/enrolling pts for RCT? for pts screening/enrolling of Feasibility 1. 2. Equipoise Lost? Equipoise 2. Platinum doublet Platinum Platinum doublet Platinum + drug X EFFECT CLINICALLY DETECTION “FAILURE” HIGHRISK 30 ) % ( 25 s n Patients with TARGET Gene events by category (%) o i t 0 25 50 75 100 a r 20 e All t l a Common (5% or greater) e 15 Intermediate (2−5%) n e g Rare (Less than 2%) T 10 2 E G R A 5 T 0 3 1 3 4 5 1 2 4 L 2 1 2 2 3 3 1 1 7 1 1 2 1 2 2 1 1 4 1 1 3 1 1 4 4 2 2 6 1 6 2 1 1 1 4 1 L 4 2 2 2 1 1 2 1 1 1 3 1 3 1 1 3 3 1 2 2 2 2 1 L 2 4 5 L 1 1 1 1 2 3 6 F T T T F F A A S P S A B S K K A B B A S A A A A R N C R R R C R R G O Q M I I 5 L L L 1 L 1 L − F T T T T F F T T P 2 A B A S A A K B B B K 1 K A B X L K V 2 K K P 3 V K E K T S V V P B K 1 A H H R H E H R E D H D R 1 H H C R N D D D R R R H H D D H C H D A OR F T A B A A Y O A K C E P R Y R A M M R A T D W O R I K M L B 2 P X K 2 B 2 2 A 3 C K T E T T L A T T C K K A B N Z F F F F N B B A B A A A S 3 N H H C M C R R N N A C N D S S S E N R A S S N S V C D N A R T C C F D R D C R F N N D R N D R R B O S P R A R N R A
    [Show full text]
  • Trastuzumab and Paclitaxel in Patients with EGFR Mutated NSCLC That Express HER2 After Progression on EGFR TKI Treatment
    www.nature.com/bjc ARTICLE Clinical Study Trastuzumab and paclitaxel in patients with EGFR mutated NSCLC that express HER2 after progression on EGFR TKI treatment Adrianus J. de Langen1,2, M. Jebbink1, Sayed M. S. Hashemi2, Justine L. Kuiper2, J. de Bruin-Visser2, Kim Monkhorst3, Erik Thunnissen4 and Egbert F. Smit1,2 BACKGROUND: HER2 expression and amplification are observed in ~15% of tumour biopsies from patients with a sensitising EGFR mutation who develop EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumour responses. METHODS: A single arm phase II study was performed to study the safety and efficacy of trastuzumab and paclitaxel treatment in patients with a sensitising EGFR mutation who show HER2 expression in a tumour biopsy (IHC ≥ 1) after progression on EGFR TKI treatment. Trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) and paclitaxel (60 mg/m2) were dosed weekly until disease progression or unacceptable toxicity. The primary end-point was tumour response rate according to RECIST v1.1. RESULTS: Twenty-four patients were enrolled. Nine patients were exon 21 L858R positive and fifteen exon 19 del positive. Median HER2 IHC was 2+ (range 1–3). For 21 patients, gene copy number by in situ hybridisation could be calculated: 5 copies/nucleus (n = 9), 5–10 copies (n = 8), and >10 copies (n = 4). An objective response was observed in 11/24 (46%) patients. Highest response rates were seen for patients with 3+ HER2 IHC (12 patients, ORR 67%) or HER2 copy number ≥10 (4 patients, ORR 100%). Median tumour change in size was 42% decrease (range −100% to +53%).
    [Show full text]
  • ASCO Virtual • 41 Patient Data (N~70) • Final Results Scientific Program • Incl
    A YEAR OF CLINICAL, REGULATORY & COMMERCIAL PROGRESS Corporate Presentation April 7, 2021 Nasdaq / AIM: HCM Safe Harbor Statement & Disclaimer The performance and results of operations of the HUTCHMED Group contained within this presentation are historical in nature, and past performance is no guarantee of future results. This presentation contains forward-looking statements within the meaning of the “safe harbor” believes that the publications, reports, surveys and third-party clinical data are reliable, HUTCHMED has provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements not independently verified the data and cannot guarantee the accuracy or completeness of such data. can be identified by words like “will,” “expects,” “anticipates,” “future,” “intends,” “plans,” “believes,” You are cautioned not to give undue weight to this data. Such data involves risks and uncertainties and “estimates,” “pipeline,” “could,” “potential,” “first-in-class,” “best-in-class,” “designed to,” “objective,” are subject to change based on various factors, including those discussed above. “guidance,” “pursue,” or similar terms, or by express or implied discussions regarding potential drug candidates, potential indications for drug candidates or by discussions of strategy, plans, expectations Nothing in this presentation or in any accompanying management discussion of this presentation or intentions. You should not place undue reliance on these statements. Such forward-looking constitutes, nor is it intended to constitute or form any part of: (i) an invitation or inducement to engage statements are based on the current beliefs and expectations of management regarding future events, in any investment activity, whether in the United States, the United Kingdom or in any other jurisdiction; and are subject to significant known and unknown risks and uncertainties.
    [Show full text]
  • Targeted Therapy and Immunotherapy for Lung Cancer
    Targeted Therapy and Immunotherapy for Lung Cancer Evan C. Naylor, MD*, Jatin K. Desani, MD, Paul K. Chung, MD KEYWORDS Molecular Targeted therapy Immunotherapy Non–small cell lung cancer KEY POINTS Targeted therapy and immunotherapy have had an increasing role in the management of patients with advanced non–small cell lung cancer (NSCLC). Therapies targeting patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements have proved most successful, whereas others specific for additional genetic alterations seem promising. Immunotherapy in lung cancer, primarily through checkpoint inhibition, permits the activa- tion of tumor-specific T cells often suppressed by cancer cells. Adverse effects of these drugs are often mild and manageable, improving quality of life and limiting cumulative toxicity seen with use of cytotoxic chemotherapy. INTRODUCTION The management of patients with advanced NSCLC has evolved dramatically over the past decade. Therapeutic options were previously limited to cytotoxic chemotherapy in a 1-size-fits-all approach. As more information becomes known about the driving molecular events behind tumorigenesis, however, researchers are designing drugs capable of interfering with these events in a more individualized approach. The first such drugs in NSCLC were the targeted agents, biologic compounds that interact with cell surface receptors or their downstream partners critical in cancer develop- ment. These agents have shown a monumental benefit in a small number of patients with NSCLC. The more recent addition has been the immunotherapeutic agents, which seem to have a broader benefit and are providing durable responses in NSCLC not previously seen. The authors have nothing to disclose.
    [Show full text]
  • Agents Available Under CTEP Collaborative Agreements for Clinical and Non-Clinical Studies 1 As of 7/28/2021
    Agents Available Under CTEP Collaborative Agreements for Clinical and Non-clinical Studies 1 as of 7/28/2021 Pharmaceutical Agent Name Alternate Name Collaborator NSC Number Drug Monitor Mechanism of Action Targets Classes abemaciclib LY2835219 Eli Lilly 783671 Piekarz CDK4/6 inhibitor CDK4/6 Small Molecule AMG510 Amgen 825510 Wright Inhibits G12C-mutated KRAS mutated KRAS protein Small Molecule Anti cell surface glycoprotein mesothelin conjugated to anetumab maytansinoid DM4 with potential antineoplastic Antibody-Drug Conjugate; ravtansine* BAY 94-9343 Bayer 791065 Moscow activity mesothelin Monoclonal Antibody anti-apoptotic Bcl-2 family Inhibits B-cell lymphoma 2 (Bcl-2) and B-cell proteins, including Bcl-2, Bcl-xL, APG-1252*** Pelcitoclax Ascentage 831685 Gore lymphoma – extra-large (Bcl-xL) Bcl-w, and Mcl-1 Small Molecule Combination of cedazuridine and ASTX727 decitabine Astex Pharmaceuticals 820631 Piekarz DNA methyltransferase (DNMT) inhibitor DNA methyltransferase Small Molecule Targets PD-L1 expressed on tumor and infiltrating programmed cell death ligand 1 Atezolizumab MPDL3280A Genentech 783608 Sharon immune cells, preventing binding to PD-1 and B7.1 (PD-L1) Monoclonal Antibody AZD5363 Capivasertib AstraZeneca 782347 Sandlund Inhibits all AKT isoforms AKT Small Molecule Inhibits Ataxia Telangiectasia and Rad3 related (ATR) AZD6738 AstraZeneca 802785 Gore serine/threonine protein kinase ATR Small Molecule Inhibitor of ataxia telangiectasia mutated and Rad3- BAY1895344 Bayer 810486 Gore related (ATR) kinase ATR Small Molecule
    [Show full text]
  • NSCLC (Update) • Cotellic + Zelboraf: Phase III 1L Melanoma (Cobrim), Overall Survival
    Roche YTD September 2015 sales Basel, 22 October 2015 This presentation contains certain forward-looking statements. These forward-looking statements may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this presentation, among others: 1 pricing and product initiatives of competitors; 2 legislative and regulatory developments and economic conditions; 3 delay or inability in obtaining regulatory approvals or bringing products to market; 4 fluctuations in currency exchange rates and general financial market conditions; 5 uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side-effects of pipeline or marketed products; 6 increased government pricing pressures; 7 interruptions in production; 8 loss of or inability to obtain adequate protection for intellectual property rights; 9 litigation; 10 loss of key executives or other employees; and 11 adverse publicity and news coverage. Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. For marketed products discussed in this presentation, please see full prescribing information on our website www.roche.com All mentioned trademarks are legally protected.
    [Show full text]
  • Circulating Tumour DNA Profiling Reveals Heterogeneity of EGFR Inhibitor Resistance Mechanisms in Lung Cancer Patients
    ARTICLE Received 18 Mar 2016 | Accepted 3 May 2016 | Published 10 Jun 2016 DOI: 10.1038/ncomms11815 OPEN Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients Jacob J. Chabon1,2,*, Andrew D. Simmons3,*, Alexander F. Lovejoy1,2, Mohammad S. Esfahani1,2, Aaron M. Newman1,2, Henry J. Haringsma3, David M. Kurtz4,5, Henning Stehr1,2, Florian Scherer2,4, Chris A. Karlovich3, Thomas C. Harding3, Kathleen A. Durkin6, Gregory A. Otterson7, W. Thomas Purcell8, D. Ross Camidge8, Jonathan W. Goldman9, Lecia V. Sequist10, Zofia Piotrowska10, Heather A. Wakelee4, Joel W. Neal4, Ash A. Alizadeh1,2,4,11 & Maximilian Diehn1,2,12 Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in B33% of patients after osimertinib treatment, occurs in o3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
    [Show full text]
  • Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy
    cancers Review Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy 1,2, 3,4 1 2 3, Charles Pottier * , Margaux Fresnais , Marie Gilon , Guy Jérusalem ,Rémi Longuespée y 1, and Nor Eddine Sounni y 1 Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University Hospital of Liège, 4000 Liège, Belgium; [email protected] (M.G.); [email protected] (N.E.S.) 2 Department of Medical Oncology, University Hospital of Liège, 4000 Liège, Belgium; [email protected] 3 Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany; [email protected] (M.F.); [email protected] (R.L.) 4 German Cancer Consortium (DKTK)-German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany * Correspondence: [email protected] Equivalent contribution. y Received: 17 January 2020; Accepted: 16 March 2020; Published: 20 March 2020 Abstract: Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs.
    [Show full text]
  • Molecular Imaging in Cancer Drug Development
    THE STATE OF THE ART Molecular Imaging in Cancer Drug Development Stijn J.H. Waaijer*1, Iris C. Kok*1, Bertha Eisses1, Carolina P. Schröder1, Mathilde Jalving1, Adrienne H. Brouwers2, Marjolijn N. Lub-de Hooge2,3, and Elisabeth G.E. de Vries1 1Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 2Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and 3Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands effect, and a randomized phase 3 study to define its effect compared Development of new oncology drugs has increased since the with standard treatment. improved understanding of cancer’s complex biology. The oncology To improve and streamline cancer drug development, the ‘‘3 field has become the top therapeutic research area for new drugs. pillars of survival’’ (7), and more recently the pharmacological However, only a limited number of drugs entering clinical trials will audit trail, were proposed (8). This trail consists of a set of key be approved for use as the standard of care for cancer patients. questions to be asked during discovery and development, covering Molecular imaging is increasingly perceived as a tool to support go/ aspects such as population identification, pharmacokinetics, phar- no-go decisions early during drug development. It encompasses a macodynamics, and combination therapy (8). Molecular imaging wide range of techniques that include radiolabeling a compound of interest followed by visualization with SPECT or PET. Radiolabeling can give additional information about, for example, target valida- can be performed using a variety of radionuclides, which are pref- tion; tumor targeting; whole-body target expression, including the erably matched to the compound on the basis of size and half-life.
    [Show full text]
  • Update on Recent Preclinical and Clinical Studies of T790M Mutant
    Liao et al. Journal of Biomedical Science (2016) 23:86 DOI 10.1186/s12929-016-0305-9 REVIEW Open Access Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors Bin-Chi Liao1,2,3, Chia-Chi Lin1,5, Jih-Hsiang Lee1,6 and James Chih-Hsin Yang1,2,3,4* Abstract The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy. The structures of the novel 3G EGFR-TKIs are different from those of 1/2G EGFR-TKIs. Particularly, 3G EGFR-TKIs have lower affinity to wild-type EGFR, and are therefore associated with lower rates of skin and gastrointestinal toxicities. However, many of the adverse events (AEs) that are observed in patients receiving 3G EGFR-TKIs have not been observed in patients receiving 1/2G EGFR-TKIs. Although preclinical studies have revealed many possible mechanisms for these AEs, the causes of some AEs remain unknown. Many mechanisms of resistance to 3G EGFR-TKI therapy have also been reported. Here, we have reviewed the recent clinical and preclinical developments related to novel 3G EGFR-TKIs, including osimertinib, rociletinib, olmutinib, EGF816, and ASP8273.
    [Show full text]