Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib a C Ezra Y

Total Page:16

File Type:pdf, Size:1020Kb

Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib a C Ezra Y Published OnlineFirst October 20, 2020; DOI: 10.1158/1078-0432.CCR-20-2278 CLINICAL CANCER RESEARCH | RESEARCH BRIEFS: CLINICAL TRIAL BRIEF REPORT Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib A C Ezra Y. Rosen1, Melissa L. Johnson2, Sarah E. Clifford3, Romel Somwar4, Jennifer F. Kherani5, Jieun Son3, Arrien A. Bertram3, Monika A. Davare6, Eric Gladstone4, Elena V. Ivanova7, Dahlia N. Henry5, Elaine M. Kelley3, Mika Lin3, Marina S.D. Milan3, Binoj C. Nair5, Elizabeth A. Olek5, Jenna E. Scanlon3, Morana Vojnic4, Kevin Ebata5, Jaclyn F. Hechtman4, Bob T. Li1,8, Lynette M. Sholl9, Barry S. Taylor10, Marc Ladanyi4, Pasi A. Janne€ 3, S. Michael Rothenberg5, Alexander Drilon1,8, and Geoffrey R. Oxnard3 ABSTRACT ◥ Purpose: The RET proto-oncogene encodes a receptor tyrosine Results: MET amplification was identified in posttreatment kinase that is activated by gene fusion in 1%–2% of non–small biopsies in 4 patients with RET fusion–positive NSCLC treated with cell lung cancers (NSCLC) and rarely in other cancer types. selpercatinib. In at least one case, MET amplification was clearly Selpercatinib is a highly selective RET kinase inhibitor that has evident prior to therapy with selpercatinib. We demonstrate that recently been approved by the FDA in lung and thyroid cancers increased MET expression in RET fusion–positive tumor cells causes with activating RET gene fusions and mutations. Molecular resistance to selpercatinib, and this can be overcome by combining mechanisms of acquired resistance to selpercatinib are poorly selpercatinib with crizotinib. Using SPPs, selpercatinib with crizo- understood. tinib were given together generating anecdotal evidence of clinical Patients and Methods: We studied patients treated on the first- activity and tolerability, with one response lasting 10 months. in-human clinical trial of selpercatinib (NCT03157129) who were Conclusions: Through the use of SPPs, we were able to offer found to have MET amplification associated with resistance to combination therapy targeting MET-amplified resistance iden- selpercatinib. We validated MET activation as a targetable mediator tified on the first-in-human study of selpercatinib. These data of resistance to RET-directed therapy, and combined selpercatinib suggest that MET dependence is a recurring and potentially with the MET/ALK/ROS1 inhibitor crizotinib in a series of single targetable mechanism of resistance to selective RET inhibition patient protocols (SPP). in advanced NSCLC. Introduction patient selection. While several combination therapies are approved (e.g., MEK inhibition with BRAF inhibition in BRAF-mutant mela- Combination targeted therapy represents a compelling strategy for þ noma; CDK4/6 inhibition with endocrine therapy in ER breast overcoming drug resistance in metastatic cancer. However, the clinical cancer; refs. 1–4), no drug combination has yet met the standard of development of combination approaches has been challenging due to regulatory approval for effective treatment of resistance to targeted toxicity from combining two agents and the need for appropriate kinase inhibitors (TKI) in genotype-selected patients. Because resis- tance to targeted TKIs is universal, effective strategies to overcome acquired resistance are key to prolonging clinical benefit. To that end, 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 2Department of Medicine, Sarah Cannon Cancer Center, Nashville, combination approaches remain a compelling investigational strategy – Tennessee. 3Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, in oncogene-dependent non small cell lung cancer (NSCLC) with Boston, Massachusetts. 4Department of Pathology, Memorial Sloan Kettering several clinical trials ongoing (5–8). Cancer Center, New York, New York. 5Loxo Oncology, Inc., a wholly owned The RET proto-oncogene encodes a receptor tyrosine kinase which 6 subsidiary of Eli Lilly and Company, Stamford, Connecticut. Oregon Health and is activated by gene fusion in 1%–2% of NSCLC and rarely in many 7 Science University, Portland, Oregon. Belfer Center for Applied Cancer Science, other tumor types. RET gene fusions are bona fide cancer drivers and Dana-Farber Cancer Institute, Boston, Massachusetts. 8Weill Cornell Medical College, New York, New York. 9Department of Pathology, Brigham and they display the key characteristics of oncogene addiction preclini- Women’s Hospital, Boston, Massachusetts. 10Department of Epidemiology and cally (9). Selpercatinib is a highly selective and potent anti-RET TKIs Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. which has recently reported durable responses in lung and thyroid fi Note: Supplementary data for this article are available at Clinical Cancer cancers, and these responses were maintained regardless of the speci c Research Online (http://clincancerres.aacrjournals.org/). RET alteration or prior TKI use, and also in the setting of the RET V804 “gatekeeper” mutation (10). Selpercatinib was recently approved by E.Y. Rosen and M.L. Johnson contributed equally to this article. A. Drilon and G.R. Oxnard contributed equally to this article. the FDA for use in these cancers. Mechanisms of acquired resistance to treatment with selective RET inhibitors are not well understood. While Corresponding Author: Alexander Drilon, Memorial Sloan Kettering Cancer a secondary mutation in the RET kinase domain has recently been Center, 530 East 74th Street, New York, NY 10021. Phone: 646-888-4206; fi Fax: 646-888–4263; E-mail: [email protected] reported (11), activation of bypass tracts, such as MET ampli cation, also represent a recurring mechanism of resistance to driver genotypes Clin Cancer Res 2020;XX:XX–XX in NSCLC (12, 13). Here we piloted combination therapy to target doi: 10.1158/1078-0432.CCR-20-2278 MET amplification detected in 4 patients with RET-positive NSCLC Ó2020 American Association for Cancer Research. (of a total 79 patients with NSCLC enrolled at all three sites) with AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst October 20, 2020; DOI: 10.1158/1078-0432.CCR-20-2278 Rosen et al. Preclinical RET-dependent models Translational Relevance RET fusion–positive human bronchioepithelial (HBEC-RET) Molecular mechanisms of acquired resistance to selpercatinib, a cell lines expressing a CCDC6-RET fusion were engineered to highly selective and potent RET kinase inhibitor, are poorly overexpress MET and a patient-derived organoid was also estab- understood. We identified MET amplification as a recurrent lished. These models were subsequently studied to investigate mechanism of resistance to targeted therapy in patients with the role of MET in selpercatinib resistance (see Supplementary non–small cell lung cancer (NSCLC) treated with selpercatinib. Methods). We show that MET amplification is sufficient to cause selpercatinib resistance in vitro, and that the addition of the MET/ALK/ROS1 SPPs of selpercatinib and crizotinib inhibitor crizotinib can rescue this phenotype. We then utilize a Each SPP was sponsored by LOXO and drafted in collaboration series of single-patient protocols to treat these patients with between LOXO and the site primary investigator. Each protocol combination therapy, and this combination treatment showed enrolled a single patient after review by the FDA and approval by clinical activity, with one response lasting 10 months. These data the site IRB. Dosing was individualized per patient and dose escalation suggest that MET dependence is a recurring and potentially was permitted as tolerated up to the established tolerable dose for each targetable mechanism of resistance to selective RET inhibition in drug. Patients initiated combination therapy directly after demon- advanced NSCLC. Prospective clinical trials are needed to validate strating resistance to prior targeted therapy (Table 1; Supplementary these findings and to identify effective combination therapies to Fig. S1). treat acquired resistance to selpercatinib. Results MET-dependent resistance to selpercatinib in patients with resistance to selpercatinib. This was made possible through the use of advanced NSCLC multiple single-patient protocols (SPP) which allowed for the quick Case 1 delivery of potentially effective combination therapy to patients with The first patient was a 36-year-old female former smoker with clear unmet clinical need. stage IV NSCLC metastatic to bone, heavily pretreated. Molecular testing identified a RET rearrangement by break-apart FISH (83% of cells) as well as MET copy-number gain (CNG) by FISH (6 copies). Patients and Methods She initiated treatment with alectinib, an ALK TKI with some Analysis of resistance to selpercatinib degree of anti-RET activity preclinically (14), and progressed in Patients were included in this analysis if they had received less than 2 months. Next-generation sequencing (NGS) analysis of selpercatinib (LOXO-292) for RET-positive NSCLC on the first- plasma circulating cell-free tumor DNA (cfDNA) then identified an in-human study of selpercatinib (NCT03157128) and exhibited EML4-RET fusion (AF 14%; ref. 15). She started treatment with evidence of MET amplification following drug resistance. All selpercatinib and experienced a clinical response (decreased tumor- patients provided written informed consent wherever necessary. related pain
Recommended publications
  • Lung Cancer Drugs in the Pipeline
    HemOnc today | JANUARY 10, 2016 | Healio.com/HemOnc 5 Lung Cancer Drugs in the Pipeline HEMONC TODAY presents this guide to drugs in phase 2 or phase 3 development for lung cancer-related indications. Clinicians can use this chart as a quick reference to learn about the status of those drugs that may be clinically significant to their practice. Generic name (Brand name, Manufacturer) Indication(s) Development status abemaciclib (Eli Lilly) non–small cell lung cancer phase 3 ABP 215 (Allergan/Amgen) non–small cell lung cancer (advanced disease) phase 3 ACP-196 (Acerta Pharma) non–small cell lung cancer (advanced disease) phase 2 ado-trastuzumab emtansine (Kadcyla, Genentech) non–small cell lung cancer (HER-2–positive disease) phase 2 afatinib (Gilotrif, Boehringer Ingelheim) lung cancer (squamous cell carcinoma) phase 3 aldoxorubicin (CytRx) small cell lung cancer phase 2 alectinib (Alecensa, Genentech) non–small cell lung cancer (second-line treatment of ALK-positive disease) phase 2 non–small cell lung cancer (first-line treatment of ALK-positive disease); phase 3 alisertib (Takeda) malignant mesothelioma, small cell lung cancer phase 2 avelumab (EMD Serono/Pfizer) non–small cell lung cancer phase 3 AZD9291 (AstraZeneca) non–small cell lung cancer (first-line treatment of advancedEGFR -positive disease; phase 3 second-line treatment of advanced EGFR-positive, T790M-positive disease) bavituximab (Peregrine Pharmaceuticals) non–small cell lung cancer (previously treated advanced/metastatic disease) phase 3 belinostat (Beleodaq, Spectrum
    [Show full text]
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • 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.
    [Show full text]
  • RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients Shumei Kato1, Vivek Subbiah2, Erica Marchlik3, Sheryl K
    Published OnlineFirst September 28, 2016; DOI: 10.1158/1078-0432.CCR-16-1679 Personalized Medicine and Imaging Clinical Cancer Research RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients Shumei Kato1, Vivek Subbiah2, Erica Marchlik3, Sheryl K. Elkin3, Jennifer L. Carter3, and Razelle Kurzrock1 Abstract Purpose: Aberrations in genetic sequences encoding the tyrosine (52/88)], cell cycle–associated genes [39.8% (35/88)], the PI3K kinase receptor RET lead to oncogenic signaling that is targetable signaling pathway [30.7% (27/88)], MAPK effectors [22.7% with anti-RET multikinase inhibitors. Understanding the compre- (20/88)], or other tyrosine kinase families [21.6% (19/88)]. hensive genomic landscape of RET aberrations across multiple RET fusions were mutually exclusive with MAPK signaling cancers may facilitate clinical trial development targeting RET. pathway alterations. All 72 patients harboring coaberrations Experimental Design: We interrogated the molecular portfolio had distinct genomic portfolios, and most [98.6% (71/72)] of 4,871 patients with diverse malignancies for the presence of had potentially targetable coaberrations with either an FDA- RET aberrations using Clinical Laboratory Improvement Amend- approved or an investigational agent. Two cases with lung ments–certified targeted next-generation sequencing of 182 or (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) 236 gene panels. thatrespondedtoavandetanib(multikinase RET inhibitor)- Results: Among diverse cancers, RET aberrations were iden- containing regimen are shown. tified in 88 cases [1.8% (88/4, 871)], with mutations being Conclusions: RET aberrations were seen in 1.8% of diverse the most common alteration [38.6% (34/88)], followed cancers, with most cases harboring actionable, albeit dis- by fusions [30.7% (27/88), including a novel SQSTM1-RET] tinct, coexisting alterations.
    [Show full text]
  • BLU-667 Is a Potent and Highly Selective RET Inhibitor in Development for RET-Driven Thyroid Cancers
    BLU-667 is a potent and highly selective RET inhibitor in development for RET-driven thyroid cancers Rami Rahal, PhD Blueprint Medicines July 30, 2017 Disclosure ▪ Employee and shareholder of Blueprint Medicines ▪ BLU-667 is an investigational agent currently in development by Blueprint Medicines 2 REarranged during Transfection (RET) ▪ Receptor tyrosine kinase that transduces signals from GDNF-family ligands ▪ One of the first oncogenic kinase fusions cloned from an epithelial tumor Mulligan, NRC, 2014 NRC, Mulligan, 1987 1990 1993 2012 2013 2014 2015 RET = RTK Papillary Thyroid Medullary Thyroid Lung CMML Colon, Breast, Inflammatory Cancer Cancer (MTC) Adeno Salivary, Myofibroblastic PTC1 = RET Ovarian Tumors Tumors 3 RET Kinase Fusions and Mutations are Oncogenic RET fusions RET mutations Kinase RET + Dimerization domain Fusion Partner ECD M918T V804L/M * * * * * Dimerization domain Kinase RET/PTC Fusion Kinase ▪ ~10% of papillary thyroid cancer ▪ ~60% of medullary thyroid cancer patients (MTC) patients harbor oncogenic ▪ 1-2% of NSCLC patients RET mutations ▪ <1% of patients with colon, ovary, ▪ M918T is the most prevalent RET breast, or hematological cancer mutation 4 Kinase Inhibitors Approved for Treating MTC were Not Designed to Selectively Inhibit RET ▪ Broad kinome activity with potent inhibition of VEGFR-2 ▪ Off-target related dose limiting toxicities hamper ability to inhibit fully RET VEGFR-2 RET Overall Compound Intended Serious adverse Biochem. Biochem. Response (Trade Name) Target(s) events IC50 (nM) IC50 (nM) Rate in MTC Cabozantinib Perforations and VEGFR-2 / MET 2 11 27% (Cometriq) fistulas; hemorrhage QT prolongation; Vandetanib VEGFR-2 / EGFR 4 4 Torsades de pointes; 44% (Calpresa*) sudden death *Only available through Calpresa REMS due to safety concerns 5 BLU-667: a Highly Potent and Selective RET Inhibitor 1.
    [Show full text]
  • 2017 Immuno-Oncology Medicines in Development
    2017 Immuno-Oncology Medicines in Development Adoptive Cell Therapies Drug Name Organization Indication Development Phase ACTR087 + rituximab Unum Therapeutics B-cell lymphoma Phase I (antibody-coupled T-cell receptor Cambridge, MA www.unumrx.com immunotherapy + rituximab) AFP TCR Adaptimmune liver Phase I (T-cell receptor cell therapy) Philadelphia, PA www.adaptimmune.com anti-BCMA CAR-T cell therapy Juno Therapeutics multiple myeloma Phase I Seattle, WA www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 "armored" CAR-T Juno Therapeutics recurrent/relapsed chronic Phase I cell therapy Seattle, WA lymphocytic leukemia (CLL) www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 CAR-T cell therapy Intrexon B-cell malignancies Phase I Germantown, MD www.dna.com ZIOPHARM Oncology www.ziopharm.com Boston, MA anti-CD19 CAR-T cell therapy Kite Pharma hematological malignancies Phase I (second generation) Santa Monica, CA www.kitepharma.com National Cancer Institute Bethesda, MD Medicines in Development: Immuno-Oncology 1 Adoptive Cell Therapies Drug Name Organization Indication Development Phase anti-CEA CAR-T therapy Sorrento Therapeutics liver metastases Phase I San Diego, CA www.sorrentotherapeutics.com TNK Therapeutics San Diego, CA anti-PSMA CAR-T cell therapy TNK Therapeutics cancer Phase I San Diego, CA www.sorrentotherapeutics.com Sorrento Therapeutics San Diego, CA ATA520 Atara Biotherapeutics multiple myeloma, Phase I (WT1-specific T lymphocyte South San Francisco, CA plasma cell leukemia www.atarabio.com
    [Show full text]
  • The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer
    Journal of Clinical Medicine Review The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer Ramon Andrade De Mello 1,2,3,* , Nathália Moisés Neves 2 , Giovanna Araújo Amaral 2, Estela Gudin Lippo 4, Pedro Castelo-Branco 1, Daniel Humberto Pozza 5 , Carla Chizuru Tajima 6 and Georgios Antoniou 7 1 Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine University of Algarve (DCBM UALG), 8005-139 Faro, Portugal; [email protected] 2 Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil; [email protected] (N.M.N.); [email protected] (G.A.A.) 3 Precision Oncology and Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo 01525-000, Brazil 4 School of Biomedical Sciences, Santo Amaro University, São Paulo 01525-000, Brazil; [email protected] 5 Department of Biomedicine & I3S, Faculty of Medicine, University of Porto (FMUP), 4200-317 Porto, Portugal; [email protected] 6 Hospital São José & Hospital São Joaquim, A Beneficência Portuguesa de São Paulo, São Paulo 01323-001, Brazil; [email protected] 7 Division of Medical Oncology, Mount Vernon Cancer Center, London HA6 2RN, UK; [email protected] * Correspondence: [email protected] Received: 15 May 2020; Accepted: 10 June 2020; Published: 19 June 2020 Abstract: Introduction: Non-small cell lung cancer (NSCLC) is the second most common cancer globally. The mesenchymal-epithelial transition (MET) proto-oncogene can be targeted in NSCLC patients. Methods: We performed a literature search on PubMed in December 2019 for studies on MET inhibitors and NSCLC.
    [Show full text]
  • Atezolizumab Plus Nab-Paclitaxel As First-Line Treatment for Unresectable, Locally Advanced Or Metastatic Triple-Negative Breast
    Articles Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial Peter Schmid*, Hope S Rugo*, Sylvia Adams, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Véronique Diéras, Volkmar Henschel, Luciana Molinero, Stephen Y Chui, Vidya Maiya, Amreen Husain, Eric P Winer, Sherene Loi, Leisha A Emens, for the IMpassion130 Investigators† Summary Lancet Oncol 2020; 21: 44–59 Background Immunotherapy in combination with chemotherapy has shown promising efficacy across many different Published Online tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study November 27, 2019 assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or https://doi.org/10.1016/ metastatic triple-negative breast cancer. S1470-2045(19)30689-8 See Comment page 3 Methods In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and *Contributed equally community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically †Investigators are listed in the documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group appendix performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method Barts Cancer Institute, Queen Mary University of London, (block size of four) and an interactive voice–web response system. Randomisation was stratified by previous taxane London, UK (Prof P Schmid MD); use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells.
    [Show full text]
  • The Two Tontti Tudiul Lui Hi Ha Unit
    THETWO TONTTI USTUDIUL 20170267753A1 LUI HI HA UNIT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017 /0267753 A1 Ehrenpreis (43 ) Pub . Date : Sep . 21 , 2017 ( 54 ) COMBINATION THERAPY FOR (52 ) U .S . CI. CO - ADMINISTRATION OF MONOCLONAL CPC .. .. CO7K 16 / 241 ( 2013 .01 ) ; A61K 39 / 3955 ANTIBODIES ( 2013 .01 ) ; A61K 31 /4706 ( 2013 .01 ) ; A61K 31 / 165 ( 2013 .01 ) ; CO7K 2317 /21 (2013 . 01 ) ; (71 ) Applicant: Eli D Ehrenpreis , Skokie , IL (US ) CO7K 2317/ 24 ( 2013. 01 ) ; A61K 2039/ 505 ( 2013 .01 ) (72 ) Inventor : Eli D Ehrenpreis, Skokie , IL (US ) (57 ) ABSTRACT Disclosed are methods for enhancing the efficacy of mono (21 ) Appl. No. : 15 /605 ,212 clonal antibody therapy , which entails co - administering a therapeutic monoclonal antibody , or a functional fragment (22 ) Filed : May 25 , 2017 thereof, and an effective amount of colchicine or hydroxy chloroquine , or a combination thereof, to a patient in need Related U . S . Application Data thereof . Also disclosed are methods of prolonging or increasing the time a monoclonal antibody remains in the (63 ) Continuation - in - part of application No . 14 / 947 , 193 , circulation of a patient, which entails co - administering a filed on Nov. 20 , 2015 . therapeutic monoclonal antibody , or a functional fragment ( 60 ) Provisional application No . 62/ 082, 682 , filed on Nov . of the monoclonal antibody , and an effective amount of 21 , 2014 . colchicine or hydroxychloroquine , or a combination thereof, to a patient in need thereof, wherein the time themonoclonal antibody remains in the circulation ( e . g . , blood serum ) of the Publication Classification patient is increased relative to the same regimen of admin (51 ) Int .
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub
    US 20170172932A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub. Date: Jun. 22, 2017 (54) EARLY CANCER DETECTION AND A 6LX 39/395 (2006.01) ENHANCED IMMUNOTHERAPY A61R 4I/00 (2006.01) (52) U.S. Cl. (71) Applicant: Gholam A. Peyman, Sun City, AZ CPC .......... A61K 9/50 (2013.01); A61K 39/39558 (US) (2013.01); A61K 4I/0052 (2013.01); A61 K 48/00 (2013.01); A61K 35/17 (2013.01); A61 K (72) Inventor: sham A. Peyman, Sun City, AZ 35/15 (2013.01); A61K 2035/124 (2013.01) (21) Appl. No.: 15/143,981 (57) ABSTRACT (22) Filed: May 2, 2016 A method of therapy for a tumor or other pathology by administering a combination of thermotherapy and immu Related U.S. Application Data notherapy optionally combined with gene delivery. The combination therapy beneficially treats the tumor and pre (63) Continuation-in-part of application No. 14/976,321, vents tumor recurrence, either locally or at a different site, by filed on Dec. 21, 2015. boosting the patient’s immune response both at the time or original therapy and/or for later therapy. With respect to Publication Classification gene delivery, the inventive method may be used in cancer (51) Int. Cl. therapy, but is not limited to such use; it will be appreciated A 6LX 9/50 (2006.01) that the inventive method may be used for gene delivery in A6 IK 35/5 (2006.01) general. The controlled and precise application of thermal A6 IK 4.8/00 (2006.01) energy enhances gene transfer to any cell, whether the cell A 6LX 35/7 (2006.01) is a neoplastic cell, a pre-neoplastic cell, or a normal cell.
    [Show full text]
  • Selpercatinib LOXO-292 LY3527723
    Selpercatinib LOXO-292 LY3527723 RET INHIBITOR Selpercatinib, LOXO-292, LY3527723 | RET INHIBITOR Target Rearranged during transfection (RET) fusions have been identified in approximately 2% of non-small cell lung cancer,2,3 10% to 20% of papillary thyroid cancer,4,5 and a subset of colon and other cancers.6-8 RET point mutations account for approximately 60% of medullary thyroid cancer.9-11 Cancers that harbor activating RET fusions or RET mutations depend primarily on this single constitutively activated kinase for their proliferation and survival. This dependency renders such tumors highly susceptible to small-molecule inhibitors targeting RET. Molecule Selpercatinib (LOXO-292, LY3527723) is a highly selective, potent, CNS-active small-molecule inhibitor of RET. Selpercatinib possesses nanomolar potency against diverse RET alterations, including RET fusions, activating RET point mutations, and acquired resistance mutations. Selpercatinib has been shown in vitro and in vivo to exhibit high selectivity for RET, with limited activity against other tyrosine kinases.12,13 Clinical Development Selpercatinib is being investigated in clinical trials in patients with medullary thyroid cancer, non-small cell lung cancer, papillary thyroid carcinoma, pediatric cancer, or other advanced solid tumors. References: 1. Mulligan LM. Nat Rev Cancer. 2014;14:173-186. 2. Lipson D, et al. Nat Med. 2012;18(3):382-384. 3. Takeuchi K, et al. Nat Med. 2012;18(3):378-381. 4. Bounacer A, et al. Oncogene. 1997;15(11):1263-1273. 5. Prescott JD, Zeiger MA. Cancer. 2015;121(13):2137-2146. 6. Ballerini P, et al. Leukemia. 2012;26(11):2384-2389. 7. Bossi D, et al.
    [Show full text]
  • Prescribing Information
    HIGHLIGHTS OF PRESCRIBING INFORMATION • QT Interval Prolongation: Monitor patients who are at significant risk of These highlights do not include all the information needed to use developing QTc prolongation. Assess QT interval, electrolytes and TSH at RETEVMO safely and effectively. See full prescribing information for baseline and periodically during treatment. Monitor QT interval more RETEVMO. frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. RETEVMOTM (selpercatinib) capsules, for oral use Withhold and dose reduce or permanently discontinue RETEVMO based Initial U.S. Approval: 2020 on severity. (2.5, 5.3) • Hemorrhagic Events: Permanently discontinue RETEVMO in patients ----------------------------INDICATIONS AND USAGE--------------------------­ with severe or life-threatening hemorrhage. (2.5, 5.4) RETEVMO is a kinase inhibitor indicated for the treatment of: • Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon • Adult patients with metastatic RET fusion-positive non-small cell lung resolution, resume at a reduced dose and increase dose by 1 dose level cancer (NSCLC)1 (1.1) each week until reaching the dose taken prior to onset of hypersensitivity. • Adult and pediatric patients 12 years of age and older with advanced or Continue steroids until patient reaches target dose and then taper. (2.5, 5.5) metastatic RET-mutant medullary thyroid cancer (MTC) who require • Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days systemic therapy1 (1.2) prior to elective surgery. Do not administer for at least 2 weeks following • Adult and pediatric patients 12 years of age and older with advanced or major surgery and until adequate wound healing.
    [Show full text]