DOCSLIB.ORG

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: the VIKTORY Umbrella Trial

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: the VIKTORY Umbrella Trial Published OnlineFirst July 17, 2019; DOI: 10.1158/2159-8290.CD-19-0442 RESEARCH ARTICLE Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial Jeeyun Lee1, Seung Tae Kim1, Kyung Kim1, Hyuk Lee2, Iwanka Kozarewa3, Peter G.S. Mortimer4, Justin I. Odegaard5, Elizabeth A. Harrington3, Juyoung Lee1, Taehyang Lee1, Sung Yong Oh6, Jung-Hun Kang7, Jung Hoon Kim8, Youjin Kim9, Jun Ho Ji9, Young Saing Kim10, Kyoung Eun Lee11, Jinchul Kim1, Tae Sung Sohn12, Ji Yeong An12, Min-Gew Choi12, Jun Ho Lee12, Jae Moon Bae12, Sung Kim12, Jae J. Kim2, Yang Won Min2, Byung-Hoon Min2, Nayoung K.D. Kim13,4, Sally Luke3, Young Hwa Kim4, Jung Yong Hong1, Se Hoon Park1, Joon Oh Park1, Young Suk Park1, Ho Yeong Lim1, AmirAli Talasaz5, Simon J. Hollingsworth14, Kyoung-Mee Kim15, and Won Ki Kang1 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 17, 2019; DOI: 10.1158/2159-8290.CD-19-0442 ABSTRACT The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative,TSC2 deficient, orRIC - TOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), ada- vosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was success- fully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. SIGNIFICANCE: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. INTRODUCTION It has been suggested by previous studies that this interpa- tient tumor molecular heterogeneity may affect the outcomes Recent advances in molecular analysis have revealed that of clinical trials, especially with molecularly targeted agents there are patient subsets with differing genomic alterations (4, 5). To deliver a more tailored approach for each patient, despite the same histologic diagnosis in gastric cancer (1–3). umbrella or platform clinical trials have been developed (6, 7), which assign treatment arms based on the molecular charac- teristics of the tumor. 1Division of Hematology-Oncology, Department of Medicine, Samsung Gastric cancer was the third leading cause of cancer- Medical Center, Sungkyunkwan University School of Medicine, Seoul, related mortality in 2018, causing 783,000 deaths world- 2 Korea. Division of Gastroenterology, Department of Medicine, Samsung wide (8). The prognosis of patients with metastatic gastric Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 3Oncology Translational Sciences, IMED Biotech Unit, AstraZeneca, cancer remains extremely poor, with a median overall sur- Cambridge, United Kingdom. 4Clinical, Research and Early Development, vival (OS) of less than 12 months with cytotoxic chemo- Oncology R&D, AstraZeneca, Cambridge, United Kingdom. 5Guardant therapy (9, 10). In addition, gastric cancer is a disease with Health, Redwood, California. 6Dong-A University School of Medicine, significant molecular and histologic heterogeneity (1, 3, 7 Busan, Korea. Department of Internal Medicine, College of Medicine, 11), in which advancements based on “one-size-fits-all” Gyeongsang National University, Jinju, Korea. 8Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, clinical trials have yielded only modest survival benefits. Korea. 9Division of Hematology-Oncology, Samsung Changwon Hospital, To identify optimal molecular targets and optimal bio- Sungkyunkwan University School of Medicine, Changwon, Korea. 10Depart- markers, we designed an umbrella trial for second-line ment of Internal Medicine, Gachon University Gil Medical Center, Incheon, (2L) treatment in metastatic gastric cancer based on tumor Republic of Korea. 11Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University, Seoul, Korea. 12Department molecular profiling. We took advantage of an umbrella trial of Surgery, Samsung Medical Center, Sungkyunkwan University School design where patients of a single tumor type are directed of Medicine, Seoul, Korea. 13Samsung Genome Institute, Seoul, Korea. toward different arms of the study based on the tumor 14Oncology Business Unit, AstraZeneca, Cambridge, United Kingdom. molecular biomarkers relevant to one or more of the can- 15 Department of Pathology & Translational Genomics, Samsung Medical didate drugs (12). VIKTORY (targeted agent eValuation Center, Sungkyunkwan University School of Medicine, Seoul, Korea. In gastric cancer basket KORea, trial NCT#02299648) was Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). designed to classify patients with metastatic gastric cancer based on clinical sequencing and comprised eight different S.T. Kim, K. Kim, H. Lee, and I. Kozarewa contributed equally to this article. biomarker groups (RAS aberration, TP53 mutation, PIK3CA Corresponding Authors: Jeeyun Lee, Samsung Medical Center, Sungky- unkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul mutation/amplification, MET amplification, MET protein 06351, Korea. Phone: 822-3410-1779; Fax: 822-3410-1754; E-mail: overexpression, all negative, TSC2 deficient, orRICTOR [email protected]; Kyoung-Mee Kim, [email protected]; and Won Ki amplification) to assign patients to one of the 10 associ- Kang, [email protected] ated phase II clinical trials in 2L treatment. The study drugs Cancer Discov 2019;9:1–18 used were capivasertib (AKT inhibitor), savolitinib (MET doi: 10.1158/2159-8290.CD-19-0442 inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 ©2019 American Association for Cancer Research. inhibitor), and vistusertib (TORC inhibitor). The umbrella OCTOBER 2019 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 17, 2019; DOI: 10.1158/2159-8290.CD-19-0442 RESEARCH ARTICLE Lee et al. design was based on the preclinical evidence of known The primary tumor was located in the body (53.2%) or molecular alterations, the prevalence of molecular altera- antrum (37.7%) of the stomach in the majority of patients. tions, and the availability of the targeted agents for clinical All patients underwent 1L cytotoxic chemotherapy (>85% trials from AstraZeneca at the time of the study design. The with fluoropyrimidine/platinum regimen). In all, 460 of candidate molecular alterations for the umbrella trial at 715 patients (64.3%) were eligible for 2L therapies: 143 of the time of clinical trial design were molecular alterations 715 (20.6%) were assigned to one of the umbrella-associated in the p53, PIK3CA, MET, EGFR, FGFR2, RAS, and DDR parallel clinical trials in 2L (105 with Biomarker A–E or G; 38 pathways (3). Adavosertib is one of the most potent inhibi- with Biomarker F, unselected), whereas 317 patients received tors targeting WEE1 (13), which is a tyrosine kinase that conventional treatment or treatment via other clinical trials phosphorylates cyclin-dependent kinase 1 (CDK1, CDC2) (Figs. 1B and 2A). to inactivate the CDC2/cyclin B complex (14). Inhibition of WEE1 activity prevents the phosphorylation of CDC2 Tumor Genome Profiling and impairs the G2 DNA-damage checkpoint, leading to The tumor profiles of the 715 patients are shown in Sup- cancer-cell death. Preclinical studies have demonstrated plementary Fig. S1, and the detailed sequencing method is a very promising antitumor efficacyin vivo, especially in provided in the Supplementary Material. The prevalence combination with other cytotoxic chemotherapeutic agents of the predefined biomarkers was as follows (Fig. 2B): Bio- (15) including paclitaxel (16). Capivasertib is a selective marker A1: RAS mutation/amplification (81/715, 12.2%; pan-AKT inhibitor that inhibits the kinase activity of all KRAS 62/715, 8.7%; HRAS 6/715, 0.8%; NRAS 19/715, 2.7%); three AKT isoforms (AKT1–3; ref. 17). Preclinically, sensi- Biomarker A2: high or low MEK signature (49/107, 45.8%); tivity to capivasertib has been strongly correlated with the Biomarker B: TP53 mutation (321/715, 44.9%); Biomarker presence of PIK3CA mutations in gastric cancer models (18, C: PIK3CA mutation/amplification (54/715, 7.6%); Bio- 19). Savolitinib is a potent small-molecule reversible MET marker D: MET amplification (25/715, 3.5%); Biomarker E: kinase inhibitor that inhibits MET kinase at an IC50 of 4 MET overexpression by IHC 3+ (42/479, 8.8%); Biomarker
Load more

Recommended publications
  • 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]
  • Crusader Newsletter Q2 2021 Research Edition
    Your resource for the latest research into the MET alteration. CRUSADER NEWSLETTER Q2 2021 RESEARCH EDITION MET Crusaders is a community of Lung Cancer patients and care givers collaborating with advocates and medical professionals collectively dedicated to helping patients with a MET alteration live normal lives. Come Join Us! www.metcrusaders.org Contact us at In this edition [email protected] Co-occurring MET amplification predicts ....... 2 MET amplification attenuates lung tumor ...... 9 inferior clinical response to first line erlotinib in response to immunotherapy by inhibiting STING advanced stage EGFR-mutated NSCLC patients Once-daily savolitinib in Chinese patients .... 10 Tepotinib in patients with NSCLC harbouring .... 3 with pulmonary sarcomatoid carcinomas and MET exon 14 skipping: Japanese subset other non-small-cell lung cancers harbouring EDITOR analysis from the Phase II VISION study MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study Jessica McKernan, PharmD A Phase II Study of Telisotuzumab Vedotin ..... 4 Atrium Health, Charlotte, NC in Patients With c-MET-positive Stage IV or Phase I results of S49076 plus gefitinib in ...... 11 Recurrent Squamous Cell Lung Cancer patients with EGFR TKI-resistant non-small cell (LUNG-MAP Sub-study S1400K, NCT03574753) lung cancer harbouring MET/AXL dysregulation CONTRIBUTING EDITORS Julia Stevens, PharmD Durvalumab consolidation therapy in a ............ 5 Case Report: High-Level MET Amplification .... 12 patient with stage IIIB unresectable NSCLC as a Resistance Mechanism of ROS1-Tyrosine Beth Israel Deaconess harboring a MET exon 14 splice site alteration Kinase Inhibitors in ROS1-Rearranged Medical Center, Boston, MA Non-Small Cell Lung Cancer Early Alectinib Resistance From MET ..............
    [Show full text]
  • 2018 Interim Results
    2018 Interim Results AIM/Nasdaq: HCM July 27, 2018 Safe harbor statement & disclaimer The performance and results of operations of the Chi-Med 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” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements can be identified by words like “will,” “expects,” “anticipates,” “future,” “intends,” “plans,” “believes,” “estimates,” “pipeline,” “could,” “potential,” “believe,” “first-in-class,” “best-in-class,” “designed to,” “objective,” “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 or intentions. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that any of our drug candidates will be approved for sale in any market, or that any approvals which are obtained will be obtained at any particular time, or that
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Therapeutic Strategies in MET Exon 14 Skipping Mutated Non-Small Cell
    Drusbosky et al. J Hematol Oncol (2021) 14:129 https://doi.org/10.1186/s13045-021-01138-7 REVIEW Open Access Therapeutic strategies in METex14 skipping mutated non-small cell lung cancer Leylah M. Drusbosky2, Richa Dawar3, Estelamari Rodriguez3 and Chukwuemeka V. Ikpeazu1,3* Abstract METex14 skipping mutations occur in about 3–4% of lung adenocarcinoma patients and 1–2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated signifcant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profle. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efcacy in the frst- and second-line settings, including patients with aggressive pulmonary sarcoma- toid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the devel- opment of acquired resistance.
    [Show full text]
  • Download Presentation (PDF)
    INVESTOR UPDATE R&D, COMMERCIAL AND ASCO UPDATE WEBCAST May 26, 2021 Nasdaq / AIM: HCM 1 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” firms, including Frost & Sullivan, IQVIA, independent market research firms, clinical data of competitors, provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements and other publicly available data. All patient population, market size and market share estimates are can be identified by words like “will,” “expects,” “anticipates,” “future,” “intends,” “plans,” “believes,” based on Frost & Sullivan or QuintilesIMS/IQVIA research, unless otherwise noted. Although HUTCHMED “estimates,” “pipeline,” “could,” “potential,” “first-in-class,” “best-in-class,” “designed to,” “objective,” believes that the publications, reports, surveys and third-party clinical data are reliable, HUTCHMED has “guidance,” “pursue,” or similar terms, or by express or implied discussions regarding potential drug not independently verified the data and cannot guarantee the accuracy or completeness of such data. candidates, potential indications for drug candidates or by discussions of strategy, plans, expectations You are cautioned not to give undue weight to this data. Such data involves risks and uncertainties and or intentions. You should not place undue reliance on these statements. Such forward-looking are subject to change based on various factors, including those discussed above. statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties.
    [Show full text]
  • Efficacy of Savolitinib Vs Sunitinib in Patients with MET-Driven Papillary Renal Cell Carcinoma the SAVOIR Phase 3 Randomized Clinical Trial
    Research JAMA Oncology | Original Investigation Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma The SAVOIR Phase 3 Randomized Clinical Trial Toni K. Choueiri, MD; Daniel Y. C. Heng, MD; Jae Lyun Lee, MD; Mathilde Cancel, MD; Remy B. Verheijen, PhD; Anders Mellemgaard, MD; Lone H. Ottesen, MD; Melanie M. Frigault, PhD; Anne L’Hernault, PhD; Zsolt Szijgyarto, PhD; Sabina Signoretti, MD; Laurence Albiges, MD Visual Abstract IMPORTANCE Papillary renal cell carcinoma (PRCC) is the most common type of non–clear Supplemental content cell RCC. Because some cases of PRCC are MET-driven, MET inhibition could be a targeted treatment approach. In previous studies, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in this patient group. OBJECTIVE To determine whether savolitinib is a better treatment option for this patient population, vs standard of care, sunitinib. DESIGN, SETTING, AND PARTICIPANTS The SAVOIR phase 3, open-label, randomized clinical trial was a multicenter study carried out in 32 centers in 7 countries between July 2017 and the data cutoff in August 2019. Overall, 360 to 450 patients were to be screened, to randomize approximately 180 patients. Patients were adults with MET-driven (centrally confirmed), metastatic PRCC, with 1 or more measurable lesions. Exclusion criteria included prior receipt of sunitinib or MET inhibitor treatment. Overall, 254 patients were screened. INTERVENTIONS Patients received 600 mg of savolitinib orally once daily (qd), or 50 mg of sunitinib orally qd for 4 weeks, followed by 2 weeks without treatment. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS, assessed by investigator and confirmed by blinded independent central review).
    [Show full text]
  • Small-Cell Lung Cancer: Evidence to Date Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid
    Targeting the MET-Signaling Pathway in Non- Small-Cell Lung Cancer: Evidence to Date Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid To cite this version: Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid. Targeting the MET-Signaling Pathway in Non- Small-Cell Lung Cancer: Evidence to Date. OncoTargets and Therapy, Dove Medical Press, 2020, Volume 13, pp.5691-5706. 10.2147/OTT.S219959. hal-02886104 HAL Id: hal-02886104 https://hal.sorbonne-universite.fr/hal-02886104 Submitted on 1 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Targeting the MET-Signaling Pathway in Non- Small–Cell Lung Cancer: Evidence to Date This article was published in the following Dove Press journal: OncoTargets and Therapy Olivier Bylicki 1,2 Abstract: The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, Nicolas Paleiron1 affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small–cell – Jean-Baptiste Assié2 4 lung cancer (NSCLC) is a potential therapeutic target. The development of high-output next- fi Christos Chouaïd2,3 generation sequencing techniques has enabled better identi cation of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation.
    [Show full text]
  • Tyrosine Kinase Inhibitors for Solid Tumors in the Past 20 Years (2001–2020) Liling Huang†, Shiyu Jiang† and Yuankai Shi*
    Huang et al. J Hematol Oncol (2020) 13:143 https://doi.org/10.1186/s13045-020-00977-0 REVIEW Open Access Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020) Liling Huang†, Shiyu Jiang† and Yuankai Shi* Abstract Tyrosine kinases are implicated in tumorigenesis and progression, and have emerged as major targets for drug discovery. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Over the past 20 years, multiple robust and well-tolerated TKIs with single or multiple targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT have been developed, contributing to the realization of precision cancer medicine based on individual patient’s genetic alteration features. TKIs have dramatically improved patients’ survival and quality of life, and shifted treatment paradigm of various solid tumors. In this article, we summarized the developing history of TKIs for treatment of solid tumors, aiming to provide up-to-date evidence for clinical decision-making and insight for future studies. Keywords: Tyrosine kinase inhibitors, Solid tumors, Targeted therapy Introduction activation of tyrosine kinases due to mutations, translo- According to GLOBOCAN 2018, an estimated 18.1 cations, or amplifcations is implicated in tumorigenesis, million new cancer cases and 9.6 million cancer deaths progression, invasion, and metastasis of malignancies. occurred in 2018 worldwide [1]. Targeted agents are In addition, wild-type tyrosine kinases can also func- superior to traditional chemotherapeutic ones in selec- tion as critical nodes for pathway activation in cancer.
    [Show full text]
  • MEK Inhibitors for the Treatment of Non-Small Cell Lung Cancer
    Han et al. J Hematol Oncol (2021) 14:1 https://doi.org/10.1186/s13045-020-01025-7 REVIEW Open Access MEK inhibitors for the treatment of non-small cell lung cancer Jing Han1†, Yang Liu2†, Sen Yang1, Xuan Wu1, Hongle Li3* and Qiming Wang1* Abstract BRAF and KRAS are two key oncogenes in the RAS/RAF/MEK/MAPK signaling pathway. Concomitant mutations in both KRAS and BRAF genes have been identifed in non-small cell lung cancer (NSCLC). They lead to the prolifera- tion, diferentiation, and apoptosis of tumor cells by activating the RAS/RAF/MEK/ERK signaling pathway. To date, agents that target RAS/RAF/MEK/ERK signaling pathway have been investigated in NSCLC patients harboring BRAF mutations. BRAF and MEK inhibitors have gained approval for the treatment of patients with NSCLC. According to the reported fndings, the combination of MEK inhibitors with chemotherapy, immune checkpoint inhibitors, epidermal growth factor receptor-tyrosine kinase inhibitors or BRAF inhibitors is highly signifcant for improving clinical efcacy and causing delay in the occurrence of drug resistance. This review summarized the existing experimental results and presented ongoing clinical studies as well. However, further researches need to be conducted to indicate how we can combine other drugs with MEK inhibitors to signifcantly increase therapeutic efects on patients with lung cancer. Keywords: Non-small cell lung cancer, MEK inhibitors, Targeted therapy, RAS, RAF, MEK, ERK signaling pathway Introduction as squamous cell carcinoma, adenocarcinoma, large cell Lung cancer is the most common cause of cancer-related or undiferentiated carcinoma. Non-squamous carci- death worldwide, with over 1.8 million lung cancer deaths noma (70–75%) and squamous cell carcinoma (25–30%) annually [1].
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma
    cancers Review Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma Pierangela Sepe *, Arianna Ottini , Chiara Carlotta Pircher, Andrea Franza, Melanie Claps, Valentina Guadalupi, Elena Verzoni and Giuseppe Procopio Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milan, Italy; [email protected] (A.O.); [email protected] (C.C.P.); [email protected] (A.F.); [email protected] (M.C.); [email protected] (V.G.); [email protected] (E.V.); [email protected] (G.P.) * Correspondence: [email protected] Simple Summary: Non-clear cell renal cell carcinomas (ncRCC) make up a heterogeneous group subclassified into different subtypes that differ in genetic and biochemical characteristics from each other and from ccRCC. ncRCC are a rare finding in clinical practice, and no standard-of-care has yet been established. Treatment choices are in fact based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. The aim of this review is to supplyt precise recommendations for each histological type focusing on pathogenetic mechanisms of nc-RCC, summarizing the therapeutic strategies adopted over the last few decades, and exploring the emerging role of immunotherapy and new targeted drugs as future potential treatment options. Abstract: Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described Citation: Sepe, P.; Ottini, A.; Pircher, diseases, often characterized by bad prognosis and with no standard treatments available. The C.C.; Franza, A.; Claps, M.; gap in their clinical management is linked to the poor molecular characterization in handling the Guadalupi, V.; Verzoni, E.; Procopio, treatment of non clear-cell RCC with untailored therapies.
    [Show full text]