Literature DB >> 33296125

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer.

Emilie M J van Brummelen1, Sanne Huijberts1, Carla van Herpen2, Ingrid Desar2, Frans Opdam3, Robin van Geel1,4, Serena Marchetti3, Neeltje Steeghs3, Kim Monkhorst5, Bas Thijssen6, Hilde Rosing6, Alwin Huitema6,7, Jos Beijnen6,8, Rene Bernards9,8, Jan Schellens8.   

Abstract

LESSONS LEARNED: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined.
BACKGROUND: Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase-AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors.
METHODS: Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy.
RESULTS: Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response.
CONCLUSION: Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Entities:  

Keywords:  Afatinib; Colorectal cancer; KRAS; Non-small cell lung cancer; Pancreatic cancer; Selumetinib

Year:  2020        PMID： 33296125      PMCID： PMC8018304          DOI： 10.1002/onco.13631

Source DB:  PubMed          Journal:  Oncologist        ISSN： 1083-7159


  10 in total

1.  Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3.

Authors:  Chong Sun; Sebastijan Hobor; Andrea Bertotti; Davide Zecchin; Sidong Huang; Francesco Galimi; Francesca Cottino; Anirudh Prahallad; Wipawadee Grernrum; Anna Tzani; Andreas Schlicker; Lodewyk F A Wessels; Egbert F Smit; Erik Thunnissen; Pasi Halonen; Cor Lieftink; Roderick L Beijersbergen; Federica Di Nicolantonio; Alberto Bardelli; Livio Trusolino; Rene Bernards
Journal:  Cell Rep       Date:  2014-03-27       Impact factor: 9.423

2.  Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.

Authors:  J C-H Yang; L V Sequist; C Zhou; M Schuler; S L Geater; T Mok; C-P Hu; N Yamamoto; J Feng; K O'Byrne; S Lu; V Hirsh; Y Huang; M Sebastian; I Okamoto; N Dickgreber; R Shah; A Märten; D Massey; S Wind; Y-L Wu
Journal:  Ann Oncol       Date:  2016-09-06       Impact factor: 32.976

3.  KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.

Authors:  Michael R Burgess; Eugene Hwang; Rana Mroue; Craig M Bielski; Anica M Wandler; Benjamin J Huang; Ari J Firestone; Amy Young; Jennifer A Lacap; Lisa Crocker; Saurabh Asthana; Elizabeth M Davis; Jin Xu; Keiko Akagi; Michelle M Le Beau; Qing Li; Benjamin Haley; David Stokoe; Deepak Sampath; Barry S Taylor; Marie Evangelista; Kevin Shannon
Journal:  Cell       Date:  2017-02-16       Impact factor: 41.582

4.  Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer.

Authors:  Sanne C F A Huijberts; Robin M J M van Geel; Emilie M J van Brummelen; Frans L Opdam; Serena Marchetti; Neeltje Steeghs; Saskia Pulleman; Bas Thijssen; Hilde Rosing; Kim Monkhorst; Alwin D R Huitema; Jos H Beijnen; René Bernards; Jan H M Schellens
Journal:  Cancer Chemother Pharmacol       Date:  2020-04-09       Impact factor: 3.333

5.  Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial.

Authors:  Pasi A Jänne; Michel M van den Heuvel; Fabrice Barlesi; Manuel Cobo; Julien Mazieres; Lucio Crinò; Sergey Orlov; Fiona Blackhall; Juergen Wolf; Pilar Garrido; Artem Poltoratskiy; Gabriella Mariani; Dana Ghiorghiu; Elaine Kilgour; Paul Smith; Alexander Kohlmann; David J Carlile; David Lawrence; Karin Bowen; Johan Vansteenkiste
Journal:  JAMA       Date:  2017-05-09       Impact factor: 56.272

6.  SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo.

Authors:  Sara Mainardi; Antonio Mulero-Sánchez; Anirudh Prahallad; Giovanni Germano; Astrid Bosma; Paul Krimpenfort; Cor Lieftink; Jeffrey D Steinberg; Niels de Wit; Samuel Gonçalves-Ribeiro; Ernest Nadal; Alberto Bardelli; Alberto Villanueva; Rene Bernards
Journal:  Nat Med       Date:  2018-05-28       Impact factor: 53.440

7.  Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer.

Authors:  H S Hochster; N Uboha; W Messersmith; P J Gold; B H ONeil; D Cohen; C Denlinger; S Cohen; C G Leichman; L Leichman; H-J Lenz
Journal:  Cancer Chemother Pharmacol       Date:  2014-10-17       Impact factor: 3.333

8.  Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models.

Authors:  Ryan B Corcoran; Katherine A Cheng; Aaron N Hata; Anthony C Faber; Hiromichi Ebi; Erin M Coffee; Patricia Greninger; Ronald D Brown; Jason T Godfrey; Travis J Cohoon; Youngchul Song; Eugene Lifshits; Kenneth E Hung; Toshi Shioda; Dora Dias-Santagata; Anurag Singh; Jeffrey Settleman; Cyril H Benes; Mari Mino-Kenudson; Kwok-Kin Wong; Jeffrey A Engelman
Journal:  Cancer Cell       Date:  2012-12-13       Impact factor: 31.743

9.  RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.

Authors:  Robert J Nichols; Franziska Haderk; Carlos Stahlhut; Christopher J Schulze; Golzar Hemmati; David Wildes; Christos Tzitzilonis; Kasia Mordec; Abby Marquez; Jason Romero; Tientien Hsieh; Aubhishek Zaman; Victor Olivas; Caroline McCoach; Collin M Blakely; Zhengping Wang; Gert Kiss; Elena S Koltun; Adrian L Gill; Mallika Singh; Mark A Goldsmith; Jacqueline A M Smith; Trever G Bivona
Journal:  Nat Cell Biol       Date:  2018-08-13       Impact factor: 28.824

10.  Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer.

Authors:  Robin M J M van Geel; Emilie M J van Brummelen; Sanne C F A Huijberts; Ferry A L M Eskens; Filip Y F L de Vos; Martijn P J K Lolkema; Lot A Devriese; Frans L Opdam; Serena Marchetti; Neeltje Steeghs; Kim Monkhorst; Bas Thijssen; Hilde Rosing; Alwin D R Huitema; Jos H Beijnen; René Bernards; Jan H M Schellens
Journal:  Br J Cancer       Date:  2020-03-09       Impact factor: 7.640
  10 in total
  5 in total

1.  Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options.

Authors:  Daniel Alexander Hescheler; Milan Janis Michael Hartmann; Burkhard Riemann; Maximilian Michel; Christiane Josephine Bruns; Hakan Alakus; Costanza Chiapponi
Journal:  Cancers (Basel)       Date:  2022-05-31       Impact factor: 6.575

2.  Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy.

Authors:  Abdulaziz A Almotlak; Mariya Farooqui; Adam C Soloff; Jill M Siegfried; Laura P Stabile
Journal:  Int J Mol Sci       Date:  2021-12-22       Impact factor: 5.923

Review 3.  Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.

Authors:  Thomas Yul Avery; Natalie Köhler; Robert Zeiser; Tilman Brummer; Dietrich Alexander Ruess
Journal:  Front Oncol       Date:  2022-07-27       Impact factor: 5.738

4.  Pre-Training on In Vitro and Fine-Tuning on Patient-Derived Data Improves Deep Neural Networks for Anti-Cancer Drug-Sensitivity Prediction.

Authors:  Paul Prasse; Pascal Iversen; Matthias Lienhard; Kristina Thedinga; Ralf Herwig; Tobias Scheffer
Journal:  Cancers (Basel)       Date:  2022-08-16       Impact factor: 6.575

5.  Identification of a lncRNA based signature for pancreatic cancer survival to predict immune landscape and potential therapeutic drugs.

Authors:  Di Ma; Yuchen Yang; Qiang Cai; Feng Ye; Xiaxing Deng; Baiyong Shen
Journal:  Front Genet       Date:  2022-09-14       Impact factor: 4.772
  5 in total

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