Abstract
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. Although preliminary signs of antitumou...Continue Reading
References
Aug 12, 1994·Science·S J MansourN G Ahn
Jan 2, 2003·Nature Reviews. Cancer·Julian Downward
Apr 9, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alex A AdjeiS Gail Eckhardt
Nov 26, 2008·Nature Medicine·Jeffrey A EngelmanKwok-Kin Wong
Dec 23, 2008·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·E A EisenhauerJ Verweij
Mar 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Patricia M LoRussoAlejandro D Ricart
Mar 25, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Eric B HauraShirish M Gadgeel
Jan 12, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pasi A JänneJan H M Schellens
Oct 19, 2011·Future Medicinal Chemistry·Antonio T BainesChanning J Der
Jan 28, 2012·Nature·Anirudh PrahalladRené Bernards
Mar 7, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Giorgia MigliardiAndrea Bertotti
Mar 27, 2012·Cancer Discovery·Ryan B CorcoranJeffrey A Engelman
Oct 30, 2012·Cell·René Bernards
Dec 4, 2012·The Lancet Oncology·Pasi A JänneLucio Crinò
Apr 2, 2014·Cell Reports·Chong SunRene Bernards
Oct 18, 2014·Cancer Chemotherapy and Pharmacology·H S HochsterH-J Lenz
Dec 2, 2014·Nature Reviews. Drug Discovery·Ahmed A Samatar, Poulikos I Poulikakos
Apr 2, 2017·Cancer Discovery·Robin M J M van GeelJan H M Schellens
May 12, 2017·JAMA : the Journal of the American Medical Association·Pasi A JänneJohan Vansteenkiste
Oct 1, 2019·The New England Journal of Medicine·Scott KopetzJosep Tabernero
Nov 2, 2019·Nature·Jude CanonJ Russell Lipford
Citations
Sep 19, 2020·Expert Review of Gastroenterology & Hepatology·Jose Carlos RuffinelliVictor Moreno
Dec 10, 2020·The Oncologist·Emilie M J van BrummelenJan Schellens
May 19, 2021·Nature Reviews. Drug Discovery·Philip CohenPasi A Jänne