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

Robin M. J. M. van Geel, Emilie M. J. van Brummelen, Ferry A. L. M. Eskens, Sanne C. F. A. Huijberts*, 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, Rene Bernards, Jan H. M. Schellens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)

Abstract

Background 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). Methods 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). Results 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. Conclusions Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.

Original languageEnglish
Pages (from-to)1166-1174
Number of pages9
JournalBritish Journal of Cancer
Volume122
Issue number8
DOIs
Publication statusPublished - Apr 2020

Keywords

  • RAS
  • ARRY-142886
  • DOCETAXEL
  • AZD6244

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