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

Br J Cancer. 2020 Apr;122(8):1166-1174. doi: 10.1038/s41416-020-0776-z. Epub 2020 Mar 9.

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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Benzamides / pharmacokinetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Diphenylamine / administration & dosage
  • Diphenylamine / adverse effects
  • Diphenylamine / analogs & derivatives*
  • Diphenylamine / pharmacokinetics
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mutation*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Quinazolinones / administration & dosage*
  • Quinazolinones / adverse effects
  • Quinazolinones / pharmacokinetics

Substances

  • Benzamides
  • KRAS protein, human
  • PD 0325901
  • Quinazolinones
  • dacomitinib
  • Diphenylamine
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • ClinicalTrials.gov/NCT02039336