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

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, Rene Bernards, Jan H. M. Schellens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)

Abstract

Purpose KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Methods Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Results Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Conclusion Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.

Original languageEnglish
Pages (from-to)917-930
Number of pages14
JournalCancer Chemotherapy and Pharmacology
Volume85
Issue number5
DOIs
Publication statusPublished - May 2020

Keywords

  • Lapatinib
  • Trametinib
  • KRAS mutation
  • Phase I
  • MEK INHIBITOR TRAMETINIB
  • TYROSINE KINASE INHIBITOR
  • DOSE-ESCALATION
  • COLON-CANCER
  • GROWTH
  • MULTICENTER
  • COMBINATION
  • PLACEBO
  • ARRY-142886
  • DABRAFENIB

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