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, René Bernards, Jan H M Schellens

Research output: Contribution to journalArticleAcademicpeer-review

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 - 1 May 2020

Keywords

  • KRAS mutation
  • Lapatinib
  • Phase I
  • Trametinib

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