Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session 1

3482 - Phase I study of lapatinib and trametinib in patients with KRAS mutant colorectal, non-small cell lung and pancreatic cancer


28 Sep 2019


Poster Display session 1


Clinical Research

Tumour Site

Non-Small Cell Lung Cancer;  Pancreatic Adenocarcinoma


Sanne Huijberts


Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244


S.C.F.A. Huijberts1, E. van Brummelen2, R. van Geel3, F.L. Opdam4, S. Marchetti4, N. Steeghs4, S. Pulleman4, B. Thijssen5, H. Rosing5, K. Monkhorst6, A.D.R. Huitema5, J.H. Beijnen5, R. Bernards7, J.H.M. Schellens8

Author affiliations

  • 1 Pharmacology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 2 Early Phase Clinical Development, Centre for Human Drug Research (CHDR), 2333 CL - Leiden/NL
  • 3 Pharmacy, Maastricht university medical centre, 6229HX - Maastricht/NL
  • 4 Medical Oncology & Clinical Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 5 Pharmacy And Pharmacology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 6 Pathology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 7 Molecular Carcinogenesis, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 8 Pharmaceutical Sciences, Utrecht University, 1066 CX - Amsterdam/NL


Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 3482


KRAS oncogene mutations are causing sustained signaling through the mitogen-activated protein kinase (MAPK) pathway resulting in uncontrolled cell growth. Efforts to target KRAS directly or to inhibit downstream effectors have been unsuccessful. Preclinical research revealed that KRAS mutated (KRASm) cells are intrinsically resistant to MEK inhibitors due to upstream growth receptors that reactivate the MAPK and phosphoinositide 3-kinase (PI3K) pathway. Concurrent inhibition of MEK, EGFR and HER2 resulted in synergistic anti-tumor activity, with complete inhibition of tumor growth in vitro and in vivo.


This is a single-center, phase I dose-escalation study to assess the safety, tolerability and anti-tumor activity of the MEK inhibitor trametinib combined with the dual EGFR/HER2 inhibitor lapatinib in patients with advanced KRASm and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic cancer. Patients received escalating doses of continuous or intermittent, once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg, respectively. The primary objective was to determine the recommended phase 2 dose (RP2D) and schedule.


Thirty-four patients with CRC (n = 16), NSCLC (n = 15) or pancreatic cancer (n = 3) were enrolled across five dose-levels, 2 patients are still on treatment. Dose-limiting adverse events were reported in twelve patients; grade 3 diarrhea (n = 3), rash (n = 2), nausea (n = 1), several grade 2 toxicities (n = 1) and aspartate aminotransferase elevation (n = 1) resulting in inability to receive 75% of the planned doses (n = 2) or treatment delay (n = 2). The established RP2D was 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Out of 22 patients evaluable for response, regression of target lesions was seen in six, with one confirmed partial response in NSCLC. Reductions in pERK and pS6 levels were demonstrated in paired tumor biopsies. Pharmacokinetic results were as expected.


Lapatinib and trametinib could be combined in an intermittent dosing schedule with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed with sufficient target engagement.

Clinical trial identification


Editorial acknowledgement

Legal entity responsible for the study

The Netherlands Cancer Institute.




N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Meyers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. K. Monkhorst: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Benecke; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: Abbvie; Advisory / Consultancy: Diaceutics. J.H.M. Schellens: Shareholder / Stockholder / Stock options, and patent holder on oral taxanes: Modra Pharmaceuticals. All other authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.