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01-05-2020 | NSCLC | Original Article

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

Authors: 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2020

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.

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Title: Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer
Authors: 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
Publication date: 01-05-2020
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
NSCLC
Lapatinib
Pancreatic Cancer
Pancreatic Cancer
Colorectal Cancer
Colorectal Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04066-4

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