Sanne C F A Huijberts1, Robin M J M van Geel2,3,4, Emilie M J van Brummelen2,5, Frans L Opdam6, Serena Marchetti2, Neeltje Steeghs2, Saskia Pulleman2, Bas Thijssen7, Hilde Rosing7, Kim Monkhorst8, Alwin D R Huitema7,9, Jos H Beijnen7,10, René Bernards11, Jan H M Schellens10. 1. Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. s.huijberts@nki.nl. 2. Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. 3. Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands. 4. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. 5. Centre for Human Drug Research, Leiden, The Netherlands. 6. Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. f.opdam@nki.nl. 7. Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 8. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 9. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands. 10. Utrecht University, Utrecht, The Netherlands. 11. Division of Molecular Carcinogenesis, Oncode Institute and The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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.
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.
Authors: Emilie M J van Brummelen; Sanne Huijberts; Carla van Herpen; Ingrid Desar; Frans Opdam; Robin van Geel; Serena Marchetti; Neeltje Steeghs; Kim Monkhorst; Bas Thijssen; Hilde Rosing; Alwin Huitema; Jos Beijnen; Rene Bernards; Jan Schellens Journal: Oncologist Date: 2020-12-29
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