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

abstracts

Annals of Oncology

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

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 1 Pharmacology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKIAVL), Amsterdam, Netherlands, 2Early Phase Clinical Development, Centre for Human Drug Research (CHDR), Leiden, Netherlands, 3Pharmacy, Maastricht University Medical Centre, Maastricht, Netherlands, 4Medical Oncology & Clinical Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 5Pharmacy and Pharmacology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 6Pathology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital (NKI-AVL), Amsterdam, Netherlands,7Molecular carcinogenesis, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital (NKI-AVL), Amsterdam, Netherlands, 8Pharmaceutical Sciences, Utrecht University, Amsterdam, Netherlands Background: 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. Methods: 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,

v178 | Developmental Therapeutics

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Annals of Oncology

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respectively. The primary objective was to determine the recommended phase 2 dose (RP2D) and schedule. Results: Thirty-four patients with CRC (n ¼ 16), NSCLC (n ¼ 15) or pancreatic cancer (n ¼ 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 ¼ 3), rash (n ¼ 2), nausea (n ¼ 1), several grade 2 toxicities (n ¼ 1) and aspartate aminotransferase elevation (n ¼ 1) resulting in inability to receive 75% of the planned doses (n ¼ 2) or treatment delay (n ¼ 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. Conclusions: 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: NCT02230553. Legal entity responsible for the study: The Netherlands Cancer Institute. Funding: Novartis. Disclosure: 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.

Volume 30 | Supplement 5 | October 2019

doi:10.1093/annonc/mdz244 | v179