Abstract 3482
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, respectively. The primary objective was to determine the recommended phase 2 dose (RP2D) and schedule.
Results
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.
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.
Editorial acknowledgement
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.
Resources from the same session
3305 - A phase I dose-escalation and expansion trial of intratumorally administered CV8102, alone and in combination with anti-PD-1 in patients with advanced solid tumors
Presenter: Jürgen Krauss
Session: Poster Display session 1
Resources:
Abstract
5353 - Phase 1/2 Study of 9-ING-41, a small molecule selective Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined with Chemotherapy, in Patients with Refractory Hematological Malignancies or Solid Tumors
Presenter: Benedito Carneiro
Session: Poster Display session 1
Resources:
Abstract
3946 - Trial in progress: a Phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumors (NCT03447314).
Presenter: Aaron Hansen
Session: Poster Display session 1
Resources:
Abstract
3449 - Radiographic Phenotyping to Identify Intracranial Disseminated Recurrence in Brain metastases Treated With Radiosurgery Using Contrast-enhanced MR Imaging
Presenter: CheYu Hsu
Session: Poster Display session 1
Resources:
Abstract
4553 - Association between TP53 mutations and efficacy of Osimertinib for brain metastasis from EGFR-mutant lung cancer
Presenter: Lijuan Chen
Session: Poster Display session 1
Resources:
Abstract
4942 - Response assessment of melanoma brain metastases treated by stereotactic radiotherapy or immunotherapy or both: a comparison of RECIST 1.1, RANO and iRANO criteria
Presenter: Emilie Le Rhun
Session: Poster Display session 1
Resources:
Abstract
3529 - Management of multiple brain metastases by Staged SRS focusing on utmost risk lesions
Presenter: shaoqun Li
Session: Poster Display session 1
Resources:
Abstract
5315 - Whole brain radiotherapy plus simultaneous in-field boost versus whole brain radiotherapy plus fractionated stereotactic radiotherapy for multiple brain metastases of non-small cell lung cancer
Presenter: Lu Li
Session: Poster Display session 1
Resources:
Abstract
1116 - 3D based texture analysis serving as potential diagnostic factor in discriminating primary central nervous system lymphoma from metastatic brain tumors: A preliminary study
Presenter: Wen Guo
Session: Poster Display session 1
Resources:
Abstract
5344 - Global trends in population-based survival for 303,169 adults diagnosed with glioblastoma in 44 countries during 2000-2014 (CONCORD-3)
Presenter: Fabio Girardi
Session: Poster Display session 1
Resources:
Abstract