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
3993 - Prophylaxis with Lipegfilgrastim in patients with primary breast cancer receiving dose dense chemotherapy: results from the German NIS NADENS
Presenter: Marion Kiechle
Session: Poster Display session 1
Resources:
Abstract
3471 - Randomized phase 2 trial evaluating the safety of peripherally inserted central catheters vs implanted port catheters during adjuvant chemotherapy in early breast cancer patients.
Presenter: Florian Clatot
Session: Poster Display session 1
Resources:
Abstract
1327 - Simultaneous intravenous fluid infusion to prevent oxaliplatin infusion-related venous pain
Presenter: Stefan Van Ravensteijn
Session: Poster Display session 1
Resources:
Abstract
5004 - Clinical practice evaluation of opioids induced constipation management in cancer patients: The EIO-Praxis project.
Presenter: Enrique Aranda Aguilar
Session: Poster Display session 1
Resources:
Abstract
2222 - Analysis of the efficacy of naloxegol in a real-world 12 weeks of follow-up study, in patients with cancer and opioid-induced constipation with laxative-inadequate response.
Presenter: Manuel Cobo Dols
Session: Poster Display session 1
Resources:
Abstract
5556 - Consensus on strategies in the management of opioid-induced constipation in cancer patients
Presenter: Regina Girones Sarrio
Session: Poster Display session 1
Resources:
Abstract
3913 - Effect of Chinese Herbal Compound LC09 on Patients With Capecitabine-Associated Hand-Foot Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Presenter: Yanni Lou
Session: Poster Display session 1
Resources:
Abstract
2208 - A prospective study about the complementary medicine among patients with cancers
Presenter: Wala Ben Kridis
Session: Poster Display session 1
Resources:
Abstract
1082 - Prevalence and management of Potentially Inappropriate Medication use and Potential Omissions in Medication in older cancer patients - the PIM POM study
Presenter: Fianne van Loveren
Session: Poster Display session 1
Resources:
Abstract
1701 - Immunogenicity and optimal timing of 13-valent pneumococcal conjugate vaccination during adjuvant chemotherapy in gastric and colorectal cancer : A randomized controlled trial
Presenter: Wonyoung Choi
Session: Poster Display session 1
Resources:
Abstract