There is a need for more effective therapies for patients with advanced NSCLC driven by the
RAS/MEK/ERK pathway. These tumors are generally aggressive, are almost exclusively of
non-squamous histology, and represent the largest group of patients with advanced NSCLC
harboring specific driver mutations in Western populations.
Based on recent preclinical and clinical evidence, mitogen-activated protein kinase kinase
(MEK)-inhibition plus first-line chemotherapy is a promising new treatment for patients with
NSCLC and KRAS [v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog] mutations.
Binimetinib is a medication without marketing authorization. Pemetrexed and cisplatin have
marketing authorization in Switzerland and in EU for the treatment of non-small cell lung
cancer (NSCLC) and will be administered as standard backbone treatment according to their
Swissmedic-approved indication, dose and route of administration. Binimetinib, pemetrexed and
cisplatin are IMP in the context of this phase I trial.
Inclusion Criteria:
- Written informed consent according to the Swiss HRA and ICH-GCP regulation before
registration and prior to any trial-specific procedure.
- Histologically or cytologically confirmed diagnosis of NSCLC, predominantly
non-squamous subtype (adenocarcinoma, large cell carcinoma, NOS).
- Locally advanced or metastatic stage III-IV disease according to the 7th TNM
classification, ineligible for curative treatment.
- Presence of KRAS exon 2 or 3 (codon 12, 13 or 61) mutations by local testing
(concomitant EGFR and ALK mutations are excluded).
- CT scan showing measurable disease, which is defined as at least one lesion that can
be measured in at least one dimension (non-nodal lesions ≥10 mm in longest diameter,
lymph nodes ≥15 mm in short axis) according to RECIST 1.1.
- Eligible for cisplatin-based chemotherapy and able to take oral medications.
- WHO performance status 0-1.
- Age from 18 to 75 years.
- Adequate hematological values: hemoglobin ≥ 90 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100
x 109/L.
- Adequate hepatic function: total bilirubin ≤ 1.5 x ULN and < 34.2 μmol/L; ALT and
alkaline phosphatase ≤ 2.5 x ULN.
- Adequate renal function: calculated creatinine clearance ≥ 60 mL/min, according to the
formula of Cockcroft-Gault.
- Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as
determined by echocardiogram; QTcF interval must be ≤ 480 ms.
- Women with child-bearing potential are using effective contraception, are not pregnant
or lactating and agree not to become pregnant during trial treatment and 6 months
thereafter. A negative serum pregnancy test before inclusion into the trial is
required for all women with child-bearing potential.
- Men agree not to father a child during trial treatment and 6 months thereafter.
Exclusion Criteria:
- NSCLC with any additional small cell carcinoma (SCLC) component by local diagnostic
pathology report.
- Meningeosis carcinomatosa, symptomatic or untreated central nervous system (CNS)
metastases. Patients with treated, controlled CNS metastases can be enrolled 2 weeks
after the end of radiotherapy if asymptomatic (no residual neurologic deficits) and no
longer on corticosteroids.
- Previous or concurrent malignancy with the following exceptions:
- adequately treated basal cell or squamous cell carcinoma of the skin (adequate
wound healing is required prior registration),
- in situ carcinoma of the cervix, treated curatively and without evidence of
recurrence for at least 5 years prior registration,
- superficial bladder cancer, prostate intraepithelial neoplasm, other noninvasive
or indolent malignancy, or other solid tumor treated curatively and without
evidence of recurrence for at least 5 years prior registration.
- Leptomeningeal disease.
- Concurrent radiotherapy (patients with prior radiotherapy other than for brain
metastases ≥ 7 days prior to registration can be enrolled).
- Previous systemic therapy for advanced NSCLC; previous adjuvant or neoadjuvant
chemotherapy allowed if last dose was administered at least 6 months ago.
- Major surgery within 3 weeks before registration.
- Concurrent treatment with any other experimental drug or other anticancer therapy.
- Impaired cardiovascular function or clinically severe or uncontrolled cardiovascular
diseases, including any of the following:
- congestive heart failure NYHA III or IV,
- history of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
months prior to registration,
- symptomatic chronic heart failure (G2 or higher), history or current evidence of
clinically significant cardiac arrhythmia requiring medication and/or conduction
abnormality < 6 months prior to registration except atrial fibrillation and
paroxysmal supraventricular tachycardia.
- Uncontrolled arterial hypertension defined as persistent elevation of systolic blood
pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite medical treatment.
- History or current evidence of retinal vein occlusion (RVO) or current risk factors to
RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyper-viscosity or
hypercoagulability syndromes); history of retinal degenerative disease.
- History of Gilbert's syndrome.
- Neuromuscular disorders that are associated with elevated creatine phosphokinase (CPK;
e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy).
- Neuropathy (> G1) or hearing impairment/ tinnitus (> G1).
- Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel
resection).
- History of thromboembolic or cerebrovascular events within 6 months prior to
registration, including transient ischemic attacks, cerebrovascular accidents, deep
vein thrombosis or pulmonary emboli.
- Known history of acute or chronic pancreatitis.
- History of chronic inflammatory bowel disease or Crohn's disease requiring medical
intervention (immunomodulatory or immunosuppressive medications or surgery) within 12
months prior to registration.
- Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
and/or active hepatitis C infection.
- Active infection within 14 days prior to registration.
- Planning on embarking on a new strenuous exercise regimen after first dose of
binimetinib (NB: muscular activities, such as strenuous exercise, that can result in
significant increases in plasma CPK levels should be avoided while on binimetinib
treatment).
- Known lactose intolerance.
- Known hypersensitivity to the trial drugs or hypersensitivity to any other component
of the trial treatment, including premedication.
- Any concomitant drugs contraindicated for use with pemetrexed and cisplatin according
to the Swissmedic-approved current product information or with binimetinib according
to the latest version of the Investigator's Brochure.
- Any other serious underlying medical, psychiatric, psychological, familial or
geographical condition, which in the judgment of the investigator may interfere with
the planned staging, treatment and follow-up, affect patient compliance or place the
patient at high risk from treatment-related complications.
