Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.

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.