Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.

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.