Background: RAS is the most commonly mutated oncogene in lung cancer. While direct inhibitors of RAS have not yet been successfully developed, MEK inhibitors have shown activity in RAS mutated tumors including KRAS mutant NSCLC. Binimetinib (ARRAY, Boulder CO) is an oral highly selective inhibitor of MEK1/2 and has demonstrated preclinical and clinical activity. Distinct from other MEK inhibitors in clinical development, it has activity against NRAS mutant cancers, with improved PFS as a single agent in NRAS mutant melanoma compared to dacarbazine (NEMO). Methods: In this phase I/Ib study, binimetinib is combined with pemetrexed/carboplatin in advanced non-squamous NSCLC patients. Primary study objectives include determination of the RP2D of continuous binimetinib plus pemetrexed/carboplatin, safety (NCI CTCAE v. 4) of the combination and exploration of efficacy (ORR per RECIST v.1.1). Population PK is being characterized and potential relationships between RAS mutation subtypes and response explored. A 3+3 dose-escalation design with 3 treatment groups will be used to determine the maximum administered dose and RP2D of the combination. The cohort will be expanded at the RP2D to a total of 35 patients with stratification by genotype (RAS/RAF wild type (10), KRAS G12C mutant (10), non-G12C mutant (10), BRAF/NRAS mutant (5)). Binimetinib 30-45 mg BID daily (starting day -7 with a 48 hour break pre-chemotherapy) is combined with pemetrexed 500 mg/m² IV and carboplatin AUC 5-6 mg*min/mL. Patients who have completed 4-6 cycles of chemotherapy may continue to receive MEK162 until disease progression. Patient population: Patients must be chemo-naïve with EGFR wild type, non-ALK rearranged non-squamous NSCLC, have ECOG PS 0/1, adequate organ, marrow, and normal cardiac function. Those with prior retinal vein occlusion, coronary syndromes, active infection and significant comorbidities are excluded. Patients with stable treated CNS metastases are permitted. Accrual to cohort 1 is ongoing. Clinical trial information: NCT02185690