Background: RO5126766 is a novel MEK inhibitor with functional RAF inhibition. A dose escalation Phase 1 study, comparing 2 intermittent schedules, has previously been reported, with a recommended phase 2 dose (RP2D) of 4 mg twice weekly (Monday/Thursday (M/Th)). We now present results from the expansion cohort of this study, which aims to assess tolerability and preliminary activity in pts with KRAS, NRAS or BRAFmutated tumours. Methods: Pts with KRAS, NRAS or BRAF mutated tumours were treated with RO5126766 at the RP2D dose of 4 mg M/Th in 4 week cycles. Tumour assessment was performed with CT imaging every 2 cycles. Tumour pharmacodynamics was assessed in pre and post treatment biopsies where available. Results: To date, 18 evaluable pts (8 Non Small Cell Lung Carcinoma (NSCLC), 4 colorectal, 3 ovarian, 1 endometrial, 1 uterine carcinosarcoma, 1 melanoma) have been treated. Pts had received 1-7 (median 3) lines of treatment previously. Skin rashes were common G1-2 12pts, G3-4 4pts. Other adverse events were CK elevation, visual disturbances, peripheral oedema, mucositis, dry skin, diarrhoea and fatigue. Toxicities were manageable, however, dose reduction to 3.2 mg or 2.4 mg was required in 10 pts. Tumour size reduction was seen in 4/8 (50%) of pts with KRAS mutant NSCLC, of which 3/8 (37.5%) were RECIST partial responses (PR). The 8 NSCLC pts, had previously received 1-4 (median 2) lines of treatment, all having received platinum doublet chemotherapy. G12V, G12R and unknown codon 12/13 mutations were detected in responding NSCLC pts. RECIST PR was seen in 1 pt with KRAS mutated endometrial carcinoma and 1 pt with KRAS mutated ovarian cancer, whilst additionally, 1 pt with BRAF mutated ovarian cancer showed tumour size reduction. These two ovarian carcinoma pts had both received two separate MEK/BRAF inhibitors previously. Currently 5 pts overall remain on study and responses range from 4 -16.8 months. Recruitment is ongoing with plans to expand further in KRASmutated malignancies. Conclusions: These preliminary results, especially in KRAS mutant NSCLC pts who have been previously treated with standard of care chemotherapy, are encouraging. Clinical trial information: NCT02407509