Background: The MAPK and PI3K pathways share common upstream activators and contribute to cell proliferation, differentiation, and survival. Due to compensatory signaling, only partial tumor growth inhibition may occur when targeting either pathway alone. Preclinically-observed synergistic effects of combined PI3K and MEK inhibitors suggest that dual inhibition may be more effective. Methods: This phase 1b, open-label study (CMEK162X2109) is evaluating the PI3Kα inhibitor BYL719 combined with MEK inhibitor binimetinib (MEK162) in patients (pts) with RAS- or BRAF-mutant advanced solid malignancies (> 10 types). The objective for dose escalation was estimation of the maximum-tolerated dose (MTD) and/or recommended dose for expansion (RDE), guided by the Bayesian logistic regression model. Results: As of September 2, 2013, 58 pts were enrolled and BYL719 was orally co-administered at 80, 120, 160, 200, 220, or 270 mg once-daily (QD) with binimetinib at 30 or 45 mg twice-daily (BID) in 28-day cycles. Thirty two pts (55%) had ≥3 prior anticancer regimens. Median exposure was 7.4 wks. Common adverse events (AEs), regardless of study drug relationship, were diarrhea (86%), nausea (66%), vomiting (52%), reduced appetite (50%), rash (48%), pyrexia (41%), fatigue (38%), and hyperglycemia (36%). Grade 3/4 AEs occurred in 46 individual pts (79%), most commonly diarrhea (12%) and elevated creatine phosphokinase (10%). Dose-limiting toxicities were observed in 9 pts (19%), out of which 4 had grade 3/4 AEs including gastrointestinal and skin disorders. The MTD of the combination was determined to be BYL719 200 mg QD plus binimetinib 45 mg BID, at which 3/6 pts had grade 3/4 AEs. Of 4 ovarian cancer pts with KRAS-mutant status, 3 had confirmed partial responses (PRs). PRs were also observed in 1 pt with NRAS-mutant melanoma (confirmed) and 1 with KRAS-mutant endometrial cancer (unconfirmed). Stable disease lasting > 6 weeks was reported as best response for 18 pts (31%). Conclusions: The MTD/RDE for combined BYL719 and binimetinib was reached, and the preliminary safety and efficacy profile justifies further exploration, particularly in pts with RAS-mutant ovarian cancer. Clinical trial information: NCT01449058.