Background: Combined inhibition of the MAPK pathway and CDK4/6 is an emerging treatment strategy for cancer. Dual inhibition of MEK, a key mediator of the MAPK pathway, and CDK4/6 showed synergy in cellular growth and survival assays in preclinical models, particularly in the setting of activating Ras mutations. Trametinib (Tram) is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2 that is non-competitive towards adenosine triphosphate (ATP) and inhibits both MEK activation and kinase activity. Palbociclib (Palbo) is a highly selective reversible oral inhibitor of CDK4/6. This phase 1b study (NCT02065063) evaluated trametinib once daily combined with palbociclib 21 days-on / 7 days-off (21/7) in patients (pts) with advanced solid malignancies. Methods: The primary objectives were to determine the safety, tolerability, recommended combination regimen (RCR). Secondary objectives were to characterize the pharmacokinetics (PK) and describe anti-cancer activity. Pts were accrued to dose escalating cohorts and treated with Tram at 1.5 or 2.0 mg once-daily (QD) co-administered with Palbo at 75, 100, or 125 mg 21/7 in 28-day cycles. Results: As of 24 August 2015, 28 pts were enrolled [18 M, 10 F; median age 59 yr (range 31 to 77)]. Systemic exposure to trametinib or palbociclib in combination was similar to that observed with single agents. The RCRs were determined to be Tram 2.0 mg QD plus Palbo 75 mg 21/7 (RCR1) and Tram 1.5 mg QD plus Palbo 100 mg 21/7 (RCR2). DLTs were observed in 1 (Gr 3 mucocitis) out of 7 (14.3%) and 1 (Gr 3 left ventricular ejection fraction decrease) out of 6 (16.7%) evaluable pts at RCR1 and RCR2, respectively. Two higher dose levels above RCR1 and RCR2 were deemed intolerable with DLTs observed in 2 out of 7 evaluable pts at Tram 2.0 mg QD plus Palbo 100 mg 21/7 (Gr 3 fatigue, and Gr 3 LVEF decrease); and in 2 out of 4 evaluable pts at Tram 1.5 mg QD and Palbo 125 mg 21/7 (Gr3 hypertension and vitreous hemorrhage, and Gr 4 thrombocytopenia, respectively). Common adverse events (AEs), regardless of study drug relationship, were diarrhea (67.9%), acneiform rash (64.3%), and fatigue (53.6%). Grade 3 AEs and Grade 4 AEs occurred in 21 (75%) and 6 (21.4%) individual patients, respectively. Two patients with melanoma and CRC treated at RCR1 experienced partial responses that are ongoing, with duration of drug exposure of 13.6 and 10.8 months respectively at time of data cut-off. The patient with melanoma does not have any known BRAF or RAS mutations, while the patient with CRC has a known NRAS mutation Q61K 181C->A but no known BRAF mutation. Conclusions: Two RCRs for trametinib and palbociclib combination were determined together with the preliminary safety and PK/PD profile, as well as clinical activity. (This study is funded by GlaxoSmithKline and Pfizer, Inc.) Citation Format: Ryan J. Sullivan, Rodabe N. Amaria, Donald P. Lawrence, John Brennan, Cathie Leister, Rajendra Singh, Jeff Legos, Holger Thurm, Li Yan, Keith T. Flaherty, Michael A. Davies, Jeffrey Sosman. Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR06.