Background: ARQ 197 (A) is a selective, oral, non-ATP competitive inhibitor of c-MET, a RTK implicated in tumor cell proliferation, invasion and metastasis, currently in phase II/III clinical trials. Based on preclinical synergy of A and sorafenib (S) in multiple cell lines, a phase I study was undertaken to define safety and RP2D of the A+S combination. Methods: A traditional 3+3 dose escalation schema was employed. Two dose levels were evaluated, dose level (DL) 1 (A 360 mg PO BID + S 200 mg PO BID) and DL2 (A 360 mg BID + S 400 mg BID), which was deemed the RP2D, since it represents full single-agent doses of both drugs. Extension cohorts have been opened at this dose in patients with five tumor types: renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), breast cancer (BC), non-small cell lung cancer (NSCLC) or melanoma, based on the preclinical and clinical data. Results: To date, 54 pts (17 F/37 M; mean age: 61.4 yrs; 13 RCC, 8 HCC, 12 NSCLC, 8 melanoma, 7 BC, 6 others) have been treated, 5 at DL1 w/o DLT, 9 at DL2 with 2 DLTs in 1 pt (a Grade 3 fatigue and a Grade 3 dyspnoea) and 40 at the RP2D (extension cohort). Adverse events (AEs) considered related to one or both study drugs occurred in 45 (83.3%) pts with the most common ones (≥10%) being fatigue (35.2%), rash (31.5%), diarrhea (29.6%), anorexia (29.6%), nausea (18.5%), stomatitis (18.5%), alopecia (18.5%), hypophosphataemia (18.5%), vomiting (13.0%), pruritus (13.0%), hand-foot syndrome (11.1%) and lymphopenia (11.1%). Among 48 pts on extension cohorts, 37 (77.1%) were evaluable (defined as having at least one post-treatment CT scan) for efficacy. Their data are summarized in the table. Conclusions: The A+S combination therapy is well tolerated at full single-agent doses and RP2D has been identified. Preliminary evidence of anti-cancer activity has been observed, indicating that the combined inhibition of c-MET and angiogenic signalling demonstrates therapeutic potential.