A phase 1/1b study of RXDX-105, an oral RET and BRAF inhibitor, in patients with advanced solid tumors

Background: RXDX-105 is a multikinase inhibitor that has demonstrated potent inhibition of RET and BRAF with biochemical IC50 values of 0.3-0.8 nM against RET rearrangements, 4nM against RET M918T, and 54 nM against BRAF V600E. RET alterations can be oncogenic drivers in various types of cancer, including NSCLC and thyroid cancer. Similarly, acquired BRAF mutations can result in constitutive activation of the MAP kinase signaling pathway, which fuels cancer growth. Clinical inhibition of these targets has been associated with tumor regression. Methods: Pts with advanced solid tumors were enrolled in a Ph 1/1 b basket study, RXDX-105-01. RXDX-105 was administered orally, once daily, in the Ph 1 portion at doses ranging from 20 mg to 350 mg. The RP2D was determined to be 350 mg, fed condition, on a continuous dosing schedule, which is being evaluated further in Ph 1b. Tumor response was assessed every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) analysis was performed. Results: As of 15Jun16, 74 (55 Ph 1; 19 Ph 1b) pts (33 M; 41 F) received RXDX-105; 23 pts remain on treatment. Median age was 61 years (range 27-81). Number of cycles ranged from 1 to 36. In the Ph 1b portion, 8 pts with RET alterations have been enrolled (6 NSCLC, 1 CRC, and 1 chondrosarcoma) and 11 pts with BRAF alterations have been enrolled (4 NSCLC, 4 CRC, 2 papillary thyroid, and 1 glioblastoma). The safety profile of RXDX-105 in Ph 1b appears consistent with what was observed in Ph 1, in which the most common (>15%) AEs, regardless of attribution, were: fatigue, nausea, rash, vomiting, muscle spasms, decreased appetite, constipation, diarrhea, anemia, abdominal pain, hypokalemia, dyspnea and hypertension. The most common ;sG3 events were: anemia (8 pts; 15%), diarrhea (5 pts; 9%), abdominal pain (3 pts; 6%), hypokalemia (3 pts; 6%), constipation (3 pts; 6%), hyponatremia (3 pts; 6%), dehydration (3 pts; 6%) and pneumonia (3 pts; 6%). There were no treatment-related G4 or G5 events. Three SAEs were considered treatment-related: G2 headache, G3 hyperbilirubinemia and G3 drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Preliminary efficacy has been noted, including a confirmed PR in a pt with RET-rearranged NSCLC and an unconfirmed PR (confirmation pending) in a pt with RET M918T mutated medullary thyroid cancer who had received 4 prior multikinase RET inhibitors. Additionally, as previous