Background: Most metastatic GISTs have primary (1⁰) mut in KIT exons (ex) 9 or 11, which confer sensitivity to imatinib and other agents. Tumors develop clonal secondary (2^y) resistance mut, typically in ex 13, 14, 17, and 18. PLX9486 inhibits KIT 1⁰ mut and ex 17 and 18 2^y mut. Pexi (PLX3397) and su inhibit 1⁰ mut and ex 13 and 14 2^y mut. Combo of PLX9486 with pexi or su may have activity against a broader spectrum of mutations. Methods: 3 + 3 dose escalation study in pts with solid tumors and GIST who had progressed on imatinib and other TKI. Safety, efficacy per RECIST, and PK were assessed. Ct DNA was assessed as a biomarker. Part (P) 1: single agent PLX9486 dose escalation once (QD) and twice daily (BID). P2: combos of PLX9486 500 mg QD with pexi 600 mg QD fed and fasted or su 25 mg QD with food. Results: As of January 8, 2018, 36 pts (31 GIST; Part 1-20 pts, part 2-11 pts) were enrolled; median age was 63 years (range 49-82). GIST pts had a median of 4 prior therapies (range 1-7), and all progressed on imatinib. Most pts had tumors with ex 11 and 17 mut. QD dosing of PLX9486 had saturable absorption at steady state with a half-life of 71.4 hrs. No PK advantage to BID dosing and no food effect. One DLT of Grade (G) 3 anemia was reported at the 1000 mg dose level. Escalation stopped due to PK plateau; the RP2D was 1000 mg QD. In P2, no DLTs were observed at the doses studied. PK of PLX9486 was not affected by pexi. Pexi food effect was observed. Adverse events (AEs) in P1 in ≥ 20% pts (N = 24) were diarrhea, nausea, increased AST (29% each) and fatigue (21%). AEs in P2 in ≥ 20% pts (N = 12) were hair color changes (42%), anemia (25%), nausea (25%), and anorexia (25%). Majority were G1-2. No ≥ G3 LFT changes in P1 or P2. In P1, 2 partial responses (PR) were seen with PLX9486 1000 mg and PFS was > 24 weeks. In P2, 1 pt had a PR in the pexi/PLX9486 combo, and the median PFS has not been reached. Conclusions: PLX9486 alone and in combo with pexi was generally well tolerated with evidence of activity against resistant GIST. Combos with su and pexi, agents with complementary activity against KIT 2^y resistance mut in GIST, are accruing. Clinical trial information: NCT02401815