Background: Glutaminase (GLS) is a key enzyme that controls glutamine utilization, a metabolic pathway upregulated in RCC and important for tumor proliferation and survival. CB-839 is a first-in-clinic, small molecule, reversible, oral GLS inhibitor that synergizes with cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, in preclinical RCC models to inhibit metabolic pathways and enhance anti-tumor activity. Cabo monotherapy is associated with a 17% overall response rate (ORR) for clear cell (cc) mRCC (Choueiri et al. Lancet Oncol. 2016). Here we present findings from a Phase 1 study cohort evaluating the safety, efficacy, and recommended Phase 2 dose (RP2D) of CB-839 + Cabo in patients (pts) with mRCC as 2L+ therapy. Methods: Eligible pts had mRCC with cc or papillary histology, ECOG 0-1, RECIST measurable disease, and, for cc pts, treatment with ≥1 prior anti-VEGF therapy. Escalating doses of CB-839 (600-800 mg PO BID) plus Cabo (60 mg PO QD) were evaluated using a 3+3 design. Tumor response was assessed per RECIST 1.1 every 8 wks. Results: The CB-Cabo cohort enrolled 13 pts with a median 3 (range, 0-7) prior lines of therapy. No maximum tolerated dose was reached; 800 mg was selected as the CB-839 RP2D. The most common treatment-related AEs (occurring in >25% of pts) were diarrhea (62%), decreased appetite (46%), ALT increased (39%), fatigue (39%), AST increased (31%), nausea (31%), and rash (31%); Gr ≥3 treatment-related AEs included diarrhea, hypertension, platelet count decreased, and hallucination (n=1 each). Among 12 evaluable pts, ORR was 42% and disease control rate (DCR = complete response + partial response [PR] + stable disease [SD]) was 100%: 42% (5/12) PR, 58% (7/12) SD. Among 10 evaluable cc mRCC pts, 50% (5/10) had PRs, 50% (5/10) SDs. As of Sept 24, 2018, 5 pts received >12 months treatment; 4 remain on study. Conclusions: CB-839 plus Cabo showed encouraging clinical activity and tolerability in heavily pretreated mRCC pts, with response rates for cc mRCC (50% ORR, 100% DCR) comparing favorably to historical Cabo monotherapy. A randomized Phase 2 study of CB-839 + Cabo vs. Cabo + placebo in cc mRCC is ongoing. (CANTATA; NCT0342821) Clinical trial information: NCT02071862