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Raczka et al. Cancer Drug Resist 2019;2:356-64 I http://dx.doi.org/10.20517/cdr.2018.004 Page 361

CB-839 plus nivolumab
PD-1 is an inhibitory receptor expressed on activated T cells, which normally functions to dampen the
immune response. PD-1 is engaged by PD-L1 (and PD-L2) expressed by tumor cells and infiltrating immune
cells. Inhibition of the interaction between PD-1 and PD-L1 enhances anti-tumor responses, delays tumor
growth, and may facilitate tumor rejection. Nivolumab is a fully humanized IgG4 PD-1 immune checkpoint
[54]
inhibitor, which prevents ligand binding to PD-1 and promotes antitumor immunity by T cells [Figure 1] .
T cells require glutamine for proliferation and compete with glutamine-addicted tumors for this amino acid,
[31]
creating a metabolic checkpoint . In contrast to reduced glutamine availability, GLS inhibition by CB-839
does not affect T cell activation, their entry into S phase or their division in vitro. Instead, CB-839 reduces
the use of glutamine by malignant cells relieving the metabolic checkpoint and making glutamine available
for T cells. CB-839 is proposed to synergize with nivolumab in syngeneic colon tumor mouse models to
[55]
improve T cell activation and proliferation, boosting their anti-cancer activity .
A Phase 1/2 study of CB-839 plus standard of care nivolumab is currently open and recruiting patients
(ClinicalTrials.gov Identifier: NCT02771626). It aims to evaluate safety, pharmacokinetics and pharmacodynamics
of the combination in patients with ccRCC, melanoma and NSCLC. Patients are receiving escalating doses of
CB-839 twice daily and standard dose nivolumab to determine recommended Phase 2 dose (RP2D). In Phase
2, patients are separated into five cohorts: ccRCC naïve to checkpoint inhibitors; ccRCC recently treated with
nivolumab; ccRCC, melanoma or NSCLC with prior PD-1 therapy. Study completion is expected in June
[56]
2019 .
CB-839 plus cabozantinib
Cabozantinib is a signal transduction inhibitor and its targets include VEGFR, ARK and MET [Figure 1].
Early pre-clinical studies using the Caki-1 cell line and Caki-1 xenografts showed superiority of cabozantinib
plus CB-839 over monotherapy when measuring its anti-proliferative effect. The combination reduced signal
transduction more than cabozantinib alone by reducing pERK and pAKT proteins . The two drugs also
[57]
synergize to inhibit TCA cycle activity as measured by oxygen consumption rate. In xenograft models,
3
where tumors of approximately 400 mm were treated with DMSO, CB-839, cabozantinib or a combination
[57]
of the drugs, monotherapy resulted in slower tumor growth, which was enhanced in combination models .
Following in vitro and mouse studies, 13 patients with ccRCC or papillary RCC were enrolled into a Phase 1
clinical trial. RP2D was evaluated at 800mg and no maximum tolerated dose was reached. Study outcomes
including ORR of 40% and DCR of 100% in ccRCC, favorable safety profile and zero patients with PD, led to
[58]
a randomized Phase 2 study, CANTANA . This study is currently recruiting patients and aims to compare
cabozantinib plus CB-839 vs. cabozantinib plus placebo in 298 patients with previous 2 or 3 lines of therapy.
The key endpoints are PFS and OS with completion expected in 2022 .
[58]

CONCLUSIONS AND FUTURE DIRECTIONS
The development of targeted therapy for RCC has revolutionized its treatment. RCC tumors are highly
vascularized and current standard of treatment focuses mainly on drugs targeting angiogenesis by inhibiting
VEGF and mTOR. However, high ITH and intrinsic and acquired therapy resistance prevents removal of
all malignant cells. Residual tumor cells expand and lead to clinical relapse, creating the need for second-
and further line therapies. Several combination therapies have been recently approved, however they are
still in their early stages of use. Moreover, checkpoint inhibitors have not been used in the clinical setting to
treat mRCC for long enough to fully evaluate their efficacy. Many RCC tumors are now being recognized to
have altered metabolism in comparison to normal cells. Although efforts to formulate efficient glutaminase
inhibitors are not a completely new concept, they are yet to be approved for use in the clinical setting.
CB-839 has been shown to be well tolerated, but as monotherapy, its preliminary efficacy is limited to