CASE REPORT
Targeting Glutamine Metabolism: the CANTATA Trial
for Patients With Metastatic Renal Cell Carcinoma (mRCC)
Andrew W.
Hahn, MD1
Nizar M.
Tannir, MD, FACP1
1Department of Genitourinary
Medical Oncology
Division of Cancer Medicine
MD Anderson Cancer Center
Houston, TX
Abstract
Despite the progress made in the management of advanced
renal cell carcinoma with the regulatory approval of
immune checkpoint inhibitor-based regimens, nivolumab
plus ipilimumab, pembrolizumab plus axitinib, and
avelumab plus axitinib as first-line therapies for the treatment
of patients with metastatic renal cell carcinoma
(mRCC), an unmet need still exits for the development
of therapies with novel mechanism of action for patients
with mRCC who do not respond or experience a relapse
after an initial response to these first-line therapies. Altered
cellular metabolism is a hallmark of cancer, and
renal cell carcinoma (RCC) cells have been shown to depend
on glutamine metabolism for energy demands. Telaglenastat
(CB-839) is a selective glutaminase inhibitor
that is being studied in combination with cabozantinib
in the randomized CANTATA trial as second-line or
third-line therapy in patients with mRCC who had progressive
disease after prior therapy with dual immune
checkpoint inhibitors or a VEGFR-TKI followed by immune
checkpoint inhibitors, or the combination of an
immune checkpoint inhibitor plus a VEGFR-TKI. Herein,
we present a clinical vignette reflective of a patient enrolled
on the CANTATA trial, review the preclinical and
early phase clinical trial rationale for telaglenastat plus
cabozantinib, and provide an in-depth discussion of the
CANTATA trial.
Case Report
Mr. L is a 58 year-old male who initially presented with
a palpable abdominal mass and was found to have a 10
x 8 centimeters (cm) right renal mass which was histologically
confirmed to be clear-cell renal cell carcinoma
(ccRCC). At that time, he had a right nephrectomy with
radical lymph node dissection and was found to have 3
lymph nodes positive for ccRCC. Two months after his
nephrectomy, a restaging CT chest, abdomen, and pelvis
showed interval development of a 1.5 cm lesion in the
liver and small pulmonary nodules suspected to be metastatic
74 Kidney Cancer Journal
RCC (mRCC). He began first-line sunitinib for
International Metastatic RCC Database Consortium
(IMDC) intermediate-risk disease. After 8 months of stable
disease, he experienced radiographic progression. He
was then started on second-line nivolumab and continued
this immunotherapy until radiographic progression
13 months later. Most recently, he was enrolled in
a clinical trial of cabozantinib plus telaglenastat versus
cabozantinib plus placebo as third-line treatment for
IMDC intermediate-risk mRCC. He experienced a durable
partial response on this clinical trial and remains on
treatment 15 months later without any grade 3 or 4 adverse
events.
In the above clinical vignette, Mr. L was enrolled on
the CANTATA trial (NCT03428217), a randomized clinical
study comparing telaglenastat (CB-839) plus cabozantinib
versus cabozantinib plus placebo in patients with
mRCC who had previously progressed on at least one
line of systemic treatment. There is a growing need for
novel salvage therapies for mRCC as combinations of
VEGF targeted therapy and immune checkpoint inhibitors
are now approved as first-line treatment. Telaglenastat
is a selective glutaminase inhibitor that is designed
to target one of the hallmarks of cancer, altered cellular
metabolism (Figure).1 In cancer cells, the Warburg effect
results in a deficit of essential metabolites for tumorigenesis.
In RCC cells, HIF-1 and HIF-2 mediate a switch
to use glutamate to fuel the tricarboxylic acid cycle (TCA)
cycle.2,3 Glutamate is also used by cancer cells to synthesize
amino acids and balance cellular oxidative stress.
Thus, RCC cells are dependent on glutamine metabolism,
and glutaminase plays a key role by converting glutamine
into glutamate.4
There is preclinical rationale and phase 1 clinical trial
data supporting the CANTATA trial. In a preclinical study
of VHL-deficient human RCC cell lines, glutaminase inhibition
compromised de novo pyrimidine synthesis, increased
levels of reactive oxygen species by impairing
glutathione biosynthesis, and impaired cell growth by
selectively inducing DNA replication stress.5 In a separate
preclinical study, telaglenastat plus cabozantinib had synergistic
antiproliferative activity in vitro and enhanced
anti-tumor activity in murine RCC xenografts.6 These
preclinical studies led to a phase 1 clinical trial of tela-
Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr.,
Professor of Cancer Research, Professor and Chair ad interim
Department of Genitourinary Medical Oncology, Division of Cancer
Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit
1374, Houston, TX 77030-4009 Email: ntannir@mdanderson.org
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