J O U R N A L C L U B
Essential Peer-Reviewed Reading in Kidney Cancer
The peer-reviewed articles summarized in this section were selected by the
Editor-in-Chief, Robert A. Figlin, MD, for their timeliness, importance, relevance,
and potential impact on clinical practice or translational research.
Emerging role of combination immunotherapy in the
first-line treatment of advanced renal cell carcinoma:
a review. George S, Rini BI, Hammers HJ. JAMA Oncol.
2018 Nov 21; doi: 10.1001/jamaoncol.2018.4604
Summary: Novel immunotherapies, notably the immune
checkpoint inhibitors, have been shown to be efficacious
in patients with advanced renal cell carcinoma (RCC), but
innate or adaptive resistance is observed with single-agent
immunotherapy. New combination treatment strategies
are needed that can improve efficacy in a broader patient
population, without exacerbating the toxic effects.
Numerous late-phase trials are ongoing to investigate (1)
dual immune checkpoint inhibition or (2) combined
inhibition of immune checkpoints and vascular endo-
thelial growth factor. Initial results from studies of the
nivolumab plus ipilimumab and atezolizumab plus bevacizumab
combinations have demonstrated efficacy compared
with sunitinib malate in treatment-naïve patients
with advanced renal cell carcinoma; moreover, the safety
profile of these combinations compare favorably with
sunitinib. Nevertheless, immune checkpoint inhibition is
associated with unique immune-related adverse events.
Conclusion: Evidence suggests that immunotherapy-based
combination regimens will be an important addition to
the treatment of advanced renal cell carcinoma in both
the first- and later-line setting; however, clinical study
data and clinical practice experience indicate that
optimizing the management of the associated immune-
related adverse events is essential to maximizing the
advantages of these therapies.
Cost-effectiveness of nivolumab plus ipilimumab as
first-line therapy in advanced renal-cell carcinoma.
Wu B, Zhang Q, Sun J. J Immunother Cancer. 2018 Nov
20;6(1):124. doi: 10.1186/s40425-018-0440-9.
Summary: The current study aimed to assess the cost-
effectiveness of nivolumab plus ipilimumab for first-line
treatment of advanced RCC from the payer perspectives
high- and middle-income regions. A decision-analytic
model was constructed to evaluate the health and economic
outcomes of first-line sunitinib and nivolumab
plus ipilimumab treatment associated with advanced
RCC. The clinical and utility data were obtained from
published reports. The cost data were acquired for the
payer perspectives of the United States (US), United Kingdom
(UK), and China. Sensitivity analyses were performed
to test the uncertainties of the results. Quality-adjusted
life-years (QALYs) and incremental cost-effectiveness
ratios (ICERs) were used. Nivolumab plus ipilimumab
gained 0.70-0.76 QALYs compared with sunitinib. The
analysis determined the following ICERs for nivolumab
plus ipilimumab over sunitinib in first-line advanced RCC
treatment: US $ 85,506 /QALY; UK $ 126,499/QALY; and
China $ 4682/QALY. Sensitivity analyses found the model
outputs to be most affected for body weight and for the
prices of nivolumab, sunitinib and ipilimumab.
Conclusion: Nivolumab plus ipilimumab as first-line
treatment could gain more health benefits for advanced
RCC in comparison with standard sunitinib, which is
considered to be cost-effective in the US and China but
not in the UK.
The identification of immunological biomarkers in
kidney cancers. Lopez-Beltran A, Henriques V,
Cimadamore A, et al. Front Oncol. 2018 Nov 2;8:456.
doi: 10.3389/fonc.2018.00456
Summary: RCC includes a large group of tumor entities,
each of them with different genetic and mutational alterations,
but also showing different clinical behavior; a
reason behind the need for a subtype specific personalized
approach to therapy of RCC. Due to the combination of
potent treatment success and potentially deadly adverse
effects from immune checkpoint inhibitors (ICI), gathering
prognostic and predictive information about FDA-
indicated tumors seems to be prudent. Robust and reliable
biomarkers are crucial for patient’s selection of treatments
with immunomodulatory drugs. PD-L1 expression is a
poor prognostic factor and predictive of better responses
from both PD-1 and PD-L1 inhibitors in a variety of
tumor types including RCC. Each FDA approved PD-1/PDL1
drug is paired with a PD-L1 Immunohistochemistry
(IHC) assay. Thus, there is need for improved knowledge
and application of PD-1/PD-L1 IHC biomarkers in daily
practice. IHC staining appears in membranous fashion.
Conclusion: The atezolizumab approved IHC assay is
unique in that only immune cell staining is quantified
for the use of this assay in RCC. A single biomarker for
patient selection may not be feasible, given that immune
responses are dynamic and evolve over time. Biomarker
development for ICI drugs will likely require integration
of multiple biologic components like PD-L1 expression,
TILs and mutational load. New methodological approaches
based on digital pathology may be relevant since
they will allow recognition of the biomarker and to objectively
quantitate its expression, and therefore might produce
objective and reproducible cut-off assessment.
Multidisciplinary approach is very much needed to fully
develop the current and future value of ICI in clinical
practice.
Genomically annotated risk model for advanced renalcell
carcinoma: a retrospective cohort study. Voss MH,
Reising A, Cheng Y, et al. Lancet Oncol. 2018 Nov 8. pii:
S1470-2045(18)30648-X.
Summary: Several mutations, including BAP1 and
PBRM1, have prognostic value in renal-cell carcinoma.
Using two independent clinical trial datasets of patients
with metastatic renal-cell carcinoma, this study aimed to
determine whether the addition of the mutation status for
several candidate prognostic genes to the MSKCC model
106 Kidney Cancer Journal
(continued on page 124)