groups. Taken together, the recent results of CheckMate
214 and IMmotion 151 suggest that anti-angiogenic therapies
can still have a place in the frontline setting.
The Role of PD-L1 Staining
PD-L1 staining by immunohistochemistry (IHC) to guide
therapy in RCC remains controversial. In the second line
setting, PD-L1 expression was shown to be associated
with a poor prognosis independent of the treatment
(nivolumab or everolimus).21 In the CheckMate 214 trial,
analysis of outcomes by PD-L1 expression status demonstrated
again that PD-L1 expression was prognostic
though the degree of benefit from the combination of
nivolumab plus ipilimumab was noticeably different
based on PD-L1 status. Using the Dako PD-L1 IHC 28-8
pharmDx test with a cutoff of 1% on tumor cells, PFS was
markedly improved in PD-L1 positive patients treated
with nivolumab plus ipilimumab compared to sunitinib,
from 5.9 months to 22.8 months. No
benefit was reported with the combination
in the PD-L1 negative group (<1%),
with respective PFS of 10.4 vs 11
months. However, OS benefit was maintained
independently of PD-L1 status,
though again the degree of benefit was
more pronounced in the PD-L1 positive
patients.
In the IMmotion 151 phase III study
of atezolizumab and bevacizumab compared
with sunitinib, treatment with
“Novel treatment strategies
involving the use of immunotherapeutic
and targeted
agents have ushered in a new
era and challenged TKI monotherapy
in the frontline setting,
with combination therapies
that will likely become the standard
of care for most patients.
However, TKI monotherapy may
represent a preferred option in
subtypes of patients in this
setting.”
atezolizumab and bevacizumab resulted
in improved investigator-assessed PFS in
PD-L1–positive patients, achieving the
study’s primary endpoint (11.2 vs 7.7
months, HR 0.74, 95% CI: 0.57-0.96, P =
0.02)1 PDL-1 positivity was defined as ≥ 1% in the tumor
infiltrating cells using expression by immunohistochemistry
with the SP142 assay. Taken in aggregate, these studies
indicate that the chance for improved efficacy may be
higher in PDL-1 positive tumors in the frontline setting,
at least with combination of nivolumab/ipilimumab and
atezo-lizumab/bevacizumab, though responses are seen
in PDL-1 negative tumors. Ongoing trials exploring different
immune checkpoint and VEGFR inhibitors may
also stratify patients using different PD-L1 tests and cutoffs
for positivity. Thus, the role of PD-L1 as a predictive
and prognostic biomarker may continue to evolve. As
such, refined predictive biomarkers to select patients for
VEGF-targeted therapy alone, checkpoint blockade, or
combination therapy are warranted to inform treatment
decision making.
Perspectives From Genomic Profiling
Genomic profiling continue to evolve in RCC; there are
several biomarker driven trials currently open in nonclear
cell RCC. SAVOIR explores the role of a pure MET inhibitor
savolitinib vs sunitinib in those with MET-driven
papillary RCC (NCT 03091192), while PAPMET is comparing
86 Kidney Cancer Journal
PFS in patients with metastatic papillary renal cell
carcinoma treated with sunitinib vs several MET (+/-
VEGF) Kinase inhibitors (NCT 02761057). However, currently
the role of universal tumor profiling in advanced
ccRCC is unclear. In clinical practice it is most commonly
used in later lines to try and find potentially targetable
mutations. Several reports mention that tumors harboring
mutations in the TOR/Akt/PI3K pathway may increase
responses to mTOR inhibitors.22,23 One report in
advanced ccRCC showed that patients with PBRM1 mutations
may respond better to immune checkpoint blockers.24
Gene expression signatures, while not readily available
in clinical practice to date, may also help improve
therapeutic strategies. The IMmotion 150 phase 2 trial included
three cohorts: sunitinib, atezolizumab, atezolizumab
plus bevacizumab.25 Correlative analyses for biomarkers
revealed that patients with a high angiogenic
genes expression had better outcomes with sunitinib
compared to the other 2 arms. Validation
of genomic profiling to assess the optimal
therapeutic sequence might come
from prospective trials, such as the phase
2 BIONIKK trial, which will randomize
patients to dedicated treatment arms according
to their molecular profile
(NCT02960906).
Conclusion
Novel treatment strategies involving the
use of immunotherapeutic and targeted
agents have ushered in a new era and
challenged TKI monotherapy in the
frontline setting, with combination therapies
that will likely become the standard
of care for most patients. . However, TKI
monotherapy may represent a preferred option in subtypes
of patients in this setting. At this point, patient comorbidities,
IMDC risk classification are critical to guide
treatment strategies. Future clinical trials should help refine
these classifications and help physicians achieve a
more personalized approach for treatment strategies.
References
1. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized
Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated
Metastatic Renal Cell Carcinoma (mRCC). JCO 2018;
36:578–578.
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Progression-Free Survival in Previously Untreated Patients with
Advanced Renal Cell Carcinoma in Phase III Study | Pfizer: One of the
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