Similar clinical trials in mRCC are currently ongoing.
In another randomized phase II trial (NCT03075423), the
combination of axitinib and pembrolizumab was evaluated
versus sunitinib in untreated advanced or metastatic
RCC. Results revealed that the combination of axitinib
and pembrolizumab significantly reduced the risk of
death (HR for death, 0.53; p < 0.0001) and disease progression
(HR for disease progression or death, 0.69; p < 0.001).
In the combination arm, the ORR was 59.3% (p < 0.001)
compared to 35.7% in the sunitinib group. These favorable
outcomes were observed across all risk groups and
regardless of PD-L1 expression.16 Similarly, pembrolizumab
is also being evaluated in the cohort B of the
KEYNOTE 427 phase II trial. In pRCC, durvalumab is
being evaluated in combination with savolitinib, a
highly selective MET tyrosine kinase inhibitor, in the CALYPSO
phase II trial (NCT02819596).
The Phase III trial IMmotion 151 (NCT02420821)
used the combination of PD-L1/PD-1 pathway inhibitor
with an anti-VEGF agent in untreated mRCC.20 This
study investigated the combination of atezolizumab, an
anti-PD-L1 antibody, with bevacizumab, as compared to
sunitinib monotherapy in mRCC. Based on PD-L1 expression
level on tumor-infiltrating immune cells, patients
were stratified by PD-L1 status. Results indicated
longer PFS (11.2 months) in the combination arm vs. 7.7
months in the sunitinib arm (HR, 0.74; p= 0.02) in the
PD-L1+ patients. Improved PFS was also observed in ITT
patients. The ORR in the PD-L1+ patients was 43% in the
combination arm as compared to 35% in the sunitinib
arm. The CR rate in the PD-L1+ patients was 9% in the
combination arm as compared to 4% in the sunitinib
arm. In the bevacizumab–atezolizumab arm, grade 3 or
4 toxicities occurred in 40% of patients group and in
54% of patients in the sunitinib group.20
In another randomized phase III trial known as
JAVELIN Renal 101 (NCT02684006), Motzer et al investigated
the combination of axitinib and avelumab in
treatment-naive RCC patients with metastatic or advanced
disease.17 In the axitinib and avelumab combination
arm, median PFS in the combination arm was
13.8 months versus 8.4 months in sunitinib arm (HR,
0.69; p< 0.001). The ORR and CR rate were 55% and 4%
were in the combination arm as compared to 26% and
2% in the sunitinib arm. When PD-L1+ patients were assessed,
the median PFS was 13.8 months in axitinib and
avelumab combination arm, versus 7.2 months in the
sunitinib arm (HR, 0.61; p < 0.001).17 This study demonstrated
that patients who received a combination of
avelumab plus axitinib had longer PFS and a higher objective
response rate than those who received sunitinib
monotherapy. KEYNOTE 426 phase III trial (NCT0285-
3331) evaluated the efficacy and safety of pembrolizumab
(MK-3475) in combination with axitinib versus
sunitinib monotherapy as a first-line treatment for 861
participants with advanced or metastatic renal cell carcinoma.
16 The combination therapy arm of pembrolizumab
plus axitinib showed a longer median PFS of
15.1 months compared to 11.1 months of the axitinib
arm (HR = 0.69; p < 0.001). The safety profile was comparable
to the results of the JAVELIN Renal 101 trial. Interestingly,
the benefit of pembrolizumab plus axitinib
54 Kidney Cancer Journal
for OS, PFS, and ORR was observed in the entire population
irrespective of the prognostic group and PD-L1
tumor expression. In the KEYNOTE-427 (NCT02853344)
trial, pembrolizumab monotherapy for treatment naïve
patients has also demonstrated promising efficacy and
acceptable tolerability in patients with accRCC. Results
indicated that ORR was 38.2 % and CR 2.7% in all treated
patients. In PD-L1 negative patients, ORR was found to
be 50.0 % as compared with 26.4% and the median PFS
was 8.7.
Although the combination of ICI and antiangiogenics
has shown encouraging preliminary antitumor activity
for advanced or mRCC, clinical trials indicate that toxicity
and tolerability may be difficult in some patients.
For instance, in the phase I study CheckMate 016
(NCT01472081), the efficacy and safety of nivolumab in
combination with antiangiogenic tyrosine kinase inhibitors
or ipilimumab for the treatment of mRCC.21 In
this study, addition of sunitinib or pazopanib to nivolumab
resulted in a high incidence of high-grade toxicities,
limiting its scope in future trials.
Future Directions
The remarkable advancement of immunotherapy into
the landscape of mRCC has improved the outlook for
many patients. In the coming years, emerging targeted
and immune therapies, or their combinations, may not
only deliver the improved efficacy achieved with overriding
immune resistance but also profoundly shape the
therapeutic landscape. There remains unmet need for
prospective ICI-based immunotherapy data in regard to
their ability to be appropriately sequenced as well as selected
after ICI. Evidently, successful outcome from ICI
plus antiangiogenic combinatorial regimens may be dependent
on prudent selection of the specific agents tailored
with optimal dose. Most importantly, appropriate
therapeutic sequence of combinatorial regimen along
with their dosage optimization will need to be ascertained
to avoid treatment discontinuation based on intolerable
toxicity and also ensure that the remarkable
therapeutic outcome will be achieved. The dosage optimization
for ICI monotherapy or the combination of ICI
with VEGF inhibitor in conjunction with optimal modulation
of TME is essential to facilitate the efficacy of ICI.
Besides, in the rapidly evolving renal cancer landscape
with the prospective of future ICI plus antiangiogenics,
efforts should be directed at obtaining consensus from
various immunotherapy agents as appropriate control
arm. Likewise, since complex immune modulatory responses
can be elicited by continuous exposure to ICI
combination, the irreversible T cell exhaustion, immuneediting,
and antigenic drift like complication should be
take into account while considering new therapeutic
combination. Currently available trials involving heterogeneous
patient populations making cross trial comparisons
impossible. Further emphasis is needed on
potential biomarkers and prospective validation of biomarkers
combinations. The treatment associated toxicities
remain a major roadblock hindering the widespread
use and applicability of these treatments. Therefore, evidence
based and algorithmic approaches in stratification,
treatment sequence, and treatment selection need