Figure 4a. Figure 4c.
(median survival of more than 3 years similar to that of
COMPARZ trial) irrespective of TKI type. The median PFS
is also comparable to COMPARZ (investigator review) at
around 10 months. Taking the unequal distribution of
patient with poorer risks between the two drug types into
consideration, efficacy and survival are comparable between
sunitinib and pazopanib and remaining true when
compared among matched prognostic subgroups. This
real world evidence reaffirms the important role of VEGF
pathway inhibition as one the main therapeutic strategy
in mRCC, particularly among patients with favorable
prognostic risk. The lower benefits among patients belonging
to intermediate and poor prognostic risk categories
in this real world data set is in keeping with published research
data and represents an on-going challenge in
mRCC.
112 Kidney Cancer Journal
Results from Checkmate-214 study represent a breakthrough
in this area. In this phase 3 randomized controlled
trial comparing ipilimumab and nivolumab with
sunitinib among patient populations of predominantly
I/P prognostic risk category, combination checkpoint inhibitors
showed superior PFS in patients with less than
favorable risk group while patients with favorable risk
achieved better outcome with sunitinib. At 30 months
update review, median OS was not reached in the combination
group (versus 37.9 months) and a complete response
rate of 11%10,11. Translational work done in the
IMMOTION 150 and151 study by Rini et al 12 found that
patients with favorable prognostic risk is characterized by
a predominantly angiogenesis gene expression signature
which correlated with improved PFS when exposed to
VEGF-directed therapy. Patients with a predominantly
immune underlying gene expression signature fared better
when exposed to immunotherapy in these trials.
These early findings provided some insight into the differential
susceptibility of tumors to VEGF or immune
checkpoint pathway blockade or even both among the
different clinical prognostic risk categories although the
full understanding is still evolving.
There is other progress in the management of patients
with I/P risk categories. Following positive results of the
METEOR trial in second line setting13, the CABOSUN
study was set up to evaluate the efficacy of Cabozantinib
compared to sunitinib among mRCC patients with Intermediate
or Poor IMDC risk group (~20% Poor IMDC risk).
Cabozantinib is a third generation VEGF pathway directed
tyrosine kinase inhibitor poised with additional
target activity against AXL and MET receptor. In CABOSUN,
ORR was significantly higher in Cabozantinib group
at 46% versus 18% and an impressive 34% reduction in
Figure 4b.
Figure 4. Kaplan-Meier curves comparing OS between Pazopanib
versus Sunitinib according to MSKCC a) good b) intermediate and
c) poor prognostic subgroups. No statistical difference shown.