Kidney Cancer Journal 85
to sunitinib in 70% of patients and 67% of physicians,
given quality-of-life and fatigue concerns.
Critics of the study point out that sunitinib was given
on a 4/2 schedule in both PISCES and COMPARZ, while
alternative schedules have since been evaluated to improve
toxicity. Nonetheless, a randomized phase 2 trial
comparing continuous dosing of sunitinib 37.5 mg daily
with conventional dosing showed a trend towards improved
PFS with traditional schedule (9.9 vs 7.1 months,
hazard ratio (HR) 0.77; 95% CI, 0.57 to 1.04; P = .090),
with no difference in side effects profile, or patient-reported
kidney cancer symptoms.14 However, a randomized
phase 2 trial comparing a 2/1 dosing schedule to
traditional dosing showed improved failure free survival
at 6 months (63 vs 44%) as well as less toxicities with alternative
dosing.15 Another phase 2 study exploring the
2/1 dosing schedule did not meet the primary end point
of decreased grade 3 toxicity though it was associated
with a lack of grade 4 toxicity and a high response rate of
57%. Given the desire to maximize dosing, it is appealing
to start with the highest dose possible. The pros- pective
phase IIB SURF trial NCT02689167, accruing now,
starts with traditional dosing; when toxicities arise, patients
are randomized to sunitinib 37.5 mg on a 4/2
schedule vs sunitinib 50 mg on a 2/1 schedule.
Cabozantinib vs Sunitinib in the CABOSUN Trial
Cabozantinib is a VEGFR inhibitor that also targets multiple
kinases, including MET and AXL receptors. MET is
a receptor to the hepatocyte growth factor (HGF), which
activates pathways involved in survival, proliferation and
invasion. MET can also regulate cortical bone osteogenesis,
16 making it an interesting target in the context of
bone metastases. AXL is binds to growth arrest specific 6
(GAS6), involved in growth, migration and differentiation
in multiple cell types. Expression of MET and AXL
have been associated with tumor progression and resistance
to VEGF-pathway inhibition in preclinical models,
and adverse outcomes in clinical studies. Initial approval
for cabozantinib came from the VEGF-refractory setting
with METEOR, a randomized phase 3 trial that compared
the efficacy and safety of cabozantinib versus the mTOR
inhi- bitor everolimus.17 Later on, the randomized ALLIANCE
phase 2 trial CABOSUN evaluated cabozantinib
against sunitinib in the first-line setting, and a recent update
evaluated the primary endpoint of PFS by central review.
18,19 Among 157 patients, cabozantinib significantly
prolonged PFS compared with sunitinib in poor or intermediate
risk patients, from 5.3 to 8.6 months. Toxicity
rates were comparable between the two arms, with increased
grade 3/4 fatigue and hematologic abnormalities
with sunitinib, but increased liver function test abnormalities,
anorexia and dysgeusia with cabozantinib. With
a median follow-up of 34.5 months, median OS was 26.6
months (95% CI 14.6-not estimable) with cabozantinib
and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR
0.80 95% CI 0.53-1.21. Another element that might account
for the improved PFS of cabozantinib over sunitinib
is the low performance of the sunitinib arm, as prior
studies rather demonstrated longer PFS with sunitinib in
the first line setting. However, the population of CABOSUN
had only patients harboring intermediate or poor
risk disease, 30% having bone metastases and 13% with
a performance status of 2. Notwithstanding this selected
population, the recent FDA approval of cabozantinib was
granted to all patients presenting with untreated advanced
RCC independently of risk classification.
The Importance of Patient Classification
The importance of patient stratification to determine the
best therapeutic approach was highlighted by the Check-
Mate 214 trial of nivolumab and ipilimumab vs sunitinib.
20 The coprimary endpoints were objective responses
rate, PFS, and OS among IMDC intermediate- and
poor-risk patients. At a median follow-up of 25.2 months,
nivolumab plus ipilimumab had a significant OS benefit
over sunitinib among intermediate- and poor-risk patients:
median OS was not reached with nivolumab plus
ipilimumab vs 26.0 months with sunitinib (HR 0.63,
99.8% CI = 0.44–0.89, P < .001). Based on these results,
the FDA granted approval to nivolumab plus ipilimumab
for the treatment of intermediate- and poor-risk treatment
naive patients with advanced renal cell carcinoma.
However, the CheckMate 214 trial also demonstrated
that prognostic risk strata differentially impacted the outcomes
in each study arm. In the favorable-risk cohort (35
% of all patients by MSKCC) , the objective response rate
was higher in sunitinib-trea-ted patients than in those receiving
nivolumab plus ipilimumab—29% with nivolumab
plus ipilimumab vs 52% with sunitinib (P < .001),
although complete responses were higher with nivolumab
and ipilimumab, observed in 11% vs 6% of patients
respectively. Additionally, PFS favored sunitinib
over nivolu- mab plus ipilimumab (25.1 months for sunitinib
vs 15.2 months for nivolumab plus ipilimumab,
P < .001). The near double improvement in PFS and ORR
with sunitinib in the favorable risk patients is notable,
though the marked improvement in CR with the combination
arm can support this immunotherapy combination
as an option for those with good risk disease despite
its FDA label. The combination is not without its toxicities.
While grade 3 and 4 toxicities were less frequent with
nivolumab+ipilimumab (46 vs 63%), 60% of patients receiving
the immunotherapy combination received corticosteroids
in the course of their treatment; of those with
immune related adverse events 35% required high dose
(>40 mg per day of prednisone)
The IMmotion 151 phase 3 that evaluates the anti-PDL1
atezolizumab plus bevacizumab sunitinib highlights
the importance of VEGF/ VEGFR-targeted therapies in favorable
risk patients.1 In this study, atezolizumab plus bevacizumab
provided a PFS improvement in PD-L1 positive
advanced RCC compared to sunitinib (HR 0.74, P =
0.02), which was the primary endpoint of the study. The
benefit of bevacizumab plus atezolizumab in IMmotion
151 was found to be consistent regardless of the risk