HR (95% CI)
0.0625 0.125 0.25 0.5 1 2
Kidney Cancer Journal 97
Median PFS (mo)
N Cabozantinib Sunitinib
All patients 157 8.6 5.3
IMDC risk group
Intermediate 127 11.4 6.1
Poor 30 6.8 2.7
Bone metastases
Yes 57 5.5 3.3
No 100 11.4 5.7
MET status*
Positive 62 13.8 3.0
Negative 69 6.9 6.1
combination group received nivolumab 3 mg/kg plus ipilimumab
1 mg/kg every 3 weeks for 4 cycles followed by
nivolumab 3 mg/kg every 2 weeks. Patients in the comparator
group received sunitinib 50 mg once daily for 4
weeks, followed by 2 weeks off before continuation of
treatment. Patients were treated until progression or unacceptable
toxic effects.
The primary endpoints of the trial were overall
survival (OS), objective response rate (ORR), and progression
free survival (PFS) in an intermediate- to poor-risk
patient population (approximately 75% of patients).8
Safety was a secondary endpoint. The key findings from
Checkmate -214 revealed:
• The median overall survival (OS) was not reached with
the combination versus 32.9 months with sunitinib
(HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003). In those
specifically with intermediate- and poor-risk RCC, who
constituted about 75% of the intent-to-treat (ITT) population,
median OS was not reached in the nivolumab
and ipilimumab arm and was 26.0 months in the sunitinib
arm, a 37% reduction in the risk of death (HR,
0.63; 99.8% CI, 0.44-0.89; P <.0001). Overall survival
for the combination versus sunitinib in those with favorable
risk has not yet been reported. (Figures 3,4)
• The overall response rate (ORR) favored the combination
over sunitinib in intermediate/poor risk patients
irrespective of baseline tumor PD-L1 expression while
a PFS benefit with the combination was seen only in
patients with PD-L1 ≥1%. (Figure) For the favorable risk
group, the sunitinib arm was favored over the combination
for PFS and ORR.
Grade 3/4 adverse events (AEs) were reported in 46%
of patients (252/547) in the combination group, compared
with 63% of patients (337/535) in the sunitinib
group. The most common grade 3/4 AEs in the combination
group were fatigue (4%), diarrhea (4%), nausea
(2%), decreased appetite (1%), and, in less than 1% each,
pruritus, hypothyroidism and hypertension. In the sunitinib
group, the most common grade 3/4 AEs were hypertension
(16%), fatigue (9%), Palmar-plantar erythrodysaesthesia
syndrome (9%), diarrhea (5%), stomatitis
(3%), mucosal inflammation (3%), nausea (1%), decreased
appetite (1%), and in less than 1% each, hypothyroidism
and dysgeusia. Adverse events (AEs) leading
to discontinuation were reported in 22% of patients
(120/547) in the combination group, compared with 12%
of patients in the sunitinib group (64/535). Seven treatment
related deaths occurred in the combination group
and four in the sunitinib group.
Checkmate -214 delineated the role of PD-L1 expression
to a greater extent than has previously been elucidated.
Programmed death-ligand 1 (PD-L1) expression
level impacted response to nivolumab plus ipilimumab,
regardless of risk category. In patients with IMDC intermediate/
poor risk and PD-L1 ≥1%, ORR was 53% with
nivolumab plus ipilimumab, versus 22% with sunitinib
(P<.0001). By comparison, if patients with IDMC intermediate/
poor risk had PD-L1 <1%, ORR with nivolumab
plus ipilimumab was 37%, compared to 22% with sunitinib
(P = .0252). Results in the ITT population showed
that nivolumab plus ipilimumab was associated with a
statistically significant improvement in ORR in patients
Figure 2. Forest Plots of Progression-Free Survival per IRC.
0.48 (0.31-0.74)
0.52 (0.32-0.82)
0.31 (0.11-0.92)
0.51 (0.26-0.99)
0.50 (0.29-0.85)
0.32 (0.16-0.63)
0.67 (0.37-1.23)
Favors cabozantinib Favors sunitinib
*Eight patients in the cabozantinib group and 18 patients in the sunitinib group had unknown MET status.
All randomized patients were included in the analyses. Hazard ratios are unstratified with the the exception of the analysis for all patients.
CI, confidence interval; HR, hazard ratio; IMDC, internationsal metastatic renal cell carcinoma database consortium; IRC, independent radiology committee;
mo, months; PFS, progression-free survival.