demonstrated overall tolerability with fewer incidences
of grade 3 or worse liver function abnormalities than was
seen with prior combination studies with pazopanib or
sunitinib. Dose-limiting toxicities were reported in 3 of
11 patients treated in the dose-finding phase of the study,
and the maximum tolerated dose was determined to be
pembrolizumab 2 mg/kg every 3 weeks and axitinib 5 mg
twice daily. Grade 3 or higher treatment-related AEs were
observed in 65% of patients, including hypertension, diarrhea,
increased transaminases, hypothyroidism, and fatigue.
Pembrolizumab plus axitinib demonstrated encouraging
anti-tumor activity. The proportion of patients who
achieved an objective response was 73% (95% CI 59-
84%), including 8% with a CR and 65% with a partial response
(PR) at a median follow-up of 20.4 months. An
additional 15% of patients had stable disease, and more
than 90% of patients experienced some degree of tumor
shrinkage. The median PFS was 20.9 months. The antitumor
activity seen in the phase Ib study was superior to
that expected from axitinib or anti-PD-1 monotherapy.
A randomized phase III trial (KEYNOTE-426;
NCT02853331) comparing the combination of pembrolizumab
plus axitinib vs sunitinib monotherapy in
treatment-naïve mRCC patients is underway and has
reached its enrollment goal. The co-primary endpoints
are PFS and OS in the PD-L1 positive population.
Avelumab plus Axitinib
JAVELIN Renal 100 was a phase Ib trial investigating the
combination of the anti-PD-L1 antibody avelumab with
axitinib in treatment-naïve patients (n=55) with advanced
ccRCC.23 Avelumab is a human IgG1 monoclonal
antibody that not only targets the immune checkpoint
protein PD-L1 but also mediates antibody-dependent cellmediated
cytotoxicity of cancer cells.30
The safety profile of avelumab plus axitinib was consistent
with the known profiles of single-agent avelumab
and axitinib. A dose-limiting toxicity of proteinuria was
reported in 1 of 6 patients treated in the dose-finding
phase. The maximum tolerated dose for the combination
was determined to be avelumab 10 mg/kg every 2 weeks
and axitinib 5 mg twice daily. Grade 3 or higher treatment
related AEs were reported in 58% of patients, most
commonly hypertension, palmar-plantar erythrodysesthesia,
and increases in transaminase, lipase, and amylase.
The combination of avelumab plus axitinib also demonstrated
encouraging anti-tumor activity. Objective response
was reported in 58% (95% CI 44-71%) of patients,
including CR in 5% and PR in 53%. An additional 20% of
patients experienced stable disease, resulting in a disease
control rate of 78%. A majority of patients experienced
early and durable responses. The anti-tumor activity of
the combination in JAVELIN Renal 100 was superior to
the expected activity of single-agent axitinib or anti-PDL1
therapy. The randomized phase III trial JAVELIN Renal
101 (NCT02684006) is comparing avelumab plus axitinib
80 Kidney Cancer Journal
against sunitinib monotherapy in treatment-naïve mRCC
patients and has reached its accrual target. The co-primary
endpoints are PFS and OS between the treatment
arms.
Pembrolizumab plus Lenvatinib
The combination of pembrolizumab plus the multikinase
TKI lenvatinib was evaluated in a phase Ib/II study in patients
with selected solid tumors. Updated preliminary results
from the ccRCC cohort (n=30) were reported at the
2018 ASCO Annual Meeting.24 Unlike the phase Ib studies
of pembrolizumab plus axitinib and avelumab plus
axitinib in treatment-naïve patients, the early evaluation
of pembrolizumab plus lenvatinib allowed for patients
who previously received systemic therapies. Treatmentexperienced
patients accounted for 60% of the mRCC cohort.
Pembrolizumab was administered at 200 mg every
3 weeks and lenvatinib administered at either 24 mg daily
or 20 mg daily.
Grade 3 or higher AEs occurred in 73% of patients
treated with the combination. The most common grade
3 or higher AEs included proteinuria, elevated lipase, hypertension,
diarrhea, and fatigue. Dose adjustment or discontinuation
due to AEs was common. Lenvatinib dose
was reduced in 73% of patients, lenvatinib discontinuation
in 20%, and pembrolizumab discontinuation in
27%.
The primary endpoint of ORR at 24 weeks was 63%
(95% CI 44-80%) in the phase Ib/II study. Twenty-nine
of the 30 patients experienced tumor shrinkage. Median
PFS was 17.7 months. Anti-tumor activity appeared to be
similar regardless of prior therapy or PD-L1 status. The
phase III CLEAR trial (NCT02811861) is currently enrolling
patients with treatment-naïve advanced ccRCC
with randomization to pembrolizumab plus lenvatinib vs
lenvatinib plus everolimus vs sunitinib. The dosing regimen
of pembrolizumab 200 mg every 3 weeks and lenvatinib
20 mg daily was selected for the phase III study. The
primary endpoint is to compare the PFS of pembrolizumab
plus lenvatinib or lenvatinib plus everolimus
vs sunitinib.
Nivolumab plus Cabozantinib
The combination of cabozantinib plus nivolumab with
or without ipilimumab was evaluated in a phase I study
that enrolled patients with a variety of metastatic genitourinary
cancers.25 Preliminary results were presented at
the 2018 Genitourinary Cancers Symposium. A total of
75 patients were enrolled, including 14 patients with previously
treated mRCC. Seven RCC patients accrued to the
nivolumab plus cabozantinib cohort and 7 RCC patients
accrued to the nivolumab plus ipilimumab plus cabozantinib
cohort. A total of 7 dose levels were included in the
study. All 7 RCC patients in the nivolumab plus cabozantinib
combination received nivolumab 3 mg/kg every 2
weeks plus cabozantinib 40 mg daily, which was ultimately
determined to be the recommended phase II dose
for the doublet combination. All 7 RCC patients in the