months), and overall response
rate (55.8% vs
29.5%) in those with
intermediate and poor
risk disease. 105 patients
(18.2%) were identified
who had sarcomatoid features;
51 in the pembrolizumab
plus axitinib arm
and 54 in the sunitinib
arm. Pembrolizumab plus
axitinib improved overall
survival (12-month overall
survival rate 83.4% vs
79.5%), progression free
survival (median not reached
vs 8.4 mo), and ORR
(58.8 vs 31.5%) in patients
with sarcomatoid
features; CR rates were 11.8% vs 0%.
Zibelman et al presented data on a small number of
patients from the phase I portion of a combined phase
I/II study of combination nivolumab and axitinib in the
second- and third-line setting. Twelve patients were enrolled
and evaluable, of those, four demonstrated a partial
response, four had stable disease, and two progressed. Toxicity
was manageable. Enrollment will proceed with the
phase II portion of the trial.
Checkpoint Inhibitor Therapy and
Comorbid Autoimmune Disease
Most trials of immunotherapy exclude patients with
known autoimmune diseases, but Chanza and colleagues
presented a retrospective review of 103 patients (57 with
RCC and 46 with urothelial carcinoma) with a broad
spectrum of comorbid autoimmune diseases such as psoriasis,
thyroiditis, rheumatoid arthritis, polymyalgia rheumatica,
inflammatory bowel disease, multiple sclerosis,
and lupus, who received immune checkpoint inhibitor.
36 of these patients had clinically active autoimmune
disease at the time of therapy, some requiring systemic
immunosuppression. Exacerbations of these autoimmune
diseases occurred in 37% of patients, with the most frequent
being arthritis and rash. New onset immune related
events occurred in 36% of the patient’s analyzed, with
the most frequent being colitis, rash, hypothyroidism,
and nephritis. Both exacerbations of existing autoimmune
diseases and new onset immune related events
were generally manageable, and the data suggests that in
certain clinical scenarios patients with autoimmune
diseases can be safely treated with immune checkpoint
inhibitor therapy.
Encouraging Results in Brain Metastases
With Nivolumab+Ipilimumab
Most trials of patients with advanced RCC also exclude
patients with brain metastases, however trials in melanoma
and lung cancer have shown efficacy of combination
nivolumab and ipilimumab in patients with brain
metastases. Emamekhoo et al, e presented data from 28
patients from the CheckMate 920 trial who had asymptomatic
brain metastases and retreated with nivolumab
54 Kidney Cancer Journal
and ipilimumab. Overall
response rate was 28.6%,
median progression-free
survival was 9 months,
and overall survival had
not been met. Toxicities
were as expected. These
data suggest encouraging
antitumor activity a combination
immunotherapy
in patients with advanced
RCC and brain metastases
and suggests that
we should more closely
evaluate this phenomenon
before excluding patients
with brain metas-
tases from clinical trials.
Redefiing Systemic Therapy After Cytoreductive Surgery
Several studies sought to better define how to use systemic
therapy along with surgery strategies. Jianjun Gao
led investigators from MD Anderson who evaluated effects
of immunotherapy when combined with cytoreductive
surgery. Patients were randomized in a 2:3:2
fashion to receive single agent nivolumab (3mg/kg every
2 weeks for three doses), nivolumab and bevacizumab
(10mg/kg every two weeks for three doses) or nivolumab
plus ipilimumab (1mg/kg q3wks x2), followed by cytoreductive
surgery (nephrectomy, metastasectomy, or biopsy),
and then went on to nivolumab maintenance
therapy for up to 2 years. Imaging response was assessed
and pre- and post-treatment blood and tissue were obtained.
104 subjects were evaluable for response. Best overall
response (complete response + partial response)
including surgery effect was 55% for single agent nivolumab,
44% for combination nivolumab + bevacizumab,
and 43% for nivolumab and ipilimumab. Median progression
free survival was 14.5 months for nivolumab, 7.6
months for the combination of nivolumab + bevacizumab,
and 7.5 months for nivolumab plus ipilimumab.
Overall survival (overall survival) at one year was 86%
with nivolumab alone, 73% for combined nivolumab
plus bevacizumab, and 83% for nivolumab plus ipilimumab.
Immune and gene profiling analyses demonstrated several
interesting observations, including: 1) tumor infiltrating
CD8 T cells correlated with imaging response to
single agent nivolumab and to combination nivolumab
plus bevacizumab, but not to nivolumab combined with
ipilimumab; 2) tumor IFN pathway gene expression correlated
with responses; and 3) PD-L1 status, tumor mutation
or mutation burden, and neoantigens did not
correlate with response. Gao et al concluded that immune
checkpoint inhibitor therapy is safe and beneficial
in mRCC patients when used with cytoreductive surgical
techniques.
Results of the ECOG E2810 study were also presented
by Leonard Appleman. In this double-blind phase III
study, investigators randomized patients to receive adjuvant
pazopanib for 1 year versus placebo following complete
metastasectomy (all patients had no evidence of