Practice Changing Results in RCC come from ASCO 2021
.
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Ochsner Precision Cancer Therapies Program and Ochsner Cancer Institute, Benson Cancer Center. New Orleans LA
ABSTRACT
For the second year in a row, the
annual meeting of the American
Society of Clinical Oncology
(ASCO) was held virtually due to the ongoing
COVID-19 pandemic. Nonetheless,
the meeting was hailed as a great
success and brought much practice
changing data in the field of genitourinary
medical oncology, including kidney
cancer.
The most ground-breaking presentation
was given by Dr. Toni Choueiri,
who presented interim results of
Keynote-564, a phase 3 double-blind trial
comparing adjuvant pembrolizumab to
placebo following nephrectomy in clear
cell RCC patients with intermediateand
high-risk of recurrence. The study
enrolled 994 patients with pT2 grade 4
or sarcomatoid, pT3-4 any grade, node
positive disease (any grade, any T stage)
RCC within 12 weeks of nephrectomy
and those with completely resected
oligometastatic disease within a year
of nephrectomy. The great majority
of patients fell into the first two
categories. The results represented
the first prespecified analysis after
approximately 265 disease free survival
(DFS) events. DFS at 12 months was
76.2 in the control arm vs 85.7% in
pembrolizumab arm and at 24 months
was 68.1 vs 77.3% in those arms. This
represented a hazard ratio (HR) of
0.68 (95% CI: 0.53-0.87, p=0.0010).
Overall survival (OS) was not mature
and only included about a quarter of
events, but still trended towards a
meaningful improvement with a 46%
reduction in the risk of death in those
receiving pembrolizumab, HR= 0.54
(95% CI 0.30 – 0.96, p=0.0164). Safety
was as expected with no new signals
emerging. This represents the first
positive adjuvant immunotherapy trial
in RCC and in the opinion of many in
the genitourinary medical oncology
community, the first step towards a
viable adjuvant option in RCC, given the
overall weak efficacy and unfavorable
toxicity profile of sunitinib in this
setting. Yet, there is still more work
to be done. As noted above, the OS
was not mature and many questions
remain, including role of PD-L1 status
as a biomarker of adjuvant benefit
of immunotherapy, how non-clear
cell might respond to this approach,
and the benefit patients with early
stage disease or who are more than 12
weeks from nephrotomy might benefit,
among others. Fortunately, several
ongoing studies are investing some of
these issues and the Keynote-564 data
continues to mature.
Novel Therapies and Combinations
Yuan-Yuan Qu and colleagues from
China provided impressive updated
results from a phase II study of the anti-
PD-L1 camrelizumab plus famitinib, a
TKI against VEGFR-2, PDGFR, c-kit,
and FGFR, in patients with advanced,
heavily pre-treated RCC and urothelial
carcinoma. Thirty-eight patients
with advanced RCC were included,
with an ORR of 63.2% (95% CI, 46.0-
78.2; 24 PRs), DCR of 89.5% (95% CI,
75.9-95.8), and median DOR which
was not reached (range 2-19+ mos) in
this cohort. Median PFS was also not
reached, and 12-mo OS rate was 88.0%.
92.1% of subjects had reduction in
target lesions with a median reduction
of 47% from baseline noted. DCR was
100% (95% CI, 77.2-100.0) in untreated
RCC patients and 84.0% (95% CI, 65.3-
93.6) in pre-treated patients. Further
study of this regimen certainly seems
warranted.
Results of a phase 1b study
of the novel IL-2v immunocytokine
Simlukafusp α were presented by
Perez-Garcia et al. This study enrolled
69 patients with unresectable clear
cell and/or sarcomatoid RCC who were
treated with the novel drug paired with
atezolizumab or bevacizumab or both.
The triplet combination was found to
be most efficacious with ORR of 47-
48% including 3 complete responses in
patients treated with triplet therapy.
Dr. Nizar Tannir of MD
Anderson presented results of the
highly anticipated CANTATA study,
which randomized 444 patients who had progressed on 1-2 prior lines
of therapy to a combination of the
glutaminase inhibitor telaglenastat
plus cabozantinib or placebo plus
cabozantinib. Unfortunately, the study
did not meet its endpoints. Median PFS
(mPFS) was 9.2 months for telaglenastat
plus cabozantinib arm vs 9.3 months
for the control arm (HR = 0.94; 95%
CI: 0.74, 1.21; stratified log-rank p=
0.65) with overall response rates (ORR;
confirmed) of 31% with Tela+Cabo vs
28% Pbo+Cabo, respectively.
Tumor growth in Von Hippel-
Lindau disease is driven by an aberrant
accumulation of HIF-2alpha due to the
inactivation of VHL, ultimately resulting
in the development of clear cell RCC,
pancreatic neuroendocrine tumors
(pNET), and hemangioblastomas.
A phase 2 study of the HIF-2alpha
inhibitor belzutifan (MK-6482) in
patients with Von Hippel-Lindau disease
associated RCC revealed promising
results. 61 patients
were enrolled with a
median follow-up of
69 weeks, of those,
92% remained on
therapy at the time
of analysis. There
were 22 confirmed
responses (36%) and
(11%) unconfirmed
responses. ORR
was 80% in pNETs
including one
complete response
and 32% in CNS
hemangioblastomas,
also including one complete response.
There were 16 retinal hemangioblastoma
patients evaluable at baseline, of which
69% showed improvement.
There is much research around the
role of the microbiome in cancer,
and particularly around response
to immunotherapy. Results of a
randomized phase 1b study of CBM-
588 (an agent principally consisting
of Clostridium butyricum) showed
a significantly improved ORR when
this drug was added nivolumab plus
ipilimumab (59%) as compared to
nivolumab plus ipilimumab alone (11%).
Median PFS was also prolonged (NR
vs 11 weeks), although sample size was
small (30 subjects) and the comparator
arm did much poorer than historically
expected.
Xinan Sheng and colleagues
from China presented a Phase 3
double-blind three arm trial in which
randomized patients received in a
1:1:1 fashion either the VEGF-targeted
vorolanib plus placebo, everolimus,
or a combination of these. 399
patients were enrolled. Median
PFS was prolonged in combination
arm compared to the single-agent
everolimus group (10.0 months [95%
CI, 8.2-10.4] vs. 6.4 months [95% CI,
4.7-8.3]; HR = 0.70 [95% CI, 0.52-0.94];
P = 0.0171). Median PFS was similar
between single-agent vorolanib and
single-agent everolimus (6.4 months
[95% CI, 4.6-8.3] vs. 6.4 months [95%
CI, 4.7-8.3]; HR = 0.94 [95% CI, 0.69-
1.24]; P = 0.6856). Response was
achieved by 33/133 (24.8%) of patients
in the combination arm, 11/133 (8.3%)
in the single-agent everolimus arm, and
14/133 (10.5%) of those receiving singleagent
vorolanib. OS was immature at the
time of the analysis. The combination
was associated with Grade 3 or greater
treated related AEs in 72% of subjects.
Trial Updates
Final results of the phase 3
KEYNOTE-426 study of pembrolizimab
plus axitinib vs sunitinib in metastatic
RCC the first line setting were presented.
Previous analysis showed the
combination significantly improved OS,
PFS, and ORR vs sunitinib monotherapy
in treatment-naive advanced clear cell
RCC and the combination gained FDA
approval. Overall, 861 subjects were
randomized with 418 deaths at this
42-month analysis. The combination of
pembrolizumab plus axitinib improved
OS compared to sunitinib (median: 45.7
vs 40.1 mo; HR, 0.73 [95% CI: 0.60-
0.88]; P<0.001) and PFS (median: 15.7
vs 11.1 mo; HR, 0.68 [95% CI, 0.58-
0.80]; P<0.0001). The 42-mo OS rate
was 57.5% with combination vs 48.5%
in the control arm; the 42-mo PFS
rate was 25.1% with the combination
vs 10.6% with sunitinib. ORR for the
combination was 60.4% vs 39.6% with
suntinib (P<0.0001), and a CR rate of
10.0% vs 3.5% in the combination arm
and control arm, respectively. No new
safety signals were observed in this
long-term analysis.
Investigators
p r e s e n t e d
updated results
focusing on
the efficacy of
nivolumab +
i p i l imu m a b
in IMDC
intermediate
and poor risk
a d v a n c e d
clear cell RCC
patients with
initial versus
late progression
with nivolumab from the TITAN-RCC
study. In this tailored immunotherapy
approach, patients who did not respond
initially were given between 2-4 doses
of nivolumab + ipilimumab as boost
cycles and patients who had PR or CR
initially on nivolumab monotherapy
were eligible for nivolumab +
ipilimumab at progression. Primary
endpoint was objective response rate
in first line and second line whereas
the secondary endpoints included
activity in nivolumab monotherapy,
remission rate of patients who receive
the nivolumab + ipilimumab boost and
safety and overall survival. Results
showed that the TITAN tailored
immunotherapy approach improved
response rates in patients compared to
those patients who had received only
nivolumab monotherapy with nearly
half of patients receiving nivolumab +
ipilimumab boosts with PD improving
to PR/CR (18%) or SD (30%).
Health-related quality-of-life
analysis from the phase 3 CLEAR study
was presented by Robert Motzer. The
trial, which showed that lenvatinib plus
pembrolizumab improved PFS, OS, and
ORR compared to sunitinib, also found
the combination of lenvatinib plus
pembrolizumab was associated with
similar better symptoms and quality of
life than sunitinib. Improvements in
physical functioning, fatigue, dyspena,
and constipation were significantly
improved with the combination when
compared with sunitinib.
Updated data on the durability
of response and overall survival from
the TIVO-3 study of tivozanib versus
sorafenib were provided. The study
enrolled patients with metastatic
RCC who failed 2 or 3 prior systemic
therapies, one of which included a
VEGFR-targeted TKI. There were 41
responders (23%) in the tivozanib and
20 responders (11%) in the sorafenib.
The median duration of response was
20.3 months (95% CI: 9.8 - 29.9) with
tivozanib and and 9.0 months (95% CI:
3.7 -16.6) with sorafenib. The HR for
overall survival favored tivozanib at
0.91 (95% CI: 0.716 - 1.165).
An interesting study of
outcomes of second-line therapy patients
who progressed on the JAVELIN Renal
101 study was presented by Laurence
Albiges. She and her colleagues
analyzed outcomes of 163 patients who
received single agent therapy (including
60 who received cabozantinib) and
41 patients who received combination
therapy (most commonly levantinib and
everolimus) following avelumab plus
axitinib on study. 36 months OS was
44.1% in those receiving single-agent
therapy (95% CI: 35.9 – 52.0) and 63.4
months (95% CI: 45.7 – 76.6) in those
receiving combination therapy in the
second-line setting. Median secondline
PFS was 20.4 months (95% CI: 17.6
– 23.0) and 24.1 months (95% CI: 17.7 –
NE) in these two groups, respectively.
Comparisons of First Line
Therapies
For many physicians, the question of
which first-line combination therapy to
use in patients with newly diagnosed
metastatic RCC is daunting given the
number of new combinations approved.
This is exacerbated by a lack of head-tohead
comparison studies among these
combinations. Two ASCO abstracts
attempted to compare regimens outside
of the scope of a prospective head-tohead
trial.
Kevin Zarrabi and colleagues
abstracted data from 821 mRCC patients
from Flatiron databases, 259 who
received axitinib plus pembrolizumab
and 562 who received ipilimumab plus
nivolumab. Demographics and clinical
parameters were well matched between
the two cohorts. Median age was 66
years, 73% were male, and 54.9% had
a nephrectomy. The adjusted median
OS between the two treatment groups
was n ot s tatistically d ifferent. T welvemonth
survival was 68.5% for those
receiving axitinib plus pembrolizumab
and 65.8% for received ipilimumab plus
nivolumab treated patients (P=0.41).
Twelve-month real world PFS was 41.4%
for the axitinib plus pembrolizumab
group and 39.7% for those in the
received ipilimumab plus nivolumab
group (P=0.14).
Bradley Alexander McGregor
and colleagues take a slightly different
approach using a matching-adjusted
indirect comparison (MDIC) of
data from the Checkmate 9ER and
Keynote-426 studies of nivolumab
plus cabozantinib and pembrolizumab
plus axitinib respectively. Nivolumab
plus cabozantinib was associated
with a median PFS of 19.3 compared
to 15.7 months with pembrolizumab
plus axitinib, and nivolumab plus
cabozantinib also achieved superior
overall response rate (ORR) and
duration of response (DoR). OS
outcomes were similar.
Cytoreducitve Nephrectomy
The role of cytoredutive nephrectomy in
RCC in the targeted and immunotherapy
era continues to be debated.
An abstract by Jaleh Fallah and
colleagues explored nephrectomy prior
to immunotherapy based combinations
via a pooled analysis of data from 5
trials. Among 849 patients with Stage
IV RCC at initial diagnosis, 62% had
nephrectomy prior to immunotherapy
based combinations. Median OS was
not reached in the prior nephrectomy
group, but appeared prolonged in
those having surgery prior to systemic
immunotherapy, even when adjusted
for age and prognostic risk scores
(HR=0.59, 95% CI: 0.46-0.75).
In a similar retrospective
study, Pooja Ghatalia et al extracted
data on 1,719 mRCC patients from
the Flatiron Health database, and
found that 972 (56.5%) received
systemic treatment alone, 605 (35.1%)
received cytoreductive nephrectomy
followed by systemic treatment, and
142 (8.2%) received systemic followed
by cytoreductive nephrectomy.
Cytoreductive nephrectomy prior to
systemic therapy was significantly
associated with prolonged OS compared
to systemic therapy alone, HR=0.82,
(95% CI: 0.70-0.95, p=0.008). Taken
together, these two retrospective studies
suggest that cytoreductive nephrectomy
may play a role in improving outcomes
in certain patients and that still more
studies of this controversial area are
needed, especially as the landscape of
system therapy continues to evolve.
Non-Clear Cell RCC
Several abstracts reported data on therapies
for non-clear cell RCC. Due to the
rarity of metastatic collecting duct carcinoma,
the BONSAI trial was opened
as a phase 2 evaluating the primary
endpoint of objective response rate of
patients taking cabozantinib 60mg
orally once daily. From January 2018 to November 2020, 25 patients were
enrolled and 23 were treated. Six patients
had stable disease, 1 with a CR,
and 7 with a PR. Secondary endpoints
showed an ORR of 35% and median
PFS of 6 months. Treatment showed optimistic
efficacy and acceptable patient
tolerability in this patient population.
Gopalakrishnan et al.
conducted a retrospective analysis of
203 patients with renal cell carcinoma
with any sarcomatoid component and
had received systemic therapy from 6
US academic cancer centers evaluating
the overall survival and response
rates. It was found that median overall
survival and response rates were
significantly higher in patients who had
previously received immune checkpoint
inhibitors compared to those patients
who had not. For instance, median
overall survival was 31% with immune
checkpoint inhibitor versus 7.6% and
a 66.2% disease control rate with
immunotherapy versus 39.1% nonimmunotherapy
drugs. Additionally,
there was a large benefit noted among
patients who had non clear cell and
mixed histology sarcomatoid renal cell
carcinoma.
In the Oracle study,
investigators wanted insight to
determine if there was antitumor
activity with new combination therapies
such as IO, VEGF, and mTOR inhibitors
in patients with metastatic nCCRCC.
Research shows that despite this patient
population having inferior rates with
new novel combination therapies than
clear cell RCC, there is some antitumor
activity observed which warrants
further prospective studies.
Rodriguez et al. evaluated the
combination of savolitinib 1500mg
every 4 weeks and durvalumab 600mg
every day in MET-driven, metastatic
papillary renal cell carcinoma in a
single arm phase I/II trial. Investigators
analyzed the confirmed response rate,
PFS, tolerability and overall survival of
the 41 patients who received treatment.
The confirmed response rate in
MET driven patients was 57% with a
duration of response of 9.4 months, and
a median PFS of 10.5 months. OS was
27.4 months (95% CI: 7.3-NR). Clinical
activity of this combination seems
promising for MET driven papillary
renal cell carcinoma patients.
The results of a phase 2 trial
of patients with advanced nccRCC on
Cabozantinib and nivolumab were
presented by Lee et al. Patients with
no history of prior immune checkpoint
inhibitors and up to 1 prior line of therapy
with measurable disease received
cabozanitinib 40mg plus nivolumab
240mg every 2 week versus 480mg every
4 weeks in two different cohorts. Cohort
1 consisted of 40 patients with papillary,
unclassified, or translocation associated
RCC and cohort 2 consisted of 7 patients
with chromophobe histology. Overall
results showed that there is promising
efficacy in metastatic non-clear cell
RCC pts with papillary, unclassified,
or translocation associated histologies.
ORR for the papillary, unclassified, or
translocation cohort was 48% (95% CI
31.5–63.9; Table), and a median PFS
of 12.5 months (95% CI 6.3–16.4) and
median OS was 28 months (95% CI
16.3–NE). Unfortunately, none of the 7
chromophobe patients has a response
suggesting there is limited efficacy in
this sub-population.
In part 2 of UNISON (ANZUP
1602), investigators evaluated the
results of treating patients with rare
variant RCC refractory to single-agent
nivolumab with salvage ipilimumab and
nivolumab. 41 patients were determined
to be refractory to single agent
nivolumab and had variant of nccRCC
histologies. One complete response
and 3 partial responses were noted.
Disease control rate at 6 months was
45% with a median PFS of 2.6 months.
The primary endpoint of this study was
not met. The results from this study
show that although a small portion
of nccRCC refractory to nivolumab
may benefit from combination therapy
with ipilimumab and nivolumab, the
majority do not, and more research is
needed to identify valuable treatment
options for nccRCC patients.
Potential Biomarkers
The search for biomarkers in RCC continues.
Soleimani et al evaluated plasma
exosome microRNAs (miRNAs) as a
potential biomarker of response to immune
checkpoint-based therapy. Prior
to initiating immunotherapy, 11 miRNAs
that are over-expressed in RCC
and/or immune-associated were evaluated
in 40 patients and in 30 healthy
volunteers. RT-PCT was used to evaluate
MiRNA expression between the two
groups and compared using the 2DDCt
method. The most common first line
immunotherapy was nivolumab + ipilimumab,
followed by pembrolizumab +
axitinib, and avelumab + axitinib. Results
showed that a lower expression of
miR-155 was associated with response
to immunotherapy in patients with metastatic
RCC and highlight the need for
additional research in this area for use
of miR-155 as a biomarker of response.
Previously, the 27-gene
immuno-oncology signature has been
shown to be associated with value
to immune checkpoint inhibitors in
breast, lung, and bladder cancers.
Investigators aimed to identify if this
could also be applied to patients with
renal cell carcinoma. Patients who had a
positive score by the 27-gene signature
had significantly better one-year PFS
compared to patients with a negative
score (hazard ratio = 0.235, 95% CI =
0.069 - 0.803, p < 0.01). Given that four
tumor types validated this algorithm,
additional research is needed to support
this assay as a pan-cancer immune
system classifier.
Tucker et al presented a
retrospective review of patients seeing
to evaluate and correlate baseline
neutrophil-to-eosinophil ratio (NER)
and neutrophil-to-lymphocyte ratio
(NLR) with treatment outcomes with
ipilimumab and nivolumab in patients
with metastatic RCC. 111 patients were
included in the analysis and it was found
that patient with NER less than median
had prolonged median PFS, OS, ORR
as compared to those with NER greater
than the median. Data suggested that
baseline NER may serve as an early
response predictor for immunotherapy
with ipilimumab and nivolumab.
Sites of Metastases
Previous studies have described RCC
with metastatic disease to the pancreas
as a distinct clinical entity with a
more indolent course as compared to
historical controls. Cassandra Duarte
and colleagues presented an analysis of
229 patients from 9 institutions. They
report a median OS for all patients
from time of metastatic disease was
prolonged at 7.7 years (95% CI 6.3-10.3).
The median OS for those who received
a first line VEGF targeted therapy was
7.6 years (95% CI 5.5-9.5) and was the
median OS was not reached for those
receiving first-line immunotherapy
(95%CI 6.5-NR). The difference was
significant with an unadjusted p-value
of 0.029, with a pair-wise comparison
between median OS of first line
immunotherapy subgroup compared
to that of the first line VEGF inhibitor
group also achieving statistical
significance (p = 0.0148). These results
suggest the choice of first-line therapy
in mRCC with pancreatic metastases
may impact outcome.
Patients with brain metastases
are often excluded from clinical trials,
limiting data on outcomes in this
populations. CheckMate 920 is an
ongoing phase 3b/4 trial of nivolumab
and ipilimumab in patients with
advanced RCC with unmet medical need,
including those with asymptomatic
brain metastases. Of the 25 mRCC
patients with brain metastases who
were evaluable for response, the ORR
was 32.0% (95% CI, 14.9–53.5). The
median duration of response was 24.0
months with 50% of responders without
reported progression.
Oligoprogressive Disease
Raquibul Hannan et al presented data
from a prospective phase II single arm
trial of mRCC patients who demonstrated
response to systemic therapy and
then had subsequent radiographic
evidence of three or fewer sites of
disease progression were treated. These
patients underwent stereotatic ablative
radiation (SAbR) to all progressive sites.
The study found that SAbR extended
PFS by > 6 months in 70.6% of the
17 evaluable oligoprogressive mRCC
patients. SAbR was safe and did not
adversely affect QOL, suggesting it is
a reasonable alterative to switching
systemic therapies in patients with
limited progression in a small number
of metastatic sites.
Healthcare Disparities
Janvi Wadiwala and colleagues highlight
access issues with regards to palliative
care among RCC patients. In a National
Cancer Database study of 50,405
patients found that socioeconomic barriers
such as age, race, Spanish/Hispanic
origin, income, education, and other
factors affected metastatic renal cell
carcinoma patients access to palliative
care resources. Older patients, African
Americans, higher income, and lower
education status patients were less likely
to receive palliative care. High education
attainment and treatment at an
integrated cancer center or comprehensive
community cancer center increased
the odds of receiving palliative care.
Gender differences in health
outcomes represent another important
area of healthcare disparity research,
Claud Grigg and colleagues explored
survival trends between men and
women with metastatic RCC. Clear cell
renal cell carcinoma is twice as common
in men as in women, and previous
studies have shown improved outcomes
in women with localized RCC as
compared to men. In this retrospective
NCDB study, patients were grouped by
date of metastatic diagnosis into three
eras, pre-Tyrosine Kinase Inhibitor
(TKI), TKi and immune checkpoint
inhibitors (ICI). Demographic features
were similar, with females being slightly
older and more likely to be black.
Women were found to be at an increased
risk of death in both the ICI era and the
TKI era, with a worse prognosis than
men that could not be explained by
demographic differences.
Patient Voice
Results from a global survey of 2,012
patients and caregivers from 41
countries were reported by Rachel H.
Giles and colleagues. They found more
than half (52%) of the responders lacked
understanding of subtype of diagnosis,
but also reported that a similar number
(51%) felt they were as involved as they
wanted to be with their care. Between
41-45% reported the no one discussed
clinical trials with them and the no one
explained their likelihood of surviving
their cancer beyond 5 years. These
results help guide provider attention to
areas where patient comprehension and
needs can be better addressed.
COVID-19 in RCC
Of course, last but certainly not least
is the impact that the COVID-19
pandemic has had on RCC patients. A
retrospective study by Jesus Garcia
Donas et al compared patients with
advanced RCC who developed COVID
while undergoing antiangiogenic
treatment vs immunotherapy vs
matched controls. Patients with
RCC who developed COVID19 had
treatment held more frequently and
presented with lower clinical benefit
rates than those not infected. Those
patients on immunotherapy required
more frequent interruptions and
longer hospitalizations than those on
antiangiogenics.
As the world continues to
address the global pandemic, cancer has
not slowed down. Thankfully, the fight
against cancer also hasn’t slowed down
either as evidenced by the remarkable
progress exemplified in the ASCO 2021
Annual Meeting. It is our hope that
we can all join together once again in
Chicago for ASCO 2022.
Correspondence to: Marc R. Matrana.
Ochsner Precision Cancer Therapies Program and Ochsner Cancer Institute
1514 Jefferson Highway, New Orleans LA - 70121.
E-mail: MaMatrana@ochsner
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