Kidney Cancer Research Highlights from
ASCO 2022 Annual Meeting
Yasser Ged,1 and Nirmish Singla2,*
1) Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
2) Department of Urology, The James Buchanan Brady Urological Institute,
The Johns Hopkins University School of Medicine, Baltimore, MD, USA
ABSTRACT
ABSTRACT
The 2022 American Society of Clinical Oncology (ASCO)
annual meeting was held June 3-7, 2022, in Chicago,
Illinois. This hybrid meeting gathered international cancer
experts across multidisciplinary specialties and was held
both virtually and in-person. Here, we highlight key kidney
cancer research updates presented at the meeting. Slides
from the meeting’s presentations are available on the ASCO
meeting library website.
INTRODUCTION
Adjuvant Therapy Updates
Locally advanced kidney cancer has traditionally been
managed surgically alone1. However, approximately 30%
of patients develop recurrent metastatic disease after
surgical resection despite curative intent, and the optimal
approaches to integrate surgery with systemic therapies
in a neoadjuvant or adjuvant approach to reduce the risk
of recurrence has been an area of active research.2 The
U.S. Food and Drug Administration (FDA) has approved
two adjuvant therapies in renal cell carcinoma (RCC)
thus far, including sunitinib in 2017 and most recently
pembrolizumab in 2021.3,4 The use of adjuvant sunitinib has
been limited despite FDA approval because of its increased
toxicity and lack of overall survival benefit.5 Pembrolizumab
is the first approved adjuvant immunotherapy for clear
cell RCC patients with intermediate-high or high risk of
recurrence after nephrectomy based on the phase 3 doubleblind,
multicenter, randomized KEYNOTE-564 study
(NCT03142334).4
.
Updated analysis from KEYNOTE-564 was
presented at the meeting evaluating the time to first
subsequent drug treatment or any-cause death (TFST)
and time from randomization to progression on next line
of therapy or any-cause death (PFS2) after treatment with
pembrolizumab or placebo in the study.6 Overall 67 patients
(13.5%) in the pembrolizumab group and 99 patients
(19.9%) in the placebo group received ≥1 line of subsequent
anticancer drug therapy. A total of 108 PFS2 events were
observed, 40 (8.1%; 12 death events and 28 progression
events) in the pembrolizumab group and 68 (13.7%; 14 death
events and 54 progression events) in the placebo group.
PFS2 was also delayed with pembrolizumab compared
with placebo (HR, 0.57; 95% CI, 0.39-0.85; medians not
reached). The authors concluded that treatment with
adjuvant pembrolizumab reduced risk for TFST and PFS2
compared with placebo. LITESPARK-022 (NCT05239728)
is the next iteration of the KEYNOTE-564 study which is a
phase 3 study designed to compare the efficacy and safety
of belzutifan plus pembrolizumab with that of placebo
plus pembrolizumab as adjuvant treatment for clear cell
RCC after nephrectomy, and this study is currently actively
enrolling.
.
Multiple adjuvant and neoadjuvant vascular
endothelial growth factor tyrosine kinase inhibitors
(VEGF-TKIs) studies in RCC were reported previously.5
To better understand the role of mammalian target of
rapamycin (mTOR) inhibitors in the adjuvant setting, the
Southwest Oncology Group (SWOG) launched the phase
3 study of everolimus in treating patients with kidney
cancer who have undergone surgery (EVEREST) study
(NCT01120249), which was reported at ASCO 2022.7
Individuals with clear or non-clear cell RCC immediately
post-nephrectomy whose tumors show intermediate
high-risk to high risk features were included in the study.
Between 4/2011 and 9/2016, 1545 patients were randomized
to e ither 1 2 m onths o f a djuvant e verolimus (n = 7 75) o r
placebo (n = 7 70) including 83% w ith clear cell RCC and
17% with non-clear cell RCC. With a median follow-up
of 76 months, the recurrence free survival was improved
with everolimus compared to placebo (HR 0.85, 95% CI,
0.72 – 1.00; P (one sided) = 0.0246), narrowly missing the
pre-specified, one-sided significance level of 0.022 which
accounted for interim analyses, and the effect of everolimus
was especially pronounced in patients with very high risk
disease. Adverse events were consistent with safety profiles
of everolimus, although there was a high discontinuation
rate of everolimus in this population (47%).
.
First Line Metastatic Kidney Cancer Treatment
Updates
The first line treatment landscape of metastatic RCC has
rapidly evolved in recent years.8 New updates on some
of the registration first line metastatic RCC studies were
presented during the meeting.
The CheckMate 9ER trial is a phase 3 trial which
compared nivolumab plus cabozantinib versus sunitinib
in patients with untreated advanced clear cell RCC and
demonstrated superior overall survival (OS), progression
free survival (PFS) and objective responses of the nivolumab
plus cabozantinib combination9. Updated analysis from the
depth of response was presented at ASCO 2022.10 Patients’
responses were classified as complete response (CR) or
partial response (PR) subdivided by a tumor reduction of
≥80%–<100% (PR1), ≥60%–<80% (PR2), or ≥30%–<60%
(PR3). Overall, greater proportions of patients receiving
nivolumab plus cabozantinib had deeper responses
versus sunitinib (CR, PR1, PR2), and deeper responses
with nivolumab plus cabozantinib were associated with
improved 12-months PFS rate versus sunitinib for CR
(94.9% vs 82.4%), PR1 (81.3% vs 37.5%), and PR2 (72.1% vs
53.2%).
.
Updates on health-related quality of life (HRQoL)
from the CheckMate-214 phase 3 clinical trial, which
compared nivolumab plus ipilimumab versus sunitinib
in patients with untreated advanced clear cell RCC, were
also presented during the meeting.11,12 As previously
reported, nivolumab plus ipilimumab was associated with
improved HRQoL compared to sunitinib. At ASCO 2022,
the investigators reported on a post-hoc analysis on the
prognostic ability of HRQoL to inform the risk of disease
progression or death. The results of the analysis showed
that higher (better) baseline scores were associated with
significantly reduced risk of death (HR [95% CI] for FKSI-
19 Total Score and DRS score was 0.83 [0.80-0.87] and
0.80 [0.76-0.84], respectively). Furthermore, patients with
improved/stable HRQoL had a 52% reduction in risk of
death compared to patients who had worsened (HR 0.48
[95% CI: 0.39-0.59]).
.
Post-hoc exploratory analyses of PFS2 were
conducted in the KEYNOTE 426 (phase 3 study comparing
pembrolizuamb plus axitinib versus sunitinib in patients
with untreated advanced clear cell RCC)13,14 and the
CLEAR (phase 3 study comparing pembrolizumab plus
lenvatinib versus sunitinib in patients with untreated
advanced clear cell RCC)15,16 studies. Both analyses
demonstrated prolongation of PFS2 in patients who received
pembrolizumab plus axitinib in KEYNOTE 426 study and
pembrolizumab plus lenvatinib in the CLEAR study.
Novel Kidney Cancer Therapies Highlights
Several exciting data were presented on novel therapies
in RCC. Batiraxcept is a GAS6-AXL inhibitor, a pathway
which is overexpressed in clear cell RCC.17 Interim results
of a phase 1b study of batiraxcept plus cabozantinib 60
mg daily were presented at the meeting.18 A total of 26
patients were enrolled in the phase 1b study so far, and the
recommended phase 2 dose of batiraxcept was identified
as 15 mg/kg every 2 weeks. Encouraging early anti-tumor
efficacy results of the combination were observed with an
objective response rate of 67% and 6 months PFS of 79%.
Hypoxia-inducible factor 2α (HIF-2α) is a key
oncogenic driver in RCC.19 Belzutifan is a HIF-2α inhibitor
which was recently approved by the FDA for patients
with VHL syndrome and currently under investigation
in sporadic RCC.20,21 LITESPARK-001 is a phase 1 study
which was designed to evaluate belzutifan in heavily
pretreated RCC and showed durable antitumor activity and
an acceptable safety profile.21 An update of the clear cell RCC
cohort in the study with more than 3 years of total followup
was presented at the meeting.22 With extended followup
of 41 months, the objective response rate was 25% with
80% disease control rate and median PFS of 14.5 months
(95% CI, 7.3-22.1). Belzutifan monotherapy continued to
show a high rate of disease control and durable responses
in this heavily pre-treated population.
.
The CALYPSO study results were presented at the
meeting as well.23 This is a randomized phase II study of
durvalumab alone or with savolitinib or tremelimumab
in previously treated advanced clear cell RCC. Savolitinib
is a potent MET inhibitor with established dosing and
activity in papillary RCC; however, its role in clear cell
RCC is unclear.24 Between 2017 and 2021, 139 patients
were randomized across the treatment arms. Savolitinib
alone and in combination with duravlumab was associated
with modest confirmed response rates (5% and 13%,
respectively) compared to confirmed response rates
of 10% for durvalumab and 28% for durvalumab plus
tremelimumab. All regimens studied in the trial appeared
to be safe and tolerable.
SUMMARY
In summary, ASCO 2022 was enriched with novel results
and concepts continually expanding the field of kidney
cancer research. Indeed, the data presented are both
hypothesis-generating and practice-informing. Herein, we
highlighted a snapshot of some of the oral presentations
from the meeting in the kidney cancer space; however,
there are considerably more exciting abstract and poster
presentations that are available for review on the meeting’s
website. In addition to the scientific content, ASCO
2022 also provided ample opportunities for networking
and collaborations among the academic kidney cancer
community, with the first in-person option since the
beginning of the COVID-19 pandemic.
.
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Correspondence to:
Nirmish Singla, MD, MSCS.
Departments of Urology and Oncology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine.
Baltimore MD 21287. EMAIL nsingla2@jhmi.edu