Expert Opinion / Conference Coverage · February 09, 2021
ASCO GU21: Abstract Recommendations (RCC) by Robert A Figlin, MD
The abstracts included in this report have been selected by Robert A. Figlin, MD, Editor-in-
Chief of the Kidney Cancer Journal. The chosen abstracts provided here highlight some of the most important trends in ongoing trials and as well as reﬂect
the foremost research and strategies from latest clinical trials that impact the current standard of care in
Background: In pts with advanced RCC, second-line treatment with LEN + EVE prolonged
progression-free survival (PFS) compared with EVE alone. LEN + PEMBRO, also showed preliminary
efficacious evidence in a phase 1/2 RCC study. Here, we describe the investigational study
results of first-line LEN + PEMBRO or LEN + EVE versus SUN in pts with advanced RCC.
Pts were randomized (1:1:1) to receive LEN 20 mg orally once daily + PEMBRO 200 mg IV every
3 weeks (wks); or LEN 18 mg + EVE 5mg orally once daily; or SUN 50 mg orally once daily (4 wks on/
2 wks off). Eligible pts had advanced RCC with no prior systemic therapy. Randomization was
stratified by geographic region and MSKCC prognostic group. The primary endpoint was PFS by
Independent Review Committee per RECIST v1.1. Secondary endpoints included overall survival
(OS), objective response rate (ORR) and safety. A sequential approach was used to test PFS first,
then OS and ORR. PFS and OS were compared across arms by a stratified log-rank test; hazard
ratios (HRs) were estimated by a stratified Cox regression model.
Results:1069 pts were randomized (Table). After a median follow-up of 27 months (data cutoff August 28, 2020),
PFS was significantly improved with LEN + PEMBRO (median 24 months [mos]) vs SUN (median
9 mos; HR 0.39, 95% CI 0.32–0.49) and LEN + EVE (median 15 mos) vs SUN (HR 0.65, 95% CI
0.53–0.80). OS was significantly longer with LEN + PEMBRO vs SUN (HR 0.66, 95% CI 0.49–0.88),
whereas OS with LEN + EVE vs SUN was not statistically different (HR 1.15, 95% CI 0.88–1.50). ORR
was significantly greater with LEN + PEMBRO (ORR 71%; complete response [CR] 16%) vs SUN
(ORR 36%; CR 4%; odds ratio 4.35, 95% CI 3.16–5.97) and LEN + EVE (ORR 54%; CR 10%) vs SUN
(odds ratio 2.15, 95% CI 1.57–2.93). Grade$3 treatment-related adverse events occurred in 72%of
pts in the LEN + PEMBRO arm and 73% of pts in the LEN + EVE arm compared with59%of pts in the
SUN arm. Conclusions: LEN + PEMBRO demonstrated significant improvements in PFS, OS and
ORR vs SUN. LEN + EVE demonstrated significant improvements in PFS and ORR vs SUN. Safety
was manageable and consistent with the known single-agent profiles.
Clinical trial information:NCT02811861.
Research Sponsor: Eisai Inc., Woodcliff Lake, NJ, USA; and Merck Sharp & Dohme
Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Background: MET signaling is a key molecular driver in pRCC. Given that there is no optimal
therapy for metastatic pRCC, we sought to compare an existing standard (sunitinib) to putative
MET kinase inhibitors.
Eligible patients had pathologically verified pRCC, Zubrod performance
status 0-1, and measurable metastatic disease. Patients may have received up to 1 prior
systemic therapy excluding VEGF-directed agents. Patients were randomized 1:1:1:1 to receive either
sunitinib 50 mg po qd (4 wks on/2 wks off), cabozantinib 60 mg po qd, crizotinib 250 mg po bid, or
savolitinib 600 mg po qd. Patients were stratified by prior therapy and pRCC subtype (I vs II vs not
otherwise specified [NOS]) based on local review. The primary objective was to compare
progression-free survival (PFS) for each experimental arm versus sunitinib. With 41 eligible
patients per arm, we estimated 85% power to detect a 75% improvement in median PFS
with a 1-sided alpha of 0.10 using intent-to-treat analysis. A pre-planned futility analysis was
performed after 50% of PFS events occurred. Secondary endpoints included toxicity, response
rate, and overall survival.
Results:Between 4/2016 and 12/2019, 152 patients were enrolled; 5 were
ineligible. Median age was 66 (range:29-89) and 76% were male; 92% had no prior therapy. By
local pathologic review, 18%, 54% and 28% of patients were characterized as having type I, type II
and NOS histology, respectively. In contrast, the frequency of type I, type II, and NOS by central
review was 30%, 45% and 25%, respectively. Accrual to the savolitinib and crizotinib arms was
halted early for futility (PFS hazard ratio . 1.0 for both); accrual continued to completion in the
sunitinib and cabozantinib arms. Median PFS was significantly higher with cabozantinib relative to
sunitinib (Table). Grade 3 or 4 adverse events occurred in 69%, 72%, 37% and 39% of patients
receiving sunitinib, cabozantinib, crizotinib and savolitinib, respectively; one grade 5 adverse event
was seen with cabozantinib. Overall survival and response data will be presented.
Conclusions: In this multi-arm randomized trial, only cabozantinib resulted in a statistically significant and clinically
meaningful prolongation of PFS in pRCC patients compared to sunitinib. These data support
cabozantinib as a reference standard for eligible patients with metastatic pRCC.
Clinical trial information: NCT02761057.
Research Sponsor: U.S. National Institutes of Health, Pharmaceutical/Biotech Company.
Background: Belzutifan (MK-6482) inhibits HIF-2a and demonstrated antitumor activity and
favorable safety as monotherapy in a phase 1 study of patients (pts) with metastatic ccRCC.
Current study (NCT03634540) investigates belzutifan plus cabozantinib for pts with advanced
ccRCC who were either treatment naive (cohort 1) or previously treated, including immunotherapy
and TKIs (cohort 2). This preliminary analysis presents data from cohort 2.
metastatic ccRCC and received no more than 2 prior systemic treatment regimens. Initially, 6 pts in
either cohort 1 or 2 were treated with belzutifan 120 mg and cabozantinib 60 mg orally once daily
for 21 days and a safety review committee performed an initial evaluation. For purpose of this
preliminary analysis, efficacy was evaluated in pts who received $1 dose of treatment and had an
opportunity of$6mo of follow-up. Primary end point: objective response rate (ORR; RECIST v1.1 by
investigator review). Secondary end points: progression free survival (PFS), overall survival (OS),
and duration of response (DOR). Safety was evaluated for all cohort participants.
Results:Evaluation of safety and tolerability of belzutifan 120 mg plus cabozantinib 60 mg was performed
in the first 6 pts. Only 1 participant experienced a dose-limiting toxicity of hand-foot syndrome,
therefore belzutifan 120 mg plus cabozantinib 60 mg was determined to be the recommended
phase 2 dose. 53 pts were included in the safety analysis population. Median age was 64 yrs, 73.6%
were male, 54.7% had ECOG PS 1. Twenty-eight (52.8%) received prior first-line and 24 (45.2%)
prior second-line therapies. Median (range) time from enrollment to data cutoff was 11.3 mo (5.6-
24.0) for pts with $6 mo of follow-up (n=41). The confirmed ORR was 22.0% (9 PRs) and 90.2%
had any tumor shrinkage. Disease control rate (CR+PR+SD) was 92.7%. Median (range) DOR was
not reached (3.7+ to 14.8+ mo); all responses were ongoing. Median (95% CI) PFS was 16.8 mo (9.2-
not reached); PFS rate at 6 mo was 78.3%. OS rate at 6 mo was 95.0%. While 52 of 53 (98.1%) pts
experienced a treatment-related adverse event (TRAE), 92% of events were grade 1 and 2. Most
common ($30%) TRAEs were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%),
diarrhea (45.3%), hypertension (43.4%), nausea (35.8%), and ALT/AST increase (32-34%).
Incidence of grade 3 TRAEs .5% were hypertension (22.4%), anemia (11.3%), fatigue (11.3%),
and ALT increase (5.7%). 2 pts experienced grade 3 hypoxia (3.8%). There were no grade 4 TRAEs
or deaths. Discontinuations due to TRAEs occurred in 6 pts (11.3%) for belzutifan and 8 pts (15.1%)
Conclusions: In this preliminary analysis, belzutifan in combination with cabozantinib
demonstrated promising antitumor activity in previously treated pts with metastatic
ccRCC. Safety was consistent with individual profiles of each agent. Clinical trial information:
NCT03634540. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,
Kenilworth, NJ, USA.
Background: In the phase III, open-label CheckMate 9ER trial (NCT03141177), patients with aRCC
were randomized 1:1 (stratified by International Metastatic Renal Cell Carcinoma Database Consortium
risk score, tumor programmed death ligand 1 expression, geographic region) to nivolumab
240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-
week cycles; n = 328) for first-line treatment until disease progression or unacceptable toxicity
(max N treatment, 2 years). N+C met primary and secondary efficacy endpoints by significantly
improving progression-free survival, overall survival, and objective response rate versus S in aRCC
patients with a clear cell component. Here, we present in-depth health-related quality of life
(HRQoL) patient-reported outcome (PRO) results, including overall between-group comparisons of
treatment groups and time to confirmed deterioration (TCD).
PROs in all randomized
patients were an exploratory endpoint assessed using the Functional Assessment of Cancer
Therapy Kidney Symptom Index-19 (FKSI-19) and EQ-5D-3L instruments. PRO assessments at
baseline, common on-treatment scheduled visits, and common follow-up visits for both arms were
analyzed. Changes from baseline were assessed using mixed-model repeated measures (MMRM),
adjusting for baseline scores and stratification factors. TCD was calculated from Kaplan–Meier
estimates and Cox proportional hazards models.
Results:Median follow-up for overall survival was
18.1 months. PRO completion rates were . 90% at baseline, and $ 80% at all on-treatment
assessments ($ 10 patients) through week 91 in both arms. The overall least squares mean
difference in change from baseline favored N+C over S in FKSI-19 (all domains) and in EQ-5D-3L.
Patients treated with N+C experienced less treatment burden, with decreased risk of confirmed
deterioration across most measurements versus S, including FKSI-19 total, disease-related symptoms
(DRS), DRS-physical (DRS-P), DRS-emotional (DRS-E), functional well-being (FWB), and EQ-
5D-3L visual analog scale (VAS) scores (Table).
Conclusions: Patients reported statistically significant HRQoL benefits with N+C versus S. Treatment with N+C significantly reduced the risk
of deterioration in HRQoL scores, including in disease-related symptoms of kidney cancer. These
results suggest that the superior efficacy of N+C over S comes with the additional benefit of
improved HRQoL. Clinical trial information: NCT03141177. Research Sponsor: Bristol Myers Squibb.
Background: First-line NIVO+CABO met primary and secondary efficacy endpoints by improving
progression-free survival (PFS; HR 0.51, P,0.0001), overall survival (OS; HR 0.60, P = 0.0010), and
objective response rate (ORR; 55.7% vs 27.1%; P , 0.0001) vs SUN in patients (pts) with aRCC in
CheckMate 9ER (Choueiri et al. ESMO 2020). Efficacy benefits with NIVO+CABO vs SUN were
consistent across prespecified subgroups including by IMDC risk group, and regardless of tumor
PD-L1 expression (database lock for primary analysis, March 30, 2020). Updated analyses are
needed to establish durability of benefit with first-line NIVO+CABO and assess outcomes in aRCC
pts with sarcomatoid features (sRCC)—an aggressive histologic subtype associated with poor
In this phase III open-label trial, adults with confirmed aRCC (with a clear cell
component including those with sRCC) were randomized 1:1 (stratified by IMDC risk score, tumor
PD-L1 expression, geographic region) to NIVO 240 mg IV Q2W + CABO 40mg PO QD vs SUN 50 mg
PO (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1-defined PFS by blinded
independent central review (BICR) in all randomized (intent-to-treat [ITT]) pts; secondary endpoints
included OS, ORR by BICR, and safety. Pts with and without sRCC were identified by local
pathology report, and outcomes in these pts were evaluated via prespecified supportive subset
Results:The presence of sRCC was assessed in ITT pts (N = 651) at enrollment. Overall,
75 (11.5%) pts had sRCC and 557 (85.6%) did not; sRCC status was not reported in 19 pts (2.9%).
Overall, 34 vs 41 pts with sRCC were randomized to NIVO+CABO vs SUN, respectively. At a median
follow-up of 18.1 months, NIVO+CABO improved PFS, OS, and ORR in sRCC pts vs SUN (Table).
Notable PFS, OS, and ORR benefits were observed with NIVO+CABO vs SUN in the subgroup of pts
without sRCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently
higher with NIVO+CABO vs SUN regardless of sarcomatoid status. Key updated PFS, OS, response,
and safety outcomes in the ITT population and in pts with and without sRCC will be reported with
additional follow-up based on a September 10, 2020 database lock.
demonstrated improved efficacy and prolonged survival vs SUN in previously untreated aRCC pts
regardless of sarcomatoid status. Updated results with extended follow-up will assess the durability
of outcomes in this trial. Clinical trial information: NCT03141177. Research Sponsor: Bristol Myers Squibb.
Background: The long-term efficacy and tolerability of nivolumab (NIVO) 3 mg/kg + ipilimumab
(IPI) 1 mg/kg Q3W 3 4 doses followed by NIVO 3 mg/kg Q2W for previously untreated advanced
RCC (aRCC) demonstrated in the registrational CheckMate 214 clinical trial was based on patients
(pts) with a predominantly clear cell component. CheckMate 920 (NCT02982954) is a US
community-based, multi-arm, phase IIIb/IV clinical trial of NIVO+IPI treatment in pts with previously
untreated aRCC and clinical features mostly excluded from phase III trials. Here, we present
the safety and efficacy results for the cohort of pts with nccRCC from CheckMate 920, a patient
population with a poor prognosis and without a definitive effective treatment.
Pts with previously untreated advanced/metastatic nccRCC, Karnofsky performance status $ 70%, and
any International Metastatic Renal Cell Database Consortium risk received NIVO 3 mg/kg + IPI 1
mg/kg (NIVO3+IPI1) Q3W 3 4 doses followed by NIVO 480 mg Q4W for # 2 years or until disease
progression/unacceptable toxicity. The primary endpoint was incidence of any-causality grade$3
immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key
secondary endpoints: progression-free survival (PFS) and objective response rate (ORR) by
RECIST v1.1 (both per investigator), duration of response (DOR), and time to response (TTR).
Exploratory endpoints included overall survival (OS).
Results:Of 52 treated pts with nccRCC,
69.2% were men; median age was 64 years (range, 23–86), and 28.8% had sarcomatoid features.
Histological subtypes were papillary (34.6%), chromophobe (13.5%), translocation associated
(3.8%), collecting duct (3.8%), renal medullary (1.9%), or unclassified (42.3%). With 24.1 months
minimum follow-up, median duration of therapy (range) was 3.5 months (0.0–25.8) for NIVO and
2.1 months (0.0–3.9) for IPI. Median (range) number of doses received was 4.5 (1–28) for NIVO and
4.0 (1–4) for IPI. No grade 5 imAEs occurred. Grade 3–4 imAEs (n = 52) by category were diarrhea/
colitis (7.7%), rash (5.8%), nephritis and renal dysfunction (3.8%), hepatitis (1.9%), adrenal
insufficiency (1.9%), and hypophysitis (1.9%). ORR (n = 46) was 19.6% (95% CI, 9.4–33.9). Two
pts achieved complete response (papillary, n = 1; unclassified pathology, n = 1), 7 achieved partial
response (papillary, n = 4; unclassified pathology, n = 3), and 17 pts had stable disease. Median TTR
was 2.8 months (range, 2.1–4.8). Median DOR was not reached (range, 0.03+–27.8+); 8 of 9
responders remain without reported progression. Median PFS (n = 52) was 3.7 months (95% CI,
2.7–4.6). Median OS (n = 52) was 21.2 months (95% CI, 16.6–not reached).
Conclusions: In pts with
previously untreated nccRCC, a population with high unmet medical need, treatment with
NIVO3+IPI1 Q3W followed by NIVO 480 mg Q4W showed no new safety signals, and encouraging
antitumor activity. Clinical trial information: NCT02982954. Research Sponsor: Bristol Myers
Background: First-line NIVO+IPI demonstrates superior survival and response benefits in intentto-
treat (ITT) patients (pts) with aRCC after long-term follow-up in the phase 3 CheckMate 214 trial.
Data are scarce on tumor relapse and patterns of disease progression with immuno-oncology
agents in this setting. This exploratory analysis of CheckMate 214 characterizes patterns of
progression with NIVO+IPI vs SUN with 4 years minimum follow-up.
Pts with clear cell
aRCC were randomized to NIVO+IPI Q3W34 followed by NIVO monotherapy Q2W, or SUN
QD34 weeks (6-week cycle). Patterns of progression were characterized in ITT pts and analyzed
post hoc using descriptive statistics. Progression patterns were defined by $ 20% target lesion
growth (T), unequivocal progression of nontarget lesions (NT), and new lesion(s) (NL). Response
and progression were assessed per independent radiology review committee via RECIST v1.1.
Results:Radiographic progression (RP) was documented in 299/550 (54.4%) ITT pts with
NIVO+IPI vs 289/546 (52.9%) with SUN. Among ITT pts with a confirmed response (objective
response = 215/550 [39.1%, NIVO+IPI] vs 177/546 [32.4%, SUN]), 71/215 (33.0%) vs 84/177
(47.5%) pts experienced post-response RP with NIVO+IPI vs SUN; 8/59 (13.6%) vs 3/14 (21.4%)
progressed after complete response, and 63/156 (40.4%) vs 81/163 (49.7%) progressed after
partial response, respectively. The pattern of RP differed between arms (Table). With NIVO+IPI,
106/299 (35.5%) RPs resulted from NL only vs 74/289 (25.6%) with SUN, and this differential was
more pronounced in pts with an initial confirmed response (36/71 [50.7%] vs 23/84 [27.4%]). Most
NL-only RPs in initial responders occurred in a single organ (34/36 [94.4%] for NIVO+IPI; 20/23
[87.0%] for SUN) with the most common being lymph nodes (11/34 [32.4%]), brain (8/34 [23.5%]),
and lung (5/34 [14.7%]) with NIVO+IPI, and lymph nodes (7/20 [35.0%]), brain (4/20 [20.0%]) and
adrenal gland (3/20 [15.0%]) with SUN. Additional progression details, baseline characteristics,
and key efficacy outcomes in progressors will be reported.
Conclusions: Differential patterns of
tumor relapse and disease progression were observed after long-term follow up of patients treated
with NIVO+IPI vs SUN in CheckMate 214. NL-only progression occurred more often with NIVO+IPI
vs SUN, in particular in the subset of pts who progressed post-response. These patterns may have
therapeutic implications. Clinical trial information: NCT02231749. Research Sponsor: Bristol Myers
Background: Patients (pts) with VHL disease are at risk of developing benign and malignant
tumors, including ccRCC, pancreatic lesions tumors, CNS hemangioblastomas, and retinal lesions.
Inactivation of VHL leads to stabilization of HIF-2a, which drives tumor growth. In a phase 1/2 study,
MK-6482, a potent, selective, oral small molecule HIF-2a inhibitor, demonstrated favorable safety
and antitumor activity in advanced ccRCC. We present results of the open-label phase 2 study of
MK-6482 for VHL disease–associated ccRCC (NCT03401788).
Adults with germline VHL
alterations, measurable, localized/non-metastatic ccRCC, no prior systemic anticancer therapy,
and ECOG PS 0/1 received MK-6482 120 mg once daily until progression, intolerable toxicity, or
decision to withdraw. Primary end point: ORR of VHL-associated ccRCC tumors per RECIST v1.1 by
independent review committee (IRC). Secondary end points: DOR, time to response (TTR), PFS, and
Results:As of June 1, 2020, 61 pts enrolled. The majority (82%) of pts had ECOG PS 0, and
median number of prior surgeries per pt was 5 (range, 1-15). Lesions outside the kidney (non-RCC
tumors) evaluable by IRC included pancreatic lesions (100%) and CNS hemangioblastomas (70%).
Median duration of treatment was 68 wk (range, 8-105), and 92% of pts remain on therapy. There
were 22 confirmed responses (ORR, 36% [95% CI, 24%-49%]) and 7 (11%) unconfirmed (documented
at 1 time point, to be confirmed at subsequent time point) responses; all PRs. In pts with
confirmed PR, median DOR was not reached (range, 12-62 wk) and median TTR was 31 wk (range, 12-
61); 14 (64%) pts had response duration of$26 wk. 56 pts (92%) had any decrease in size of target
lesions. PFS rate at 52 wk was 98% (95% CI, 89%-100%). Overall, pretreatment median linear
growth rate of ccRCC tumors was +3.6 mm/y (range, 23.4 to +33.1), compared with 24.5 mm/y
(range,212.8 to +5.1) while on treatment. For non-RCC tumors, ORR in pancreatic lesions was 64%
(39/61, including 4 CRs) and in CNS hemangioblastomas was 30% (13/43, including 5 CRs). Median
(range) TTR was 35 wk (11-60) and 12 wk (10-60) for pancreatic lesions and CNS hemangioblastomas,
respectively. 11/16 (69%) pts with evaluable retinal lesions at baseline showed improvement.
Of those 16 pts, 29 eyes were followed for retinal lesions; 16 eyes (55%) showed
improvement, 12 (41%) remained stable, and no follow-up evaluation was available for 1 (3%)
eye. Treatment-related AEs (TRAEs) occurred in 98% of pts, none grade 4/5. Most common TRAE
was anemia (87%), considered to be an on-target toxicity. One pt discontinued treatment due to a
TRAE (grade 1 dizziness). As of data cutoff, 1 pt (2%) required surgery for ccRCC tumors after
Conclusions: MK-6482 is an active and well-tolerated therapy for VHL disease–
associated ccRCC, pancreatic lesions, as well as CNS and retinal hemangioblastomas. Clinical
trial information: NCT03401788. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Kenilworth, NJ, USA.
What To Expect from ASCO GU21 - GUIDE