Kidney Cancer Journal 61
tourin Cancer. 2018 May 4; pii: S1558-7673(18)30136-8.
doi: 10.1016/j.clgc.2018.04.005.
Summary: This analysis reported benchmarks for clinical
outcomes on the basis of International Metastatic Renal
Cell Carcinoma Database Consortium (IMDC) risk groups
for patients treated with sunitinib for mRCC in a first-line
setting. A retrospective analysis was performed on data
from sunitinib-treated patients (n = 375) in the pivotal
phase III trial of sunitinib versus interferon- as first-line
treatment for mRCC. Objective response rates (ORRs) were
determined from independently reviewed radiologic
assessments. Median PFS (95% confidence interval CI)
was 14.1 (13.4-17.1), 10.7 (10.5-12.5), 2.4 (1.1-4.7), and
10.6 (8.1-10.9) months in sunitinib-treated patients in the
IMDC favorable (n = 134), intermediate (n = 205), poor
(n = 34), and intermediate + poor (n = 239) risk groups,
respectively. Median OS (95% CI) was 23.0 (19.8-27.8), 5.1
(4.3-9.9), and 20.3 (16.8-23.0) months in sunitinib-treated
patients in IMDC intermediate, poor, and intermediate +
poor risk groups, respectively, and was not reached in the
favorable risk group (>50% of patients were alive at data
cutoff). ORRs were 53.0%, 33.7%, 11.8%, and 30.5% in
sunitinib-treated patients in IMDC favorable, intermediate,
poor, and intermediate + poor risk groups, respectively.
Conclusion: This retrospective analysis showed differences
in patient outcomes for PFS, OS, and ORR on the basis of
IMDC prognostic risk group assignment for patients with
mRCC.
Phase 1 trials of anti-ENPP3 antibody drug conjugates
in advanced refractory renal cell carcinomas. Thompson
JA, Motzer RJ, Molina AM, et al. Clin Cancer Res. 2018
May 30; pii: clincanres.0481.2018. doi: 10.1158/1078-
0432.CCR-18-0481.
Summary: The study determined the safety, pharmacokinetics,
and recommended phase 2 dose of an antibody
drug conjugate (ADC) targeting ectonucleotide phosphodiesterases
pyrophosphatase 3 (ENPP3) conjugated to
monomethyl auristatin F (MMAF) in subjects with
advanced RCC. Two phase 1 studies were conducted
sequentially with 2 ADCs considered equivalent, hybridoma
derived AGS-16M8F and Chinese Hamster Ovary
derived AGS-16C3F. AGS-16M8F was administered intravenously
every 3 weeks at 5 dose levels ranging from 0.6
to 4.8 mg/kg until unacceptable toxicity or progression.
The study was terminated before reaching the maximum
tolerated dose (MTD). A second study with AGS-16C3F
started with the AGS-16M8F bridging dose of 4.8 mg/kg
given every 3 weeks. The AGS-16M8F study (n=26) closed
before reaching the MTD. The median duration of
treatment was 12 weeks. One subject had durable partial
remission (PR) (83 weeks) and 1 subject had prolonged
stable disease (48 weeks). In the AGS-16C3F study (n=34),
the protocol defined MTD as 3.6 mg/kg but this was not
tolerated in multiple doses. Reversible keratopathy was
dose limiting and required multiple dose de-escalations.
The 1.8 mg/kg dose was determined to be safe and was
associated with clinically relevant signs of antitumor
response. Three of 13 subjects at 1.8 mg/kg had durable
PRs (range 100-143 weeks). Eight (8) subjects at 2.7 mg/kg
and 1.8 mg/kg had disease control after 37 weeks (37.5 -
141 weeks).
Conclusion: AGS-16C3F was tolerated and had durable
antitumor activity at 1.8 mg/kg every 3 weeks.
Radium-223 dichloride in combination with vascular
endothelial growth factor-targeting therapy in
advanced renal cell carcinoma with bone metastases.
McKay RR, Bossé D, Gray KP, et al. Clin Cancer Res. 2018
May 30; pii: clincanres.3577.2017. doi: 10.1158/1078-
0432.CCR-17-3577.
Summary: This study investigated the biologic activity
of radium-223 with vascular endothelial growth factor
(VEGF)-targeted therapy in patients with advanced RCC
and bone metastases. Fifteen treatment-naïve patients
(n=15) received pazopanib 800 mg orally once-daily and
15 previously-treated patients received sorafenib 400 mg
orally twice-daily. Radium-223 55 kilobecquerel/kg was
administered concurrently every four weeks for up to 6
infusions in both cohorts. The primary endpoint was
decline in bone turnover markers (Procollagen I Intact
N-Terminal, N-telopeptide, C-telopeptide, osteocalcin and
bone-specific alkaline phosphatase) compared to baseline.
Secondary endpoints included safety, rate of symptomaticskeletal
event (SSE) and time to first SSE, objective
response rate, change in analgesic use and quality of life.
Exploratory analysis of tumor genomic alterations was
performed. Of the 30 patients enrolled, 83% had IMDC
intermediate- or poor-risk disease, 33% had liver metastases
and 83% had a history of SSE prior to enrolment.
No dose-limiting toxicity was observed. All bone turnover
markers significantly declined from baseline at week 8 and
16. Forty percent of patients experienced treatment-related
grade ≥3 adverse events. Response rates were 15% and 18%
per RECIST v1.1 and bone response was 50% and 30% per
MD Anderson criteria, in the pazopanib and sorafenib
cohort, respectively. Median SSE-free interval was 5.8
months and not reached, respectively. Analgesic use
remained stable over the study time.
Conclusion: Radium-223 combined with VEGF-targeted
therapy is biologically active and safe. Randomized-controlled
trials are needed to define the role of radium-223
in advanced RCC with skeletal metastases. KCJ
JOURNAL CLUB
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