Summary: This ongoing, open-label, phase 1b study,
which was done at 10 centers in the US, enrolled patients
aged 18 years or older who had advanced RCC (predominantly
clear cell) with their primary tumor resected, and at
least one measureable lesion, Eastern Cooperative Oncology
Group performance status 0-1, controlled hypertension,
and no previous systemic therapy for renal cell
carcinoma. Axitinib 5 mg was administered orally twice
per day with pembrolizumab 2 mg/kg given intravenously
every 3 weeks. The primary endpoint was investigatorassessed
dose-limiting toxicity during the first two cycles
(6 weeks) to estimate the maximum tolerated dose and
recommended phase 2 dose. Between Sept 23, 2014, and
March 25, 2015, we enrolled 11 patients with previously
untreated advanced renal cell carcinoma to the dose-finding
phase and between June 3, 2015, and Oct 13, 2015, we
enrolled 41 patients to the dose-expansion phase. All 52
patients were analyzed together. No unexpected toxicities
were observed. Three dose-limiting toxicities were reported
in the 11 patients treated during the 6-week observation
period (dose-finding phase): one patient had a transient
ischaemic attack and two patients were only able to complete
less than 75% of the planned axitinib dose because of
treatment-related toxicity. At the data cutoff date (March
31, 2017), 25 (48%) patients were still receiving study
treatment. Grade 3 or worse treatment-related adverse
events occurred in 34 (65%) patients; the most common
included hypertension (n=12 23%), diarrhea (n=5 10%),
fatigue (n=5 10%), and increased alanine aminotransferase
concentration (n=4 8%). The most common potentially
immune-related adverse events (probably related to
pembrolizumab) included diarrhea (n=15 29%), increased
alanine aminotransferase concentration (n=9 17%) or
aspartate aminotransferase concentration (n=7 13%),
hypothyroidism (n=7 13%), and fatigue (n=6 12%).
28 (54%) patients had treatment-related serious adverse
events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients
achieved an objective response (complete or partial response).
Conclusion: The treatment combination of axitinib plus
pembrolizumab is tolerable and shows promising antitumor
activity in patients with treatment-naive advanced
RCC. Whether or not the combination works better than
a sequence of VEGF pathway inhibition followed by an
anti-PD-1 therapy awaits the completion of a phase 3 trial
comparing axitinib plus pembrolizumab with sunitinib
monotherapy.
A genetic polymorphism in CTLA-4 is associated with
overall survival in sunitinib-treated patients with clear
cell metastatic renal cell carcinoma. Liu X, Swen JJ,
Diekstra MHM, et al. Clin Cancer Res. 2018 Feb 28. pii: clincanres.
2815.2017. doi: 10.1158/1078-0432.CCR-17-2815.
Summary: With the fact that TKIs interact with immune
responses, this report investigated whether polymorphisms
of genes involved in immune checkpoints are related to
the clinical outcome of cc-mRCC patients treated with
30 Kidney Cancer Journal
sunitinib as first TKI; 27 single nucleotide polymorphisms
(SNPs) in CD274 (PD-L1), PDCD1 (PD-1) and CTLA-4 were
tested for a possible association with progression-free
survival (PFS) and overall survival (OS) in a discovery
cohort of 550 sunitinib-treated cc-mRCC patients. SNPs
with a significant association (P<0.05) were tested in an
independent validation cohort of 138 sunitinib-treated
cc-mRCC patients. Finally, data of the discovery and validation
cohort were pooled for meta-analysis. CTLA-4
rs231775 and CD274 rs7866740 showed significant associations
with OS in the discovery cohort after correction for
age, gender and Heng prognostic risk group (HR=0.84,
95%CI: 0.72-0.98, P=0.028 and HR=0.73, 95%CI: 0.54-
0.99, P=0.047, respectively). In the validation cohort, the
associations of both SNPs with OS did not meet the significance
threshold of p<0.05. After meta-analysis, CTLA-4
rs231775 showed a significant association with OS
(HR=0.83, 95%CI: 0.72-0.95, P=0.008). Patients with the
GG-genotype had longer OS (35.1 months) compared to
patients with an AG (30.3 months) or AA genotype (24.3
months). No significant associations with PFS were found.
Conclusion: The G-allele of rs231775 in the CTLA-4 gene
is associated with improved OS in sunitinib-treated
cc-mRCC patients and could potentially be used as a prognostic
biomarker.
Randomized phase III trial of adjuvant pazopanib
versus placebo after nephrectomy in patients with
localized or locally advanced renal cell carcinoma.
Motzer RJ, Haas NB, Donskov F, et al. J Clin Oncol. 2017
Dec 10;35(35):3916-3923. doi: 10.1200/JCO.2017.73.5324.
Epub 2017 Sep 13.
Summary: This phase III trial evaluated the efficacy and
safety of pazopanib vs placebo in patients with locally advanced
RCC at high risk for relapse after nephrectomy. A
total of 1,538 patients with resected pT2 (high grade) or
≥pT3, including N1, clear cell RCC were randomly
assigned to pazopanib or placebo for 1 year; 403 patients
received a starting dose of 800 mg or placebo. To address
toxicity attrition, the 800-mg starting dose was lowered to
600 mg, and the primary end point analysis was changed
to disease-free survival (DFS) for pazopanib 600 mg versus
placebo (n = 1,135). Primary analysis was performed after
350 DFS events in the intent-to-treat (ITT) pazopanib 600
mg group (ITT600mg), and DFS follow-up analysis was
performed 12 months later. Secondary end point analyses
included DFS with ITT pazopanib 800 mg (ITT800mg) and
safety. The primary analysis results of DFS ITT600mg
favored pazopanib but did not show a significant improvement
over placebo (P = .165). The secondary analysis of
DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI,
0.51 to 0.94). Increased ALT and AST were common
adverse events leading to treatment discontinuation in
the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg
(ALT, 18%; AST, 7%) groups.
Conclusion: The results of the primary DFS analysis of
pazopanib 600 mg showed no benefit over placebo in the
adjuvant setting. KCJ
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