could improve the model’s prognostic performance. This
retrospective cohort study used available formalin-fixed
paraffin-embedded tumor tissue and clinical outcome
data from patients with metastatic renal-cell carcinoma
assigned to treatment with tyrosine kinase inhibitors in
the COMPARZ trial (training cohort; n=357) and
RECORD-3 trial (validation cohort; n=258). Eligible
patients in both trials were treatment-naive; had histologically
confirmed, advanced, or metastatic renal-cell carcinoma;
and a Karnofsky performance status score of at
least 70. For each cohort, data from patients in all treatment
groups (sunitinib and pazopanib in the training
cohort, and everolimus and sunitinib in the validation cohort)
were pooled for this analysis. In the training cohort,
tumor tissue was used to evaluate somatic mutations by
next-generation sequencing, and the association between
cancer-specific outcomes (overall survival, progressionfree
survival, and overall response) and the mutation
status of six genes of interest (BAP1, PBRM1, TP53, TERT,
KDM5C, and SETD2) was tested. Only those genes with
prognostic value in this setting were added to the MSKCC
risk model to create a genomically annotated version. In
the training cohort, the presence of any mutation in BAP1
or TP53, or both, and absence of any mutation in PBRM1
were prognostic in terms of overall survival (TP53wt/
BAP1mut, TP53mut/BAP1wt o TP53mut BAP1mut vs
TP53wt/BAP1wt hazard ratio HR 1·57, 95% CI 1·21-2·04;
P=0·0008; PBRM1wt vs PBRMmut, HR 1·58, 1·16-2·14;
P=0·0035). The mutation status for these three prognostic
genes were added to the original MSKCC risk model to
create a genomically annotated version. Distribution of
participants in the training cohort into the three risk
groups of the original MSKCC model changed from 87
(24%) of 357 patients deemed at favorable risk, 217 (61%)
at intermediate risk, and 53 (15%) at poor risk, to distribution
across four risk groups in the genomically annotated
risk model, with 36 (10%) of 357 deemed at favourable
risk, 77 (22%) at good risk, 108 (30%) at intermediate risk,
and 136 (38%) at poor risk. Addition of genomic information
improved model performance for predicting overall
survival (C-index: original model, 0·595 95% CI 0·557-
0·634 vs new model, 0·637 0·595-0·679) and progression
free survival (0·567 95% CI 0·529-0·604 vs 0·602
0·560-0·643) with adequate discrimination of the proportion
of patients who achieved an objective response
(Cochran-Armitage one-sided P=0·0014). Analyses in the
validation cohort confirmed the superiority of the genomically
annotated risk model over the original version.
Conclusion: The mutation status of BAP1, PBRM1, and
TP53 has independent prognostic value in patients with
advanced or metastatic renal-cell carcinoma treated with
first-line tyrosine kinase inhibitors. Improved stratification
of patients across risk groups by use of a genomically
annotated model including the mutational status of these
three genes warrants further investigation in prospective
trials and could be of use as a model to stratify patients
with metastatic RCC in clinical trials.
124 Kidney Cancer Journal
Adjuvant sunitinib in patients with high-risk renal cell
carcinoma: safety, therapy management, and patientreported
outcomes in the S-TRAC trial. Staehler M,
Motzer RJ, George DJ, et al. Ann Oncol. 2018 Oct 1;29(10):
2098-2104.
Summary: Adjuvant sunitinib has significantly improved
disease-free survival versus placebo in patients with renal
cell carcinoma at high risk of recurrence post-nephrectomy.
This study reported safety, therapy management,
and patient-reported outcomes for patients receiving sunitinib
and placebo in the S-TRAC trial. Patients were randomized
(1:1) to receive sunitinib (50 mg/day) or placebo.
Single dose reductions to 37.5 mg, dose delays, and dose
interruptions were used to manage adverse events (AEs).
Patients’ health-related quality of life, including key
symptoms typically associated with sunitinib, were evaluated
with the European Organisation for Research and
Treatment of Cancer Quality of Life Questionnaire
(EORTC QLQ-C30). Patients maintained treatment for 9.5
(mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the
sunitinib and placebo arms, respectively. In the sunitinib
arm, key AEs occurred 1 month (median) after start of
treatment and resolved within 3.5 weeks (median). Many
(40.6%) AEs leading to permanent discontinuation were
grade 1/2, and most (87.2%) resolved or were resolving by
28 days after last treatment. Patients reported symptoms
typically related to sunitinib treatment with diarrhea and
loss of appetite showing clinically meaningful increases.
Conclusion: In S-TRAC, AEs were predictable, manageable,
and reversible via dose interruptions, dose reductions,
and/or standard supportive medical therapy.
Patients on sunitinib did report increased symptoms
and reduced HRQoL, but these changes were generally
not clinically meaningful, apart from appetite loss and
diarrhea, and were expected in the context of known
sunitinib effects.
Sunitinib alone or after nephrectomy in metastatic
renal-cell carcinoma. Méjean A, Ravaud A, Thezenas S,
et al. N Engl J Med. 2018 Aug 2;379(5):417-427.
Summary: This phase 3 trial randomly assigned, in a 1:1
ratio, patients with confirmed metastatic clear-cell RCC at
presentation who were suitable candidates for nephrectomy
to undergo nephrectomy and then receive sunitinib
(standard therapy) or to receive sunitinib alone. Randomization
was stratified according to prognostic risk (intermediate
or poor) in the Memorial Sloan Kettering Cancer
Center prognostic model. Patients received sunitinib at a
dose of 50 mg daily in cycles of 28 days on and 14 days
off every 6 weeks. The primary end point was overall
survival. A total of 450 patients were enrolled from September
2009 to September 2017. At this planned interim
analysis, the median follow-up was 50.9 months, with
326 deaths observed. The results in the sunitinib-alone
group were noninferior to those in the nephrectomy-
sunitinib group with regard to overall survival. The median
overall survival was 18.4 months in the sunitinibalone
group and 13.9 months in the nephrectomy-suni-
tinib group. No significant differences in response rate or
progression-free survival were observed. Adverse events
were as anticipated in each group.
Conclusion: Sunitinib alone was not inferior to nephrectomy
followed by sunitinib in patients with metastatic
RCC who were classified as having intermediate-risk or
poor risk disease poor-risk disease. KCJ
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