Targeted drugs for metastatic renal cell carcinoma

Article (PDF Available)inThe Lancet 370(9605):2071-3 · January 2008with14 Reads
DOI: 10.1016/S0140-6736(07)61874-1 · Source: PubMed
Comment
www.thelancet.com Vol 370 December 22/29, 2007
2071
Targeted drugs for metastatic renal cell carcinoma
See Articles page 2103
Metastatic renal cell carcinoma was once considered
a cancer with a poor outlook, with treatment
options limited to cytokines (ie, interferon).
1
Antiangiogenesis-targeting agents have recently
provided new options for therapy and have improved
prognosis. In today’s Lancet, Bernard Escudier and
colleagues
2
report a randomised, double-blind
phase III trial in which they show benefi t in response
and progression-free survival for interferon alfa-2a
plus bevacizumab, which targets vascular endothelial
growth factor, compared with interferon plus placebo in
rst-line treatment of metastatic renal cell carcinoma.
Escudier and colleagues unblinded their study early,
and they explain in their report about the unblinding.
Data for the primary endpoint of overall survival were
not mature, but it was agreed that the secondary
endpoint of progression-free survival data from
the interim analysis were suffi cient for reporting.
325 patients received bevacizumab with interferon,
while 316 received placebo with interferon; 230 and
275 disease progression events occurred, respectively.
The median duration of progression-free survival
was 10·2 and 5·4 months, respectively (hazard ratio for
disease progression 0·63, 95% CI 0·52–0·75).
Previously, Yang and colleagues
3
had reported an
improvement in time to progression of renal cell
carcinoma with bevacizumab as a second-line therapy
after cytokines. Antitumour activity was then reported
in phase II trials with other antiangiogenic agents—
sunitinib, sorafenib, and temsirolimus.
4–6
Randomised
trials showed superiority of sorafenib over placebo
in second-line therapy but not over interferon as
rst-line therapy.
7, 8
Sunitinib and temsirolimus have
been compared with interferon in phase III trials (one
of us, RJM, was an investigator in both studies),
9,10
and
both showed benefi t in terms of survival endpoints
(table).
In the sunitinib versus interferon study,
9
750 previously untreated patients were enrolled.
The primary endpoint was independently evaluated
progression-free survival. At a planned interim analysis,
the median progression-free survival was longer in the
sunitinib group (11 months) than in the interferon
group (5 months; hazard ratio 0·42, 95% CI 0·32–0·54).
Sunitinib was associated with a 25% (95% CI 19–30%)
higher response rate than interferon by independent
review of response evaluation and a signifi cantly better
quality of life.
9
In the temsirolimus trial,
10
209 patients were
randomised to temsirolimus alone, 207 to interferon
alone, and 210 to temsirolimus plus interferon.
The trial studied patients with previously untreated
poor-prognosis metastatic renal cell carcinoma. Poor-
prognosis status was assigned by number of adverse
pretreatment clinical features.
1
Patients treated with
temsirolimus had improved overall survival com-
pared with those treated with interferon (median
10·9 vs 7·3 months; hazard ratio for death 0·73,
95% CI 0·58–0·92) and longer progression-free survival.
The addition of temsirolimus to interferon did not
improve survival compared with interferon alone.
Escudier and co-workers’ study addressed the question
of whether interferon is effi cacious as co-therapy with
bevacizumab.
2
Phase II trials of bevacizumab as fi rst-line
and second-line monotherapy reported response rates
(15% and 10%, respectively), similar to those observed
with interferon alone.
3,11
The high response rate (31%)
seen in Escudier’s trial suggests that interferon does
contribute to the effi cacy of this regimen.
In Escudier and co-workers’ trial, response was
assessed solely by the investigators. Lack of independent
review of response might have aff ected the proportion
of patients with reported responses, and therefore
aff ected perceived progression-free survival outcomes.
Investigators previously reported a 40% disagreement
between an investigator-assessed outcome and that of
an independent evaluation committee.
12
They analysed
data from an earlier phase III trial of cytokine therapy
in metastatic renal cell carcinoma, and concluded that
independent review should be routinely included in
therapeutic trials (as it was in trials of sunitinib and
temsirolimus
9,10
).
There are now three targeted regimens that are
reported to be benefi cial compared with interferon in
rst-line treatment of metastatic renal cell carcinoma
(bevacizumab, sunitinib, and temsirolimus; table), but
they have not been compared directly with each other
in phase III trials. Until such data are forthcoming,
information on clinical setting, nature of the treatment
programme, and outcome profi les can help to direct
Comment
2072
www.thelancet.com Vol 370 December 22/29, 2007
management of patients and future trial design. For
example, eligibility for the temsirolimus trial was
restricted to patients predicted to have a poor prognosis
(about 20% of patients with metastatic renal cell
carcinoma) according to a risk model developed at our
centre.
1
The safety profi le and survival benefi t in such
patients make temsirolimus attractive, particularly
for those with substantial symptoms related to their
underlying disease.
10
By contrast, the phase III trials of
bevacizumab plus interferon and sunitinib
9
were in a
more general population. Both showed superiority in
progression-free survival, response, and tolerability
compared with interferon alone.
Other considerations useful in decisionmaking
include the subjective experience of patients with each
regimen (ie, health-related quality of life), adverse
event profi les, and cost. Compared with interferon,
sunitinib
9
and temsirolimus
13
improve quality of life
and quality-adjusted survival, respectively, but such
benefi ts have not yet been reported for bevacizumab
plus interferon.
Drug costs for each targeted treatment are provided
in the table, on the basis of information from the British
National Formulary
14
(UK) or Medicare (USA).
15,16
These
data provide a crude comparison of drug costs faced by
governments or patients, excluding costs of infusions,
clinic time, or toxicity management, and do not refl ect
discounting which might aff ect prices paid for these
drugs by hospitals, pharmacies, oncology practices, or
patient assistance programmes. On the basis of these
data, the cost of bevacizumab plus interferon appears
to be roughly double that of sunitinib or temsirolimus
Bevacizumab plus interferon
2
Sunitinib
9
Temsirolimus
10
Design/methods
Number of patients 649 750 626
Population (MSKCC risk groups)
1
All (mostly favourable and intermediate risk) All (mostly favourable and intermediate risk) Poor risk
Comparator Interferon Interferon Interferon
Regimen Bevacizumab 10 mg/kg intravenously every
2 weeks and interferon 9 MIU subcutaneously
3 times a week in repeated cycles
50 mg orally daily for 4 weeks then 2 weeks
off , in repeated cycles
25 mg intravenous weekly infusion, in
repeated cycles
Therapy duration Bevacizumab until progression, interferon
52 weeks or until progression
Until progression Until progression
Results
Is primary endpoint met? Overall survival: no Progression-free survival: yes Overall survival: yes
Investigator-assessed median progression-free
survival (months) vs interferon
10·2 vs 5·4 (0·63, 0·52–0·75)* 11·0 vs 4·0 (0·42, 0·33–0·52) 3·8 (95% CI 3·6–5·2) vs 1·9 (1·9–2·2)
Independent radiographic assessment of
median progression-free survival benefi t
(months) vs interferon
Not done
11·0 vs 5·0 (0·42, 0·32–0·54) 5·5 (3·9–7·0) vs 3·1 (2·2–3·8)
Median overall survival benefi t (months) vs
interferon
Data not mature Data not mature
10·9 vs 7·3 (0·73, 0·58–0·92)
Health-related quality of life or quality-adjusted
survival improvement over interferon therapy
Not reported
Yes: mean FACT-G total score 82 vs 77,
p<0·001
Yes: Q-TWiST (quality-adjusted time without
symptoms of progression or toxicity)
7 months vs 5·7 months (diff erence
1·3 months), p=0·0015
13
Predominant adverse events Fatigue, proteinuria, bleeding, hypertension Diarrhoea, fatigue, sores on hands and feet,
myelosuppression
Asthenia, rash, hyperlipidaemia, anaemia
Drug discontinued for toxicity (%) Either drug 28
Bevacizumab 19
87
Costs
UK estimated cost for 12 weeks† $23 600 (bevacizumab alone $20 300,
interferon alone $3300)
$13 800 N/A‡
USA estimated cost for 12 weeks§ $30 400 (bevacizumab alone $25 600,
interferon alone $4800)
$13 600 $13 800
MSKCC=Memorial Sloan-Kettering Cancer Center. *Hazard ratio and 95% CI. Estimated drug costs rounded to 100 and provided in US dollars (correct as of Dec 5, 2007). †British National Formulary;
14
cost for
12 weeks in British pounds £9900 for bevacizumab alone, £1600 for interferon alone, £6700 for sunitinib. ‡Price not yet available. §Based on 106% of average sales price for bevacizumab and interferon alfa-2a;
15
wholesale acquisition cost for temsirolimus, based on telephone conversation with Wyeth Pharmaceuticals (Dec 5, 2007) and email correspondence with Centers for Medicare & Medicaid Services, US Department
of Health & Human Services (Dec 4, 2007; as yet, no average sales price has been assigned for this drug); and representative Medicare part D full drug cost to patients, for Humana Inc Medicare Plans (as this is an
orally administered drug);
16
US average wholesale price shows similar trend in costs of $33 700, $15 200, and $16 600 for bevacizumab–interferon alfa-2a, sunitinib, and temsirolimus, respectively.
Table: Targeted drugs tested in phase III trials for metastatic renal-cell carcinoma
Comment
www.thelancet.com Vol 370 December 22/29, 2007
2073
monotherapy. However, this comparison does not account
for possible diff erences in costs when other factors are
considered, such as route of administration (sunitinib is
oral whereas interferon, bevacizumab, and temsirolimus
are parenteral), number of clinic visits, toxicity checks,
or supportive medications. A formal cost-eff ectiveness
analysis could provide a more comprehensive comparison
of cost diff erences between regimens.
At our centre, sunitinib is the preferred fi rst-line
treatment option for most patients with metastatic
renal cell carcinoma, because of the availability of the
drug as oral therapy, its high response rates according
to studies with independent review, its safety profi le,
and its positive eff ect on health-related quality of life.
4,9
Nonetheless, the availability of alternative drugs is
benefi cial to patients, and allows for individual patients’
characteristics and preferences.
Escudier and colleagues are to be commended for their
phase III trial. The study supports the value of vascular
endothelial growth factor blockade as a therapeutic
approach to the treatment of metastatic renal cell
carcinoma, and highlights the need for further research
to defi ne the optimum in the rapidly changing era of
targeted therapy.
*Robert J Motzer, Ethan Basch
Genitourinary Oncology Service, Division of Solid Tumor Oncology,
Department of Medicine, Memorial Sloan-Kettering Cancer Center,
New York, NY 10021, USA (RJM, EB); Weil Medical College of
Cornell University, New York, NY, USA (RJM); and Health Services
Research Group, Department of Epidemiology & Biostatistics,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA (EB)
motzerr@mskcc.org
We thank Carol Pearce for review of this article and the MSKCC pharmacy and
nance departments for assistance with data gathering and confi rmation.
Mechanical bowel preparation before colorectal surgery?
Is mechanical bowel preparation of benefi t to patients
undergoing colorectal surgery? In today’s Lancet,
Caroline Contant and colleagues
1
report a randomised
trial on more than 1400 patients who underwent
colorectal surgery with or without this procedure. These
investigators found that the occurrence of clinically
signifi cant anastomotic leaks was similar in both
groups of patients (4·8% vs 5·4%, with and without
the procedure, respectively; eff ect diff erence 0·6%,
95% CI −1·7 to 2·7%). They concluded that mechanical
bowel preparation should not be done before elective
colorectal surgery. In another trial, Jung co-workers
2
recently concluded similarly. They assessed more than
1300 patients and found no appreciable diff erence
in clinical anastomotic leaks and intra-abdominal
abscesses between patients who had the procedure and
those who did not (2·6% vs 4·3%, eff ect diff erence 1·7%,
95% CI 0·7–2·7).
RJM has received honoraria from Bayer/Onyx, research funding from Genentech,
Wyeth Research, Pfi zer, and Novartis, and past research funding from Roche and
Schering-Plough. EMB has served as an unpaid guest worker for the US Food and
Drug Administration.
1 Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a
comparative treatment for clinical trials of new therapies against advanced
renal cell carcinoma. J Clin Oncol 2002; 20: 289–96.
2 Escudier B, Pluzanska A, Koralewski P, for the AVOREN Trial investigators.
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell
carcinoma: a randomised, double-blind phase III trial. Lancet 2007;
370:
2103–11.
3 Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab,
an anti-vascular endothelial growth factor antibody, for metastatic renal
cancer. N Engl J Med 2003; 349: 427–34.
4 Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib effi cacy against
advanced renal cell carcinoma. J Urol 2007; 178: 1883–87.
5 Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled
randomized discontinuation trial of sorafenib in patients with metastatic
renal cell carcinoma. J Clin Oncol 2006; 24: 2505–12.
6 Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of
multiple dose levels of CCI-779, a novel mammalian target of rapamycin
kinase inhibitor, in patients with advanced refractory renal cell carcinoma.
J Clin Oncol 2004; 22: 909–18.
7 Szczylik C, Demkow T, Staehler M, et al. Randomized phase II trial of fi rst-line
treatment with sorafenib versus interferon in patients with advanced renal
cell carcinoma: fi nal results. J Clin Oncol 2007; 25 (suppl 18): 5025 (abstr).
8 Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell
renal cell carcinoma. N Engl J Med 2007; 356: 125–34.
9 Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in
metastatic renal cell carcinoma. N Engl J Med 2007; 356: 115–24.
10 Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or
both for advanced renal cell carcinoma. N Engl J Med 2007; 356: 2271–81.
11 Bukowski R, Kabbinavar F, Figlin RA, et al. Randomized phase II study of
erlotinib combined with bevacizumab compared with bevacizumab alone
in metastatic renal cell cancer. J Clin Oncol 2007; 25: 4536–41.
12 Thiesse P, Ollivier L, Di Stefano-Louineau D, et al. Response rate accuracy in
oncology trials: reasons for interobserver variability. J Clin Oncol 1997;
15: 3507–14.
13 Parasuraman S, Hudes G, Levy D, et al. Comparison of quality-adjusted
survival in patients with advanced renal cell carcinoma receiving fi rst-line
treatment with temsirolimus (TEMSR) or interferon-alfa (IFN) or the
combination of IFN+TEMSR. J Clin Oncol 2007; 25 (suppl 18): 5049 (abstr).
14 Joint Formulary Committee. British national formulary, 54th edn.
London: British Medical Association, Royal Pharmaceutical Society of
Great Britain, 2007.
15 US Department of Health & Human Services. ASP pricing fi le: payment
allowance limits for medicare part B drugs, eff ective October 1, 2007
through December 31, 2007. http://www.cms.hhs.gov/mcrpartbdrugavg
salesprice (accessed Dec 11, 2007).
16 US Department of Health and Human Services. Medicare prescription drug
plan fi nder. 2006. http://plancompare.medicare.gov (accessed Dec 6, 2007).
See Articles page 2112
    • "A meta-analysis based on randomized controlled trials (RCTs) has shown that patients with mRCC could benefit modest response rate from IFN-α [4]. The greater and deeper understanding of the mechanisms involved in the pathogenesis of mRCC led to development of more promising target treatment options [5, 6]. Previous RCTs of targeted therapies versus cytokine therapies or placebos manifested that targeted therapies showed superiority in PFS, response, and tolerability [7, 8]. "
    [Show abstract] [Hide abstract] ABSTRACT: It is impossible to conduct head-to-head trials of all the therapies to determine optimal treatment in the rapidly advancing era of therapies for metastatic renal cell carcinoma (mRCC). In this network meta-analysis,we aimed to compare efficacy and safety of first-line treatments for mRCC. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and unpublished studies were also sought through "clinicaltrials.gov" from their inception through January 31, 2016. A database search identified 1253 articles, with 11 studies meeting the eligibility criteria. A total of 7597 patients in twelve different treatment arms were assessed. Network meta-analysis showed sunitinib had a significantly longer PFS than IFN-α (SMD=-5.68; 95%CI: -10.76,-0.86; P<0.001) and placebo (SMD=-6.71; 95%CI: -12.65,-0.79; P<0.001), meanwhile, pazopanib had a significantly longer PFS compared with placebo (SMD=5.13; 95%CI: 0.43, 10.09; P<0.001). The cumulative ranking probability curve indicated that sunitinib had the highest probability of being the best treatment modality in terms of PFS and it also had the highest probability of being the safest drugs as the first-line treatment when it came to SAE. Thus, sunitinib might be the best choice of first-line treatment for patients with mRCC because it has the most favorable balance between efficacy and safety.
    Full-text · Article · Feb 2016
    • "In the era of targeted therapy, the International mRCC Database Consortium (IMDC) prognostic model has been used to stratify patients according to the presence of six adverse prognostic factors: Karnofsky score <80%, low hemoglobin, time from diagnosis to treatment of <1 year, high corrected calcium, thrombocytosis , and neutrophilia [8,20]. In addition, histology (clear cell vs. non-clear cell), personal experience and cost are also important considerations in the decisionmaking process [30]. The intent of our study was to perform metacomparison of the pivotal RCTs to provide evidence on the best first-line treatment of patients with good to intermediate risk mRCC. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Based on improved clinical outcomes in randomized controlled clinical trials (RCTs) the FDA and EMA have approved bevacizumab with interferon, sunitinib, and pazopanib in the first-line treatment of low to intermediate risk metastatic clear cell renal cell carcinoma (mRCC). However, there is little comparative data to help in choosing the most effective drug among these agents. Methods: We performed an indirect comparative effectiveness analysis of the pivotal RCTs of bevacizumab with interferon, sunitinib, or pazopanib compared to one another or interferon alone in first-line treatment of metastatic or advanced RCC. Endpoints of interest were overall survival (OS), progression free survival (PFS), and response rate (RR). Adverse events were also examined. Results: The meta-estimate of the hazard ratio (95% confidence interval) for OS for bevacizumab with interferon vs. interferon alone was 0.86 (0.76-0.97), for sunitinib vs. interferon alone was 0.82 (0.67-1.00), for pazopanib vs. interferon alone was 0.74 (0.57-0.97), for sunitinib vs. bevacizumab with interferon was 0.95 (0.75-1.20), for pazopanib vs. bevacizumab with interferon was 0.86 (0.64-1.16), and for pazopanib vs. sunitinib was 0.91 (0.76-1.08). Similarly, bevacizumab with interferon, sunitinib, or pazopanib had better PFS and RR than interferon alone. Sunitinib and pazopanib had better RR than bevacizumab with interferon and there was suggestive evidence pazopanib may outperform sunitinib in terms of RR. Conclusions: Bevacizumab with interferon, sunitinib, and pazopanib are adequate first-line options in treatment of mRCC. Interferon alone should not be considered an optimal first-line treatment.
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    • "For the convenience of hospital staff, most intravenous chemotherapy is being applied during daytime and oral drugs are usually administered once daily, preferentially administered in morning, without putting forward a rationale for this time of dosing.[353637383940] This conventional approach cannot be used for some of the drugs as this lack of attention to the timing of therapy supposes that biological parameters are either constant throughout the 24 hours, or that their variations are unpredictable and/or stochastic. "
    [Show abstract] [Hide abstract] ABSTRACT: For many decades, researchers are aware of the importance of circadian rhythm in physiological/biochemical properties and drug metabolism. Chronopharmacology is the study of how the effects of drugs vary with biological timing and endogenous periodicities. It has been attaching substantial attention in the last years. Chronopharmacodynamics mainly deals with the biochemical and physiological effects of drugs on the body, the mechanisms of drug action, the relationship between drug concentration and effect in relation to circadian clock. In this review, we will focus on mammalian circadian pharmacodynamics and discuss new chronotherapy approaches. Moreover, we will try to highlight the chronopharmacodynamics of cardiovascular drugs, anti-cancer drugs, analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) and give some practical concerns for clinical pharmacists and pharmacy practitioners, concerning this issue.
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