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First line treatment of metastatic renal cell carcinoma Two standards with different toxicity profile

Cancer Biology & Therapy

November 2013
15(1)

DOI:10.4161/cbt.27150

Source
PubMed

Authors:

Roberto Iacovelli

Policlinico Universitario Agostino Gemelli

Elena Verzoni

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Tyrosine kinase inhibitors are de facto the more used targeted therapies for upfront treatment of metastatic renal cell carcinoma (mRCC). Among these, sunitinib and pazopanib have reported greater activity in term of progression-free survival and overall survival compared with interferon-α or placebo in two independent large phase III studies. Despite a large use in clinical practice these molecules had never been compared. The COMPARZ study recently published in the New England Journal of Medicine reports the results of a non-inferiority trial that comparing pazopanib to sunitinib as first line of therapy in mRCC patients. Here we report the activity and safety data of the study and we discuss several critical aspects related to the study design and possible confounding factors that may alter the results' interpretation.

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www.landesbioscience.com Cancer Biology & Therapy 19

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Tyrosine kinase inhibitors are de

facto the more used targeted

therapies for upfront treatment of

metastatic renal cell carcinoma (mRCC).

Among these, sunitinib and pazopanib

have reported greater activity in term

of progression-free survival and overall

survival compared with interferon-α or

placebo in two independent large phase

III studies. Despite a large use in clinical

practice these molecules had never

been compared. The COMPARZ study

recently published in the New England

Journal of Medicine reports the results

of a non-inferiority trial that comparing

pazopanib to sunitinib as first line of

therapy in mRCC patients. Here we

report the activity and safety data of

the study and we discuss several critical

aspects related to the study design and

possible confounding factors that may

alter the results’ interpretation.

Renal cell carcinoma (RCC) is the

sixth most common diagnosis of cancer in

men and the eighth in women in United

States with an estimated 65 150 new cases

and 13 680 deaths expected to occur in

the current year.1 In Europe, the incidence

and the mortality of RCC are estimated

to be 71 739 and 31 293 cases per year,

respectively.2,3

In this tumor, two pathways have

been emphasized for tumor survival and

dissemination: the vascular endothelial

growth factor (VEGF) with its receptor

(VEGFR), and the mammalian target of

rapam icin (mTOR).4,5

From 2006 to now, 5 VEGF/

VEGFR inhibitors (sorafenib, sunitinib,

pazopanib, axitinib, and bevacizumab)

and two mTOR inhibitors (temsirolimus

and everolimus), have been approved

for treatment of mRCC superseding the

cytokine-based therapy. As the result of

this evidence, the prognosis of mRCC

patients has notably improved: from 1999

to 2009, the median overall survival has

increased from 10 to 22 mo.6,7

Currently, in patients with good or

intermediate prognosis based on MSKCC

criteria,6 the use of antiangiogenic

agents such as sunitinib, pazopanib,

and bevacizumab plus interferon-α

(IFN-α) is recommended by the major

American and European guidelines, as

the first-line treatment.8,9 Despite this,

use of bevacizumab in clinical practice

has been reduced considering several

factors such as the intravenous infusion

and the concomitant administration with

subcutaneous interferon then oral tyrosine

kinase inhibitors are de facto the more

used targeted therapies.

In the phase III trial comparing

sunitinib 50 mg/day for 4 weeks followed

by 2 weeks of rest to IFN-α as first line

of therapy in 750 untreated patients.

Sunitinib reported a decrease of the risk of

progression by 58% (HR: 0.42; 95% CI,

0.32 to 0.54; P < 0.001) corresponding to

an increase of median PFS from 5 to 11

mo with a higher objective response rate

compared with IFN-α (31 vs. 6%; P <

0.001) .10 ,11

The pazopa nib phase III trial compared

the activity of pazopanib 800 mg/day to

the placebo in a non-homogeneous group

of patients, including 233 treatment-

naïve and 202 pre-treated with IFN-α.

First line treatment of metastatic renal cell carcinoma

Two standards with different toxicity proﬁle

Roberto Iacovelli1,2,*, Elena Verzoni1, Filippo De Braud1, and Giuseppe Procopio1

1Department of Medical Oncology; Fondazione IRCCS Istituto Nazionale Tumori; Milano, Italy; 2Department of Radiolog y, Oncology and Human Pathology

PhD program; Sapienza University of Rome; Rome, Italy

Keywords: pazopanib, sunitinib, renal

cancer, first line, toxicity, non-inferiority

study, phase III trial

Submitted: 10/25/2013

Acc e pte d : 11/10 / 2 013

http://dx.doi.org/10.4161/cbt.27150

*Correspondence to: Roberto Iacovelli;

Email: roberto.iacovelli@alice.it

Comment on: Motzer RJ, Hutson TE, Cella D,

Reeves J, Hawkins R, Guo J, Nathan P, Staehler M,

de Souza P, Merchan JR, et al. Pazopanib versus

sunitinib in metastatic renal-cell carcinoma. N

Engl J Med 2013; 369:722-31; PMID:23964934;

http://dx.doi.org/10.1056/NEJMoa1303989

20 Cancer Biology & Therapy Volume 15 Issue 1

Pazopanib was able to decrease the risk of

progression both in treatment-naïve (HR:

0.40; 95% CI, 0.27 to 0.60 ; P < 0.001),

and in pre-treated (HR: 0.54; 95% CI,

0.35 to 0.84; P < 0.001) with an increase

of median PFS from 2.8 to 11.1 and from

4.2 to 7.4 mo, respectively.12

Despite this evidence, both treatments

did not show any increase of median

OS because of several reasons such as

the number of patients who crossed over

to the experimental treatment and the

higher number of patients who received

subsequent lines after disease progression.

The COMPARZ study recently

published in the New England Journal

of Medicine reports the results of a non-

inferiority trial that compared pazopanib

to sunitinib as first line of therapy in

mRCC patients.13

In this study, 1100 patients have

been randomized 1:1 to receive

pazopanib or sunitinib at the standard

dosage until progression or intolerable

toxicity. Patients were stratified based

on previous nephrectomy, value of

lactate dehydrogenase, and Karnofsky

performance status at baseline. The

primary end-point of the study was to

report a non inferiority of pazopanib

compared with sunitinib with the upper

bound of the confidence interval fixed

to <1.25. Secondary end-points were the

objective response rate, the overall survival

and the health-related quality of life.

Results showed a median PFS of 8.4

and 9.5 mo for pazopanib and sunitinib,

respectively with an HR of 1.05 and lower

and higher bounds of the 95% confidence

interval of 0.90 and 1.22, respectively.

Then, the study met the primary end-

point reporting the non-inferiority of

pazopanib compared with sunitinib.

About secondary end-points the

objective responses were observed in 31%

of patients treated with pazopanib and

in 25% of patients treated with sunitinib

(P = 0.03). No significant differences in

overall survival were observed with 28.4

and 29.3 mo for pazopanib and sunitinib,

respectively (HR: 0.91; 95% CI, 0.76 to

1.08 ; P = 0.28).

Despite the positive results reached, this

study records an interesting event during

its conduction: because it was calculated

a total of 631 disease progression events

to have 80% power to reject the null

hypothesis (upper bound of HR ≥1.25),

then a number of 876 patients were

initially considered sufficient to observe

the required events. Unfortunately, the

planned number was not reached, and

the investigators decide to increase the

sample to 1100 patients. Rather re-open

the enrollment in the centers initially

involved in the study, the investigators

decide to include in the original trial

the patients enrolled in another trial

(NCT01147822) conducted only in

China and Taiwan and South Korea with

the intent to reach enough Asian patients

to have regulatory reimbursement in these

countries. Even if patients enrolled in

the latter study have the same inclusion/

exclusion criteria initially planned for the

original trial, and the decision was applied

per protocol amendment, the procedure

result is quite singular. The question is if

this may have influenced the quality of

the final data, considering recent evidence

that suggested no differences in terms of

efficacy between Asian and non-Asian

patients treated with TKIs but significant

differences in treatment discontinuation

due to adverse events, which are higher in

non-Asian patients.14

The COMPARZ trial not only showed

the non-inferiority of pazopanib over

sunitinib but also reported useful data

about the patients’ compliance and about

their toxicity profile. In the registrative

trials were reported discontinuation

rates due to adverse events for sunitinib

and pazopanib of 19% and 16%,

respectively; in the COMPARZ trial, the

discontinuation rate was 20% for sunitinib

and 24% for pazopanib. The incidence

of common adverse events (>10% of

subjects) was found to be more frequent

in the sunitinib arm, and among these

hand–foot syndrome (29% vs. 50%),

mucosal inflammation (11% vs. 26%),

hypothyroidism (12% vs. 24%), and

fatigue (55% vs. 63%). The events most

frequent in the pazopanib arm were: hair

color change (30% vs. 10%); weight loss

(15% vs. 6%), and alopecia (14% vs. 0%).

Hematological adverse events were more

frequent in the sunitinib arm: these were

anemia (31% vs. 60%), leukopenia (43%

vs. 78%), and thrombocytopenia (41% vs.

78%). Pazopanib reported an increase of

hepatic toxicity with an increase of ALT

(60% vs. 43%) and total bilirubin (36%

vs. 27%) even if the majors differences

were in high-grade hepatic toxicities

for AST (12% vs. 3%), and ALT (17%

vs. 5%), conf irming the data of recent

metaanalysis.15

About the direct applicability of these

result in clinical practice, a recent work

by Heng et al. reported the differences in

terms of prognosis between patients with

clinical characteristic meeting general

inclusion criteria for clinical trials and

who did not, with a poor prognosis for

the last category.16 In this case, the longer

use of sunitinib have offered more data

about efficacy and safety in patients from

clinical practice.17 With the same intent,

the Principal study (NCT01649778)

aims to evaluate prospectively the

activity and safety of pazopanib in a large

unselected population and plans to enroll

approximately 700–1000 patients.

Finally, the COMPARZ trial reports

the non-inferiority of pazopanib over

sunitinib in first-line treatment of mRCC

and it offers to physicians another molecule

for metastatic patients and the possibility

to choose based on drugs’ safety profile

without any eff icacy reduction.

Disclosure of Potential Conflicts of Interest

No potential conf licts of interest were

disclosed.

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Apr 2010
CURR CANCER DRUG TAR

Targeted therapies affecting specific molecular target, expressed preferentially by neoplastic cells, block cancer growth. Current targets are represented by cell-surface trans-membrane proteins, intracellular proteins, and by growth factors. Today a targeted therapy exists for most commonly diagnosed types of human cancer often combined with chemotherapy or sometimes as monotherapy option. The epidermal growth factor receptors (EGFR) and vascular endothelial growth factors (VEGF) are known as the two main control key intracellular pathways, governing fundamental processes in cancer cells. The concept of using anti-EGFR and anti-VEGF strategies, as cancer treatment, has been recently developed and exploited extensively. We review targeted drugs currently available for routine treatment of lung, breast, colorectal and renal cell cancers, summarizing the history of identification and molecular characterization of targets or signaling pathways responsible for abnormal cell growth. We also focus on new targeted strategies, still under investigation, able to affect simultaneously tightly interconnected biological pathways or directed against new molecular targets.

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial

Article

Full-text available

Feb 2010
J CLIN ONCOL

Purpose Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). Patients and Methods Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. Conclusion Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Vascular endothelial growth factor (VEGF) therapy in metastatic renal cell carcinoma (mRCC): Differences between Asian and non-Asian patients.

Article

Feb 2012

451 Background: Several reports have indicated that VEGF targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in the Asian versus Caucasian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterized. Methods: Eight centers participating in the International mRCC Database Consortium with available dose reduction data on patients with mRCC treated with VEGF targeted therapy were included in this analysis. Asian patients were derived from centers in Korea and Singapore. Results: 1024 patients with a median follow-up of 29.4 months were included in this analysis. Baseline characteristics are below. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% p=0.1197) but more patients completely discontinued treatment due to toxicity in the non-Asian vs the Asian group (28% vs 21% p=0.0197). When adjusted for the Heng et al poor prognostic criteria, there was no difference in overall survival (HR 0.887, 95%CI 0.729-1.08, p=0.2322) or progression-free survival (HR 1.069, 95%CI 0.910-1.256, p=0.4184) between non-Asians and Asians. Interestingly, when patients were dose reduced due to toxicity, they had a longer treatment duration and overall survival than those that did not require a dose reduction in both the non-Asian (10.6 vs 5.0 months p<0.0001 and 22.6 vs 16.1 months p=0.0016, respectively) and in the Asian populations (8.9 vs 5.4 months p=0.0028 and 28.0 vs 18.7 months p=0.0069). Conclusions: After adjusting for risk groups, there appears to be no difference in outcome between Asians vs. non-Asian patients with mRCC treated withVEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations possibly due to longer treatment durations, but direct comparisons are needed. [Table: see text]

A multicentered population-based analysis of outcomes of patients with metastatic renal cell carcinoma (mRCC) who do not meet eligibility criteria for clinical trials.

Article

Feb 2012

353 Background: Clinical trials have strict eligibility criteria to maintain internal validity. These criteria exclude many patients to whom the trial results are later applied to in clinical practice. Patients that do not meet eligibility criteria are poorly characterized. Methods: mRCC patients treated with VEGF targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky Performance Status (KPS) < 70%, brain metastases, non-clear cell histology, hemoglobin ≤ 9 g/dL, creatinine > 2x the upper limit of normal, platelet count of < 100x10 ³ /uL, neutrophil count < 1500/mm ³ or corrected calcium ≤ 12 mg/dL. Results: 894/2076 (43%) patients were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression free survival (PFS) and median overall survival of first-line targeted therapy were 21% vs 29%, 5.2 vs 8.8 months and 14.5 vs 28.8 months (all p < 0.0001), respectively. Second-line PFS (if applicable) was 3.2 months in the trial ineligible vs 4.4 months in the trial eligible patients (p = 0.0074). When adjusted by the Heng et al prognostic categories, the hazard ratio for death between trial ineligible vs trial eligible patients was 1.621 (95% CI = 1.431–1.836, p < 0.0001). If only KPS, brain metastases and non-clear cell histology were used as exclusion criteria, 672 (32%) patients were excluded and the results were similar. Conclusions: The number of patients that are ineligible for clinical trials is high and their outcomes are inferior. Designing more inclusive clinical trials for this “ineligible” patient population are needed. [Table: see text]

Global estimates of cancer prevalence for 27 sites in the adult population in 2008

Article

Mar 2013
INT J CANCER

Recent estimates of global cancer incidence and survival were used to update previous figures of limited duration prevalence to the year 2008. The number of patients with cancer diagnosed between 2004 and 2008 who were still alive at the end of 2008 in the adult population is described by world region, country and the human development index. The 5-year global cancer prevalence is estimated to be 28.8 million in 2008. Close to half of the prevalence burden is in areas of very high human development that comprise only one-sixth of the world's population. Breast cancer continues to be the most prevalent cancer in the vast majority of countries globally; cervix cancer is the most prevalent cancer in much of Sub-Saharan Africa and Southern Asia and prostate cancer dominates in North America, Oceania and Northern and Western Europe. Stomach cancer is the most prevalent cancer in Eastern Asia (including China); oral cancer ranks as the most prevalent cancer in Indian men and Kaposi sarcoma has the highest 5-year prevalence among men in 11 countries in Sub-Saharan Africa. The methods used to estimate point prevalence appears to give reasonable results at the global level. The figures highlight the need for long-term care targeted at managing patients with certain very frequently diagnosed cancer forms. To be of greater relevance to cancer planning, the estimation of other time-based measures of global prevalence is warranted.

Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy

Article

Aug 2013
BRIT J CLIN PHARMACO

The aim of this study is to investigate the incidence and risk of hepatic toxicity in patients receiving TKIs through a large up-to-date meta-analysis of available clinical trials. PubMed was reviewed for phase III randomized trials with axitinib, pazopanib, sorafenib, sunitinib, regorafenib or vandetanib. The characteristics of each study and incidence of all- and high-grades of ALT, AST and total bilirubin increase were collected. A total of 3,691 patients was available for meta-analysis: 1,170 had metastatic renal cell carcinoma; 950 had advanced non-small cell lung carcinoma; 454 had hepatocarcinoma; 753 had metastatic colorectal cancer, and 362 had metastatic soft-tissue sarcoma. The incidence of ALT, AST and bilirubin increase of any grade in patients treated with TKIs was 34.0% (95% CI, 31.6 - 36.3), 39.2% (95% CI, 36.7 - 41.6), and 21.8% (95% CI, 19.9 - 23.7), respectively. The incidence of the high-grade increase was 5.2% (95% CI, 4.2 - 6.4), 5.0% (95% CI, 3.8 - 6.2) and 1.7% (95% CI, 1.1 - 2.4) respectively. The relative risk of ALT, AST and total bilirubin increase resulted 1.85, 2.19 and 1.79 for any grade and 2.75, 2.39 and 1.65 for high grade, respectively. Hepatotoxicity is a relative common event occurring in 23-40% of patients treated with TKIs. Despite this, only 5% of patients have had high grade of toxicity. A better knowledge of this phenomenon may prevent high-grade toxicity and reduce treatment discontinuation due to this adverse event.

Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma

Article

Aug 2013
NEW ENGL J MED

Background: Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. Methods: We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. Results: Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons). Conclusions: Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

Safety and efficacy of sunitinib in an expanded-access trial of metastatic renal cell carcinoma (MRCC): Updated results and subpopulation analysis

Article

Mar 2008
EUR UROL SUPPL

Prognostic Factors for Overall Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor-Targeted Agents: Results From a Large, Multicenter Study

Article

Oct 2009
J CLIN ONCOL

There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.

First line treatment of metastatic renal cell carcinoma Two standards with different toxicity profile

Abstract

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