Systemic Treatment Options for Untreated Patients WithMetastatic Clear Cell Renal Cancer

Ana M. Molina,a Robert J. Motzer,a and Daniel Y. Hengb

The introduction of therapy targeting vascular endothelial growth factor (VEGF) and the

mammalian target of

with metastatic renal c

previously untreated ptherapeutic options ar

Semin Oncol 40:436-4

0270-9295/& 2013 Elshttp://dx.do

Conflicts o

aGenitourinDepartmNew Yor

bTom Bake

Address coKetteringUSA. E-

436

rapomycin (mTOR) has significantly improved the outcome of patients

ancer. In this article a comprehensive overview of treatment choices for

atients with metastatic disease is given. Both established and emerginge discussed, as are prognostic factors predicting outcome.

43 & 2013 Elsevier Inc. All rights reserved.

Renal cell carcinoma (RCC) is a malignancy of

the kidney that originates in the proximal

renal tubule and accounts for approximately3% of all cancers. In 2012, an estimated 64,770 new

cases of kidney and renal pelvis cancers are

expected to be diagnosed in the United States withan estimated 13,570 deaths within the same group.1

Surgical resection is the main treatment for tumors

that are confined to the kidney. Approximately 20%–40% of patients with localized disease will eventually

develop local recurrence or distant metastasis after

nephrectomy.2 In addition, about one third ofpatients with RCC have metastatic disease at diag-

nosis. The majority of these patients are candidates

for systemic therapy.Recently, an increased understanding of the

pathogenesis of RCC has led to the development of

novel drugs that target vascular endothelial growthfactor (VEGF) and the mammalian target of rapamy-

cin (mTOR). First-line treatment of metastatic renal

cell carcinoma (mRCC) relies heavily on the use ofsmall molecule targeted inhibitors. Phase III trials of

these agents have demonstrated substantially better

overall efficacy and fewer side effects than previ-ously used cytokines and have assumed a predom-

inant role in the standard management for mRCC.3–9

- see front matterevier Inc. All rights reserved.i.org/10.1053/j.seminoncol.2013.05.013

f interest: none.

ary Oncology Service, Division of Solid Tumor Oncology,ent of Medicine, Memorial Sloan-Kettering Cancer Center,k, NY.r Cancer Center, Calgary, AB, Canada.

rrespondence to Ana M. Molina, MD, Memorial Sloan-Cancer Center, 1275 York Ave, New York, NY 10021,

mail: molinaa@mskcc.org

Semin

Patients with advanced RCC present with a wide

spectrum of disease varying from asymptomatic or

indolent disease to symptomatic or rapidly progres-sive disease. Several prognostic factors identified

have led to the development of risk factor models

that have proven to be instrumental in the designand interpretation of clinical trials and risk-directed

therapy. Herein we review prognostic factors, clin-

ical data for established first-line therapies, andemerging first-line therapy for advanced RCC.

PROGNOSTIC FACTORS

Prognostic factors are important for the purposes

of clinical trial design, risk-directed therapy, and

patient counseling. They can be divided into patientfactors, tumor burden, inflammatory markers, and

treatment factors. Many of these factors have been

combined into multivariable models to assist theclinician in patient prognostication.10

Patient factors include symptoms such as night

sweats and weight loss, Karnofsky performance status(KPS), and Eastern Cooperative Oncology (ECOG)

performance status. A reflection of higher tumor

burden includes the presence of anemia, an elevatedlactate dehydrogenase (LDH) level, hypercalcemia,

elevated alkaline phosphatase, and the sites and num-

ber of sites of metastatic disease. Additionally, a shorterdisease-free interval or shorter time from diagnosis to

treatment indicates more aggressive disease while

longer ones depict more indolent disease. Inflamma-tory markers include and elevated erythrocyte sedi-

mentation rate (ESR), C-reactive protein (CRP),

neutrophilia, and thrombocytosis, which are all asso-ciated with poorer overall survival. Finally, treatment

factors, including a prior cytoreductive nephrectomy,

tend to be associated with a better prognosis.11

ars in Oncology, Vol 40, No 4, August 2013, pp 436-443

Figure 1. Prognostic factors can be divided into patient factors, measures of tumor burden, proinflammatory markers,and treatment-related factors. Different patients may have different predicted outcomes based on these factors.

Systemic treatment options for untreated patients 437

One of the first and most widely used prognostic

models is from the Memorial Sloan-Kettering CancerCenter (MSKCC).12,13 This model was developed

using pooled data from patients in clinical trials

treated with interferon-alpha accrued from 1982–1996. A KPS o80%, a diagnosis of RCC to treatment

interval o1 year, anemia less than the lower limit of

normal, LDH 41.5 times the upper limit of normal,and hypercalcemia 410 mg/dL were all independ-

ent predictors of poor overall survival. Patients with

none of these risk factors were in the favorablegroup and had a median overall survival of 29.6

months. Patients with one or two of these risk

factors were in the intermediate-risk group (medianoverall survival, 13.8 months). Patients with three or

more risk factors were in the poor risk group

(median overall survival, 4.9 months). This modelhas been externally validated13 and is widely used in

mRCC clinical trials.

Other models have been developed in the immu-notherapy era, including that of the Groupe Fran-

caise d’Immunotherapie,14 which identified

performance status, number of sites of metastases,disease-free interval, markers of inflammation, and

hemoglobin as independent predictors of survival. A

Japanese model developed in the era of immuno-therapy includes time from initial visit to metastasis,

ECOG performance status, hemoglobin, LDH, cor-

rected calcium, and CRP.15

With the advent of targeted therapy, improve-

ments in survival were observed. The International

mRCC Database Consortium retrospectively col-lected population-based data on 645 patients with

mRCC treated with targeted therapy.16 It found six

independent predictors of overall survival, whichincluded a KPS o80%, a diagnosis of RCC to treat-

ment interval o1 year, anemia less than the lower

limit of normal, hypercalcemia (using institutionalupper limits of normal), neutrophilia (greater than

institutional upper limit of normal), and thrombocy-

tosis (greater than institutional upper limit of nor-mal). Patients with zero risk factors were in the

favorable-risk group with a median overall survival

that was not reached (44 months in the externalvalidation cohort). Patients with one or two risk

factors were in the intermediate-risk group (median

overall survival, 27 months) and patients with 3 ormore risk factors were in the poor risk group

(median overall survival, 8 months). Although the

prognostic criteria are slightly different, new bench-marks in overall survival were achieved in each of

the prognostic categories compared to the MSKCC

criteria. Median survivals have almost doubled andare a testament to the efficacy of targeted therapy.

This model has been derived and externally vali-

dated17 in the era of targeted therapy and can beused for patient counseling and risk stratification in

clinical trials (Figure 1).

FIRST-LINE AGENTS

Four approved targeted agents have shown efficacyin randomized phase III trials as first-line treatment

in patients with metastatic clear cell RCC (Table 1).

The first three targeted agents, sunitinib, bevacizumabplus interferon (IFN-α), and temsirolimus were

A.M. Molina, R.J. Motzer, and D.Y. Heng438

compared as first-line therapy with IFN-α in separate

studies.6–8,11,12 Each of these agents was found to besuperior to IFN-α in prolonging progression-free sur-

vival (PFS), overall survival, or both. The fourth agent,

pazopanib was shown to have superior efficacy to thatof placebo in a phase III randomized controlled trial

that treated approximately one half treatment naı̈ve-

patients and one half cytokine-pretreated patients.9

In addition, the toxicity profile of these agents

varies with unique class drug effects (Table 2).

Sunitinib

Sunitinib is an oral multi-kinase inhibitor targetingseveral receptor tyrosine kinases (RTKs). In the

pivotal phase III trial of first-line treatment, 750

patients with clear cell mRCC were randomized tosunitinib (50 mg daily orally, 4 weeks on and 2 weeks

off) versus IFN-α (9 million units given subcutane-

ously three times weekly).3 The majority of thepatients treated with sunitinib (94%) and IFN-α(93%) had favorable or intermediate risk factors.3

The primary endpoint was PFS as assessed by inde-pendent, central review of radiographs. The secon-

dary endpoints were objective response rate, overall

survival, patient-reported outcomes, and safety. PFS asassessed by independent review was statistically

significant in favor of sunitinib (11 v 5 months,

≥.001).3 This benefit of sunitinib was observedacross all subgroups of patients; favorable (14.5 v7.9 months), intermediate (10.6 v 3.8 months), and

poor (3.7 v 1.2 months) risk groups. Treatment withsunitinib was also associated with a higher objective

response rate compared with the IFN-α group (31% v6%, respectively, P o.001). In the final analysis of thistrial, median overall survival was prolonged in the

sunitinib arm compared with the IFN-α arm (26.4 v21.8 months, P ¼ .051).4

Table 1. Randomized Phase III Trials of TargetedRenal Cell Carcinoma

Study n ORR %

Sunitinib v IFN-α3 750 47 v 12Bevacizumab þ IFN-α v IFN-α8 649 31 v 12Bevacizumab þ IFN-α v IFN-α7 732 25.5 v 13.1Pazopanib v placebo9 233 30 v 3* 11Temsirolimus v IFN-α6 626 8.6 v 4.8Pazopanib v sunitinib23 1110 31 v 25 8Tivozanib v sorafenib25 517 33 v 23t

Abbreviations: IFN-α, interferon-alfa; ORR, objective response rate; Pratio; NA, not available.

⁎ Treatment-naïve or cytokine-refractory mRCC.t Treatment-naïve or one prior systemic therapy for mRCC.

Hypertension, vomiting, hand-foot sydrome, and

diarrhea were observed with sunitinib treatment.Health-related quality of life as reported by patients

in post-baseline assessments was significantly better

in the sunitinib group.Furthermore, the activity and safety of sunitinib

was assessed in the expanded-access trial that pro-

vided sunitinib on a compassionate-use basis toclinical trial-ineligible patients with RCC from coun-

tries where regulatory approval had not been

granted.18 In this study, 4,564 previously treatedand untreated patients received open-label sunitinib

50 mg orally daily (4 weeks on treatment, 2 weeks

off). The patient population included 321 (7%)patients with brain metastases, 582 (13%) with

ECOG performance status of 2 or higher, 588

(13%) non-clear cell histology, and 1,418 (32%) aged65 years or greater. The objective response rate for

3,464 evaluable patients was 17% (n ¼ 603). Sub-

group overall response rates were as follows: brainmetastases (26 of 213 [12%]), ECOG performance

status 2 or higher (29 of 319 [9%]), non-clear cell

RCC (48 of 437 [11%]), and age 65 years or greater(176 of 1,056 [17%]). The median PFS was 10.9

months (95% confidence interval [CI], 10.3–11.2)and overall survival was 18.4 months (17.4–19.2).Median PFS by MSKCC risk group was 14.6 months

(95% CI, 13.8–15.6) in the favorable-risk group (n ¼1,928), 8.5 months (8.1–9.2) in the intermediate-riskgroup (n ¼ 1,928), and 4.1 months (3.1–5.0) in

the poor-risk group (n ¼ 373).18 Median overall

survival times in the favorable-, intermediate-, andpoor-risk groups were 24.7 months (23.5–NA), 14.4months (13.3–15.1), and 5.3 months (4.6–6.4),respectively.18

Sunitinib was found to be safe in this broad

population of patients and treatment-related adverse

events were manageable. Diarrhea (n ¼ 1,936 [44%])

Agents for First-Line Treatment of Metastatic

Median PFS (mo) Final Median OS (mo)

11 v 5 P o.001 26.4 v 21.8 P ¼ .05110.4 v 5.5 P o.0001 23.3 v 21.3 P ¼ .12918.4 v 4.9 P o.0001 18.3 v 17.4 P ¼ .069.1 v 2.8 P o.0000001 NA5.5 v 3.1 P o.001 10.9 v 7.3 P ¼ .0069.4 v 9.5 HR ¼ 1.0466 28.4 v 29.3 P ¼ .27511.9 v 9.1 P ¼ .042 NAFS, progression-free survival; OS, overall survival; HR, hazard

Table 2. Selected Serious Adverse Events (Grade 3/4) by Targeted Agent

Adverse Event (%) Sunitinib4 Bevacizumab þ IFN-α8 Temsirolimus6 Pazopanib9

Anorexia 2 3 3 2Asthenia 2 10 11 3Diarrhea 9 2 1 4Dyspnea 2 o1 9 –

Nausea 5 – 2 o1Vomiting 4 – 2 2Fatigue 11 12 – 2Hand-foot syndrome 9 – – –

Hyperglycemia – – 11 –

Hypertension 12 3 – 4Anemia 8 3 20 –

Neutropenia 18 4 3 1Thrombocytopenia 9 2 1 –

Leukopenia 8 – 1 –

Discontinuations due to adverse events 19 28 7 NRAbbreviation: AE, adverse event; NR, not reported.

Systemic treatment options for untreated patients 439

and fatigue (n ¼ 1,606 [37%]) were the most

common treatment-related adverse events. Fatigue(n ¼ 344 [8%]) and thrombocytopenia (n ¼ 338

[8%]) were the most common grade 3/4 adverse

events.Sunitinib was approved by the US Food and Drug

Administration (FDA) in 2006 and became a standard

first-line therapy for patients with advanced RCC,particularly those in the favorable- and intermediate-

risk groups. The expanded access trial has provided

further data to support the use of sunitinib in a broadpopulation of patients who generally have a poor

prognosis.

Bevacizumab

Bevacizumab is a recombinant humanized mono-clonal IgG1 antibody that selectively binds to and

inhibits the biologic activity of human VEGF. The

efficacy of bevacizumab in combination with IFN-αwas established by two pivotal phase III trials.7,8 The

AVOREN phase III study, randomized 649 patients

with untreated metastatic RCC to bevacizumab (10mg/kg administered intravenously every 2 weeks)

plus IFN-α (9 million units subcutaneously 3 times

per week) versus IFN-α plus placebo.8 Patients hadpredominantly (450%) clear cell RCC and the

majority (480%) had favorable or intermediate risk

factors. The primary endpoint was overall survival;secondary endpoints included PFS and safety. There

was a statistically significant difference in the median

PFS in favor of bevacizumab plus IFN-α (10.2 v5.4 months, P ¼ .0001). Subgroup analysis suggested

improved PFS in all MSKCC risk groups treated with

the combination of bevacizumab plus IFN-α.Improvements in PFS were seen in the favorable-

prognosis group (n ¼ 180; median PFS, 12.9 v7.6 months) and in the intermediate-prognosis group(n ¼ 363; median PFS, 10.2 v 4.5 months). A

significant improvement in PFS was not observed

in the poor-prognosis group (n ¼ 54; median PFS,2.2 v 2.1 months). The final analysis of overall

survival, although not statistically significant,

showed an improvement with the combination(23.3 v 21.3 months, P ¼ .3360, unstratified).19

The most commonly reported grade 3 or worse

adverse events in both the combination versus IFN-αgroups were established interferon-related toxicities

(fatigue, 12% v 8%; asthenia, 10% v 7%; and neu-

tropenia, 4 v 2%). The incidence of grade 3/4adverse events in patients treated with bevacizumab

was low, and included hypertension (3%), gastro-

intestinal perforations (1%; three grade 4) and arte-rial/venous thromboembolic events (3%, four

grade 4).

The second phase III trial, Cancer and LeukemiaGroup B (CALGB) 90206, randomized 732 previ-

ously untreated patients with metastatic clear cell

RCC to bevacizumab plus IFN-α versus IFN-α alone atthe same doses described for the AVOREN trial.7 The

majority of the patients (90%) had favorable- or

intermediate-risk factors. The primary endpoint wasoverall survival. The secondary endpoints included

PFS, objective response rate, and safety. There was a

statistically significant difference in median PFS infavor of the combination arm (8.5 v 5.2 months,

A.M. Molina, R.J. Motzer, and D.Y. Heng440

P o.0001). In an exploratory subset analysis by

MSKCC risk status, the PFS data was also confirmed.The median PFS in the favorable risk group was 11.1

versus 5.7 months and 8.4 versus 5.3 months in the

intermediate-risk group. Additionally, higher objec-tive response rates were seen in the combination

group (25.5% v 13.2%, P o.0001). Similarly to the

AVOREN study, overall survival favored the combi-nation arm but did not meet the predefined criteria

for significance.20

Bevacizumab plus IFN-α resulted in significantlymore grade 3 toxicities, including hypertension (9%

v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and

proteinuria (13% v 0%). The incidence of grade4 toxicities was low in each arm.

Based on the results of these two phase III studies,

the combination of bevacizumab plus IFN-α wasapproved for the treatment of patients with

advanced or metastatic RCC by the European Med-

icines Agency in 2007 and the FDA in 2009.Furthermore, combinations of bevacizumab with

other targeted agents have been of great interest.

The phase III INTORACT trial recently reportedcompared the combination of bevacizumab plus

temsirolimus versus bevacizumab plus IFN-α as

first-line treatment in 791 patients with predomi-nantly clear cell mRCC.21 The majority of the

patients treated (490%) had favorable- or

intermediate-risk factors. The primary endpoint wasPFS and there was no advantage to the addition of

temsirolimus over IFN-α. The median PFS with the

temsirolimus combination was 9.1 months versus9.3 months with the IFN-α combination. Based on

these results, the combination of bevacizumab plus

IFN-α remains a recommended option for first-linetreatment of patients with advanced RCC with good-

or intermediate-risk factors.

Temsirolimus

Temsirolimus is a mTOR kinase inhibitor. Efficacywas established based on the Global Advanced Renal

Cell Carcinoma (ARCC) trial that randomized 626

previously untreated patients with mRCC to receive25 mg of intravenous temsirolimus weekly, 3 million

units of IFN-α (with an increase to 18 million units)

subcutaneously three times weekly, or combinationtherapy with 15 mg temsirolimus weekly plus 6 mil-

lion units of IFN-α three times weekly.6 Eighty

percent of patients had clear cell histology and themajority of patients (74%) had poor-risk factors.

Poor-risk eligibility for the trial, defined as exhibiting

three or more of six risk criteria predictive of shortsurvival, was based on expanded MSKCC criteria.22

The primary endpoint was overall survival and there

was a statistically significant difference in favor oftemsirolimus. The median overall survival for

patients who received temsirolimus alone was 10.9

months compared with 7.3 months in the IFN-αgroup, and 8.4 months in the combination group.

Overall survival did not differ significantly in the

combination group versus the IFN-α monotherapygroup. However, compared to treatment with IFN-αalone, temsirolimus monotherapy was associated

with a significant prolongation of survival (hazardratio, 0.73; 95% CI, 0.58–0.92; P ¼ .008). PFS was

significantly longer in patients receiving temsiroli-

mus, with median PFS times of 1.9, 3.8, and3.7 months for the IFN-α, temsirolimus, and the

combination group, respectively (P o.001). The

proportion of patients with stable disease for at least6 months or an objective response was significantly

greater in the temsirolimus group (32.1%) and in

the combination therapy group (28.1%) than in theIFN-α group (15.5%; P o.001 and P ¼ .002, re-

spectively).

Common adverse events in the temsirolimus andcombination therapy groups included hyperglyce-

mia, hypercholesterolemia, and hyperlipidemia,

reflecting inhibition of mTOR-regulated glucose andlipid metabolism. Additionally, mild to moderate

rash, peripheral edema, and stomatitis affected more

patients who received temsirolimus, either alone orin combination with IFN-α. Asthenia was most

common in the two groups receiving IFN-α mono-

therapy or in combination. Overall, fewer grade 3/4adverse events occurred in patients treated with

temsirolimus (67%), as compared with 78% of

patients in the IFN-α group (P ¼ .02) and 87% ofpatients in the combination group (P ¼ .02).

Based on these results, temsirolimus was

approved by the FDA in 2007 for the treatment ofadvanced RCC and is most commonly used to treat

patients with poor-risk disease.

Pazopanib

Pazopanib is an oral multi-kinase inhibitor targetingvascular endothelial growth factor receptor (VEGFR),

platelet-derived growth factor receptor (PDGFR), and

stem cell receptor factor (c-KIT) approved by the FDAfor the treatment of advanced RCC in 2009. A

placebo-controlled, randomized, double-blind, phase

III trial evaluated the efficacy and safety of pazopanibmonotherapy. Patients received pazopanib 800 mg

orally daily or a matching placebo in a 2:1 ratio.9 The

study enrolled 435 patients with advanced RCC, 233were treatment-naı̈ve (54%), and 202 had prior cyto-

kine treatment (46%). The majority of the patients

(490%) had favorable or intermediate MSKCC riskfactors. The primary endpoint was PFS and there was

a statistically significant difference in favor of pazopa-

nib in the overall population (9.2 v 4.2 months;P o.0001), the treatment naı̈ve-subpopulation (11.1

Systemic treatment options for untreated patients 441

v 2.8 months; P o.0001), and the cytokine-pretreated

subpopulation (7.4 v 4.2 months; P o.001). Theobjective response rate was 30% with pazopanib

compared with 3% with placebo (P o.001).

Pazopanib was well tolerated and the most com-mon adverse events included diarrhea (52%), hyper-

tension (40%), hair color changes (38%), nausea

(26%), anorexia (22%), and vomiting (21%). Themost common grade 3/4 adverse events in the

pazopanib arm were hypertension (4%) and diarrhea

(4%). ALT and AST elevations were the most com-mon clinical laboratory abnormalities observed in

the pazopanib arm. In general, most adverse events

and clinical abnormalities were grade 1/2.More recently, results of the COMPARZ study, a

randomized open-label phase III trial of pazopanib

versus sunitinib in first-line treatment of patientswith mRCC, were reported at the 2012 European

Society for Medical Oncology meeting.23 The study

enrolled 1,110 previously untreated patients withmRCC to receive pazopanib 800 mg orally daily (n ¼557) or sunitinib 50 mg orally daily, 4 weeks on and

2 weeks off (n ¼ 553).Patients had clear cell RCC and the majority of the

patients (≥85%) had favorable or intermediate

MSKCC risk factors. Pazopanib demonstrated non-inferiority compared to sunitinib for PFS (8.4 v9.5 months; hazard ratio, 1.04, independent review).

Objective response rates were similar in the pazopa-nib and sunitinib treatment groups (31% v 25%,

respectively). Overall survival at interim analysis was

also similar in the pazopanib and sunitinib treatmentgroups (28.4 v 29.3 months, respectively), further

supporting the efficacy of pazopanib.

Pazopanib was found to have a different safetyprofile with a lower incidence of hand-foot syn-

drome (29% v 50%), fatigue (55% v 63%), and

mucositis (11% v 26%). There was a higher inci-dence of liver function abnormalities in the pazopa-

nib treatment group. In addition, quality-of-life

assessments favored pazopanib over sunitinib.Another randomized, double-blind, placebo-

controlled crossover study evaluated patient prefer-

ence between pazopanib and sunitinib in untreatedpatients with mRCC (PISCES study).24 One hundred

sixty-eight patients were randomized 1:1 to receive

as first-line treatment pazopanib 800 mg orally dailyfor 10 weeks followed by a 2-week washout and

then sunitinib 50 mg orally daily (4/2 weeks sched-

ule) for 10 weeks or vice versa. The primaryendpoint of patient preference was assessed at 22

weeks and demonstrated better tolerability of pazo-

panib compared to sunitinib. The most commonreasons for pazopanib preference included better

quality of life and less fatigue. Health-related quality

of life statistically favored pazopanib for fatigue,foot/hand soreness, and mouth/throat soreness.

Both pazopanib and sunitinib are valid first-line

treatment options for patients with mRCC. How-ever, the studies cited above suggest that pazopanib

may have a better safety profile and may be associ-

ated with better quality of life.

EMERGING NEW FIRST-LINE AGENTS

Tivozanib is a potent and selective VEGFR antag-

onist. In the TIVO-1 trial, patients with clear cell

mRCC who had a prior nephrectomy were random-ized to tivozanib (1.5 mg daily, 3 weeks on and

1 week off) versus sorafenib (400 mg twice daily).25

Patients could have been treated with prior immu-notherapy but previous VEGF or mTOR inhibitors

were not allowed. The primary endpoint was PFS

and there was a statistically significant difference infavor of tivozanib (11.9 v 9.1 months, P ¼ .042).

Tivozanib was well tolerated with numerically less

hand-foot syndrome (all-grade toxicity, 13% v 54%)and diarrhea (22% v 32%), but there was a higher

incidence of hypertension (44% v 34%) and dyspho-

nia (21% v 5%). Tivozanib has not been compared tothe other anti-VEGF inhibitors that are commonly

used in the first-line setting, such as pazopanib and

sunitinib.Axitinib is a highly potent VEGFR antagonist that

has been FDA-approved and is usually reserved for

patients with mRCC who have progressed on theirfirst anti-VEGF therapy. In a randomized phase II trial

to assess the importance of dose escalation, patients

with treatment-naı̈ve mRCC were treated with axiti-nib at the dose of 5 mg twice daily. Those patients

that developed side effects were maintained on the

same dose and achieved an impressive median PFSof 16.4 months and an overall response rate of

59%. Those patients that did not develop side

effects were randomized to dose escalation versusno dose escalation. The results for the individual

randomized arms of the study have not yet been

reported; however, when the entire cohort ofrandomized patients that did not develop side

effects was examined, a median PFS of 14.5

months and an overall response rate of 43% wereobserved.

These outcomes may appear to be better than

historical controls using other targeted therapies;however, patient selection bias may account in part

for these excellent outcomes. Thus, the use of

axitinib in the first-line setting requires further studyperhaps in a randomized trial compared to existing

first-line standards of care.

The axitinib phase II trial results suggest thatpatients that develop toxicities such as hypertension

tend to be associated with improved outcomes. For

example, patients that had a diastolic blood pressure≥90 mm Hg versus those who had o90 mm Hg on

Table 3. First-Line Treatment Nomogram in Patients With mRCC

Treatment Options

Patient Group Level 1a ≥ Level 2*

Good or intermediate risk Sunitinib Bevacizumab þ IFN High-dose IL-2

Poor riskPazopanib SorafenibTemsirolimus Sunitinib

Abbreviations: mRCC, metastatic renal cell carcinoma; IFN, interferon; IL-2, interleukin-2.⁎ Levels described at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat3.section.17745#17746.a Adapted from AM Molina, 2008, with permission.26

A.M. Molina, R.J. Motzer, and D.Y. Heng442

cycle 1 day 15 of the study had a median PFS and

overall response rate of 22.5 months versus 13.7

months and 65% and 50%, respectively.

CONCLUSION

VEGF and mTOR-targeted therapies have im-

proved patient outcomes and are the mainstay of

treatment for mRCC. Risk-derived models have beenincorporated into clinical trial design and conduct,

assisting clinicians with patient prognostication and

risk-directed therapy. Treatment paradigms andclinical practice recommendations are classified by

line of therapy, risk score, and level of evidence

(Table 3).Emerging TKIs, tivozanib and axitinib, provide

increased target specificity and may have less off-

target adverse event effects. These newer agentshave the potential to improve our ability to treat

patients with mRCC by allowing long-term tolerance

to treatment and improving overall quality of life.

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