Roberto SabbatiniAzienda Ospedaliero Universitaria di Modena

Policlicnico di Modena

HOT TOPICSHOT TOPICSControversie OncologicheControversie Oncologiche

Prima linea di TrattamentoPrima linea di Trattamento

Scuola di UrOncologiaTumore del rene

Roma 23-24 maggio 2014

My disclosuresMy disclosures

• RCC accounts for:– 80–85% of renal cancers1 – 2–3% of all adult malignancies2

– 63,000 new cases/year in Europe

– 26,000 mortalities annually

• RCC is: – More common in men than

women3,4

– Most frequently occurs in 60–70 year olds4

– More common in people from Northern European and North American countries3,4

1. Motzer RJ et al. N Engl J Med 1996;335:865–75; 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559; 3. GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/; 4. Cancer Research UK, UK kidney cancer statistics. 2008 http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441.

Incidence

Mortality

Renal Cell CarcinomaThe epidemiology

Renal Cell CarcinomaThe epidemiology

Renal Cell Carcinoma: an unrelenting, progressive disease

Renal Cell Carcinoma: an unrelenting, progressive disease

Presentation at diagnosis1:45% with localized disease

25% with locally advanced disease

20–30% metastatic disease

33% of patients treated for localized disease will develop metastatic disease2

Common sites of metastasis include lung (75%), liver (18%), bone (20%), brain (8%)3

Median survival for patients with metastatic RCC in the era of cytokine was 6–12 months4–7

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90 . 3. Sachdeva K et al. Renal cell carcinoma., in eMedicine. 2008; 4. Gay PC et al. J Neurooncol 1987;5:51–6; 5. Decker DA et al. J Clin Oncol 1984;2:169–73; 6. Culine S et al. Cancer 1998;83:2548–53; 7. Doh LS et al. Oncology 2006;20:603–13.

Disease specific survival by Time Period ofnon-Clear Cell RCC pts

Disease specific survival by Time Period ofClear Cell RCC pts

Disease-Specific Survival in de novo mRCC in the Cytokine and Targeted Therapy Era

Pal SK, PLoS ONE 2013

AxitinibAxitinib

Cytokine/Cytokine/Sunitinib failureSunitinib failure

2005 2006 20072005 2006 2007 2008 2008 2009 2009

Explosion of Targeted Therapy forExplosion of Targeted Therapy for mRCC (phase III trial) mRCC (phase III trial)

2006 20072006 2007 2008 2008 2009 2010 2009 2010 20142014

EverolimusEverolimus

VEGFi-failureVEGFi-failure

PazopanibPazopanib

I line and I line and cytokine-failure cytokine-failure

Key drivers in first-line treatment selection: Key drivers in first-line treatment selection: Efficacy and ExperienceEfficacy and Experience

Clinical efficacy = primary driver to guide treatment

decisions

Targeted agents: Standard of care for mRCC

Schmidinger M, Kidney Cancer Symposium, Vienna 2012

Temsirolimus (Hudes 2007)

Sorafenib (Escudier , 2007)

Bev + INF-α (Rini, 2008)

Bev + INF-α (Escudier 2007)

Sunitinib (Motzer 2007)

Pazopanib (Sternberg 2010)

Target

CALGB 90206

AVOREN

A6181034

VEG105192

3.7/5.5

5.7*

8.5*

10.2*

11.0*

11.1*

1.9

3 (Placebo)

5.4 (IFN)

5.2 (IFN)

5.1 (IFN)

2.8 (Placebo)

11 10 8 5 0

Sperimental Arm Control Arm*p<.05

4 8 mos

Ist-line phase III trials in mRCCIst-line phase III trials in mRCCProgression Free SurvivalProgression Free Survival

7–97–9Kane 2006Kane 2006

7.37.3IFNIFN10.9*10.9*TemsirolimusTemsirolimus

15.215.2PlaceboPlacebo17.817.8SorafenibSorafenib

17.417.4IFN Rini ASCO 2009IFN Rini ASCO 200918.318.3BEV/IFNBEV/IFN

18.518.5Gore ASCO 2008Gore ASCO 200818.718.7

19.819.8IFNIFNNRNR

22.922.9

Bevacizumab + IFNBevacizumab + IFN

20.520.5Sternberg EJC 2010Sternberg EJC 2010

21.821.8

PlaceboPlacebo

26.426.4IFNIFN

2007 to2007 to

presentpresent

Phase III trials in mRCCPhase III trials in mRCCOverall SurvivalOverall Survival

*p<.05

Motzer JCO 2009Motzer JCO 2009

SunitinibSunitinibMotzer 2013Motzer 2013

29.329.328.428.4

SettingSetting TherapyTherapyLevel 1Level 1 Level 2Level 2

First-line

Therapy

Low+Intermed

Risk

Sunitinib

Beva/IFN

Pazopanib

HD Il-2

Sorafenib

Poor

Risk

Temsirolimus Sunitinib

Clinical trial

Second-line

Therapy

Prior

Cytokine

Sorafenib

Pazopanib

Axitinib

Sunitinib

Clinical trial

Prior TKi Everolimus

Axitinib

Sequential TKi

Algorithm for Clear Cell RCC 2012Algorithm for Clear Cell RCC 2012

2nd-generation trials: Head to Head studies 1st-line phase III trial in mRCC

Agents N. pts Line of

treatment

Median PFS

(mos)

Median OS

(mos)

Tivozanib vs Sorafenib1 500

First or

CK treated11.9 vs 9.1* NA

Everolimus–Sunitinib vs

Sunitinib-Everolimus2

471 First 7.8 vs 10.7* NA

Axitinib vs

Sorafenib288 First 10.1 vs 6.5* NA

Pazopanib vs Sunitinib4 1110 First 8.4 vs 9.5 28.4 vs 29.3

Axitinib

“dose tritation”5213 First

16.6 (not eligible) vs

14.5 (eligible)

NA

* p< .051. Motzer R, ASCO 2012; 2. Motzer R. ASCO 2013; 3. Hudson TE, ASCO-GU 20134. Motzer R, NEJM 2013; 5. Rini B, ASCO-GU 2013

Case study: TIVO-1Treatment allocation imbalance?

Motzer RJ, et al. J Clin Oncol 2013

Sorafenib 400 mg BID (n=257)

• Recurrent or mRCC with a clear cell component

• Measurable disease

• Treatment-naïve or 1 prior treatment: cytokines, investigational agent, hormonal therapy, chemotherapy

• Prior nephrectomy

• ECOG PS 0 or 1

n=5171:1

Tivozanib 1.5 mg/day (3 weeks on-treatment;

1 week off-treatment) (n=260)

RANDOMISATION

Cross-over with Tivozanib 1.5 mg/day permitted upon disease progression;

extension protocol (NCT01076010)

Phase III randomized, open label multicenter trial:•Primary endpoint: PFS by independent review (assessment of response every 8 wks)•Secondary endpoints: overall survival, ORR, quality of life

Primary endpoint: Tivozanib significantly prolonged PFS versus sunitinib

Overall population

n Median PFS (95% CI) HR P

value

Tivozanib 260 11.9 mos (9.3–

14.7) 0.797 0.042

Sorafenib 257 9.1 mos (7.3–

9.5)

PF

S p

roba

bilit

y

Time, months0 5 10 15 20

1.0

0.8

0.6

0.4

0.2

0.0

Motzer RJ, et al. J Clin Oncol 2013

BUT - No significant difference in OS (secondary endpoint)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

0

20

40

60

80

100

Time (months)

% s

urv

iva

l

Motzer RJ, et al. J Clin Oncol 2013FDA. Tivozanib, June 2013.

n Median OS (95% CI) HR P

value

Tivozanib 260 28.8 mos (22.5–

NR)1.25 0.105

Sorafenib 257 29.3 mos (29.3–

NR)

Overall population

Why no OS benefit?

1. Garnick MB. J Clin Oncol 20132. FDA. Tivozanib, June 2013. http://www.fda.gov

• A sequential trial of two agents, sorafenib followed by tivozanib, compared with one agent, tivozanib

• “The sanctity of OS was compromised”1

Sorafenib 400 mg BID

(n=257)

Tivozanib 1.5 mg/day (3 weeks on-treatment; 1 week off-treatment)

(n=260)

RANDOMISATION

*Due to lack of available TKIs in Eastern Europe

Balanced?

Infrequent second line treatment at time of

disease progression*

Infrequent second line treatment at time of

disease progression*

Cross over to tivozanib at time of

disease progression

Cross over to tivozanib at time of

disease progression

FDA conclusion: “Inconsistent PFS and OS results and imbalance in post-study treatments make the trial results inconclusive when making a risk-benefit assessment necessary for approval.”2

At the time of the final OS

analysis, 156 patients (61%)

randomly assigned to sorafenib

had crossed over to tivozanib

Sunitinib50 mg qd

4 wk on/2 wk off

Sunitinib50 mg qd

4 wk on/2 wk off

Pazopanib800 mg qd

Continuous dosing

COMPARZ: a non-inferiority trial

• Stratification factors:

• Karnofksy Performance Status (KPS; 70/80 vs. 90/100)

• Prior nephrectomy (yes vs. no)

• Baseline lactate dehydrogenase (LDH; >1.5 vs. ≤1.5 x ULN)

Randomized 1:1

(N = 1110)

NCT01147822, n = 183

NCT00720941, n = 927

Motzer R, NEJM 2013

Primary Endpoint: PFS (Independent Review)

17

Median PFS (95% CI)

Pazopanib 8.4 mo (8.3, 10.9)

Sunitinib 9.5 mo (8.3, 11.1)

HR (95% CI ) = 1.047 (0.898,1.220)

Motzer R, NEJM 2013

18

Chemistry labs

Pazopanib (n = 554) % Sunitinib (n = 548) %

All Grades Grade 3/4 All Grades Grade 3/4

AST 61 11/1 60 3/0ALT 60 15/2 43 4/<1Hyperglycemia 54 5/0 57 4/<1Total bilirubin 36 3/<1 27 2/<1Hypophosphatemia 36 4/0 52 8/<1Hyponatremia 35 7/<1 32 7/<1Hypoalbuminemia 33 <1/0 42 2/0Creatinine 32 <1/0 46 <1/<1

Hematology labs

Leukopenia 43 1/0 78 6/0

Neutropenia 37 4/<1 68 19/1

Thrombocytopenia 41 3/<1 78 18/4

Lymphopenia 38 5/0 55 14/<1

Anemia 31 1/<1 60 6/1a Reported in (≥30%) of patients in either arm.Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib.Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib.

Laboratory Abnormalitiesa

Motzer R, NEJM 2013

19

Adverse Eventa

Pazopanib (n = 554) % Sunitinib (n = 548) %

All Grades Grade 3/4 All Grades Grade 3/4

Any eventb >99 59/15 >99 57/17

Diarrhea 63 9/0 57 7/<1

Fatigue 55 10/<1 63 17/<1

Hypertension 46 15/<1 41 15/<1

Nausea 45 2/0 46 2/0

Decreased appetite 37 1/0 37 3/0

Hair color changes 30 0/0 10 <1/0

Hand-foot syndrome 29 6/0 50 11/<1

Common Treatment-Emergent Adverse Eventsa

a Adverse events ≥30% in either armb 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib.Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib.

Motzer R, NEJM 2013

……. The median duration of treatment was similar in the two groups: 8.0 months (range, 0 to 40) in the pazopanib group and 7.6 months (range, 0 to 38) in the sunitinib group. Similar percentages of patients in the pazopanib and sunitinib groups had a dose interruption of 7 days or more (44% and 49%, respectively) or a reduction in the dose (44% and 51%, respectively). The proportion of patients who discontinued the study drug because of adverse events was 24% in the pazopanib group and20% in the sunitinib group (Table S5 in the Supplementary Appendix); the higher discontinuationrate observed for pazopanib, as compared with sunitinib, was primarily due to abnormalities in liver-function tests (6% vs. 1%).

COMPARZ trial: Adverse Events

Motzer R, NEJM 2013

….. There were no between-group differences inthe rates of cardiovascular adverse events. Thepercentages of patients meeting cardiac-dysfunctioncriteria15 were similar: 13% in the pazopanib group and 11% in the sunitinib group (Table S7 in the Supplementary Appendix). The incidence of myocardial infarction or ischemia was similar in the pazopanib and sunitinib groups (2% and 4%, respectively).

EverolimusEverolimus10 mg/day 10 mg/day

Sunitinib50 mg/day***

2nd Line*NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.

Primary

• PFS-1st line

Secondary

• Combined PFS

• ORR-1st line

• OS

• Safety

Study Study endpointsendpoints

1 : 1

RRAANNDDOOMMIIZZ

E**E**

EverolimusEverolimus10 mg/day 10 mg/day

SSCCRREEEENN Sunitinib

50 mg/day***

1st Line

RECORD-3: Phase II randomized trial comparing sequential 1st-line everolimus and 2nd-line sunitinib vs 1st-line sunitinib

and 2nd-line everolimus

Motzer R, ECC 2013

Primary Endpoint: 1st-line PFS for non-inferiority of everolimus vs sunitinib

• Bayesian method: non-inferiority declared if observed HR ≤1.1 (1-month difference in the median first-line PFS)

• 318 first-line events needed (total 460 patients)

Primary End Point: First-line PFS100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 33

Time (months)

238233

164181

118145

88108

6884

4455

3142

2328

1215

59

03

00

Number of patients still at riskEverolimusSunitinib

Everolimus (events/N = 182/238)

Sunitinib (events/N = 158/233)Cum

ulat

ive

even

t-fr

ee p

roba

bilit

y (%

)

K-M Median PFS (mo)

Everolimus Sunitinib

7.85 10.71

Hazard Ratio = 1.43Two-sided 95% CI [1.15, 1.77]

Motzer R, ECC 2013

RECORD-3: combined PFS*

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 33

EVE→SUNSUN→EVE

238

Number of patients still at risk

233186196

145171

112135

88105

6574

4852

3735

1919

612

04

00

Cum

ulat

ive

even

t-fr

ee p

roba

bilit

y (%

)

Time (months)

EVE→SUN (events/N = 88/238)

SUN→EVE (events/N = 80/233)

*Time from randomization to progression following second-line treatment or death (any time).

K-M Median PFS (mo)

EVE→SUN SUN→EVE

21.13 25.79

Hazard Ratio = 1.28Two-sided 95% CI [0.94, 1.73]

Log-rank p-value = 0.116

Motzer R, ECC 2013

RECOR-3: Overall Survival100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 33 36

Cum

ulat

ive

even

t-fr

ee p

roba

bilit

y (%

)

Time (months)

EVE→SUN (events/N = 108/238)

SUN→EVE (events/N = 96/233)

238Number of patients still at risk

233208220

189198

165185

151164

137152

103115

6671

4338

1522

26

01

00

K-M Median OS (mo)

EVE→SUN SUN→EVE

22.41 32.03

Hazard Ratio = 1.24Two-sided 95% CI [0.94, 1.64]

EVE→SUNSUN→EVE

• Drugs blinded by over-encapsulation

• Patients on sunitinib received matchingplacebo during 2-week ‘off-period’

2-week washout Period 2Period 1 Off study

1:1 Randomisation

Patient choiceof treatment

to progressionn=169

Sunitinib50 mg 4/2,10 weeks

Sunitinib50 mg 4/2,10 weeks

Pazopanib800 mg once

daily, 10 weeks

Pazopanib800 mg once

daily, 10 weeks

Sunitinib50 mg 4/2,10 weeks

Sunitinib50 mg 4/2,10 weeks

Time (weeks)0 12 2210

Double-blind

PISCESTiming assessments

Escudier B, et al. JCO 2014

Cross-over design:

Primary endpoint:Significantly more pts preferred PAZO over SUNI

Pat

ient

s, %

p<0.001

70%(n=80)

22%(n=25)

8%(n=9)

Patients were still blinded when they stated their preference

Escudier B, et al. JCO 2014

Temsirolimus (Hudes 2007)

Sorafenib (Escudier , 2007)

Bev + INF-α (Rini, 2008)

Bev + INF-α (Escudier 2007)

Sunitinib (Motzer 2007)

Pazopanib (Sternberg 2010)

Target

CALGB 90206

AVOREN

A6181034

VEG105192

3.7/5.5

5.7*

8.5*

10.2*

11.0*

11.1*

1.9

3 (Placebo)

5.4 (IFN)

5.2 (IFN)

5.1 (IFN)

2.8 (Placebo)

11 10 8 5 0

Sperimental Arm Control Arm

Tivozanib (Motzer 2013) VEG10519211.9* 9.1 (Sorafenib)

COMPARZ8.4 9.5 (Sunitinib)Pazopanib (Motzer 2013)

*p<.05 4 8 mos

Ist-line phase III trials in mRCCIst-line phase III trials in mRCCProgression Free SurvivalProgression Free Survival

RECORD-3Everolimus (Motzer 2014) 7.8 10.7 (Sunitinib)

SettingSetting TherapyTherapyLevel 1Level 1 Level 2Level 2

First-line

Therapy

Low+Intermed

Risk

Sunitinib

Beva/IFN

Pazopanib

HD Il-2

Sorafenib

Poor

Risk

Temsirolimus Sunitinib

Clinical trial

Second-line

Therapy

Prior

Cytokine

Sorafenib

Pazopanib

Axitinib

Sunitinib

Clinical trial

Prior TKi Everolimus

Axitinib

Sequential TKi

Algorithm for Clear Cell RCC 2014Algorithm for Clear Cell RCC 2014

Key drivers in first-line treatment selection: Key drivers in first-line treatment selection: Efficacy and ExperienceEfficacy and Experience

Clinical efficacy = primary driver to guide treatment

decisions

Safety and Clinical experience should also be considered when making treatment

decisions

Targeted agents: Standard of care for mRCC

Schmidinger M, Kidney Cancer Symposium, Vienna 2012

EBGuideline

Efficacy

Safety

Multiple factors that should be considered when Multiple factors that should be considered when selecting a targeted therapy for mRCC ptsselecting a targeted therapy for mRCC pts

PatientProflie

Safety

Major drugs suspected of potential drug interaction with targeted agents

EBGuideline

Efficacy

Safety

Multiple factors that should be considered Multiple factors that should be considered when selecting a targeted therapy for mRCC ptswhen selecting a targeted therapy for mRCC pts

PatientProflie

Patient Profile

Safety

Tolerability Profiles Can Help to Guide Tolerability Profiles Can Help to Guide Selection of Treatment: Selection of Treatment:

Patient-related Factors and Comorbidities Patient-related Factors and Comorbidities

Patient with reduced EF Patient with reduced EF Patients with impaired Patients with impaired mobilitymobility

Patient with nutrition Patient with nutrition disordersdisorders

Consider the Consider the patientpatient''s professions profession

ConsiderConsidercomedicationscomedications

(drug interactions)(drug interactions)33

Chronic obstructiveChronic obstructivepulmonary diseasepulmonary disease

Thromboembolic diseaseThromboembolic disease Diabetes MellitusDiabetes Mellitus

clinical trial populations may not clinical trial populations may not

represent real-life populations of represent real-life populations of

patients, because trial inclusion patients, because trial inclusion

and exclusion criteria often and exclusion criteria often

eliminate numerous patients eliminate numerous patients

from studyfrom study

Targeted Therapies Real WorldTargeted Therapies Real World

EBGuideline

Efficacy

Safety

Multiple factors that should be considered when selecting Multiple factors that should be considered when selecting a targeted therapy for mRCC ptsa targeted therapy for mRCC pts

PatientProflie

Patient Profile

ClinicianFamiliarity

Safety

Ist-line Targeted Therapy: rates of treatment Ist-line Targeted Therapy: rates of treatment interruptions, reductions and discontinuationsinterruptions, reductions and discontinuations

% of pts% of pts SUNISUNI11

n. n. 375375

BEVABEVA22

plus IFNplus IFNn. 337n. 337

PAZOPAZO33

n. 290n. 290TIVOTIVO55

n. 259n. 259TEMTEM44

n. 208n. 208SORASORA66

n. 451n. 451

Dose reductionDose reduction 32 40 24 12 23 13

Treatment Treatment interruptioninterruption

38 NA NA 18 NA 21

*Treatment *Treatment discontinuationdiscontinuation

8 28 14 4 7 10

* No lack of efficacy

SUNISUNI77

EAPEAPn. 1381n. 1381

43

NA

14

SORASORA88

ARCCSARCCSn.2504n.2504

35

50

10

1. Motzer, et al. JCO 2009; 2.1. Motzer, et al. JCO 2009; 2. Escudier, et al. Lancet 2007; 3. Escudier, et al. Lancet 2007; 3. Sternberg, et al JCO 2010 Sternberg, et al JCO 2010 4. Hudes, et al. NEJM 2007;4. Hudes, et al. NEJM 2007; 5. Motzer, et al . ASCO 2012; 6. Escudier et al. NEJM 2007 5. Motzer, et al . ASCO 2012; 6. Escudier et al. NEJM 20077. Gore et al. Lancet 2009; 8. Stadler et al, Cancer 20107. Gore et al. Lancet 2009; 8. Stadler et al, Cancer 2010

Tar

get

ed A

gen

t

Man

agem

ent

AE

s

Healthcare Resources and Increased CostsHealthcare Resources and Increased Costs

EBGuideline

Efficacy

Safety

Multiple factors that should be considered whenMultiple factors that should be considered when selecting a targeted therapy for mRCC ptsselecting a targeted therapy for mRCC pts

PatientProflie

Patient-ReportedOutcomes

Patient Profile

ClinicianFamiliarity

Safety

39

Which targeted agent do you use in 1st-line mRCC: some answers more questions

mRCC treatment: to personalize or not to personalize?

Patients Preferences: going forward by going backward?

Patient-reported Outcomes: what can we do?

Hot Question in mRCC