Tombal

ASCO 2012 Genito-Urinary cancers

Bertrand TOMBAL, MD, PhD Cliniques universitaires Saint-Luc Bruxelles

Prostate

Kidney

And what’s left….

Very few academic trials

Many pharma sponsor “updated” trials or post-marketing trials.

“If you can convince, confuse”

Prostate

Kidney


18 mm

13 mm

+ 6 m.

Steve, 72 y.o, PSA 375 ng/ml, multiple bone metastases, T/degarelix 120/80 mg

Courtesy of B.Tombal and F. Lecouvet, CUSL, UCL, Brussels

In conclusion, IAD is currently widely offered to patients with PCa in various clinical settings, and its status should no longer be regarded as investigational (LE: 2).

Calais da Silva(1) Klotz(2) Salonen((3))

Stage Loc. adv. (70%)

Metastatic (30%) Rising PSA

Loc. adv (50%) Metastatic (50%)

N enrolled 766 852

N randomized 626 1386 554

Progression IAD/CAD

N 127/107

HR (95% CI, p)

0.81 (0.63–1.05, 0.11)

0.80 (0.67-0.98,

0.024)

1,08 (0.90-1.29, 0.43)

Death IAD/CAD

N 169/170 268/256 186/206

OS (years) 8.8/9.1 3.7/3.8

HR (95% CI, p)

0.99 (0.80–1.23, 0,84)

1.02 0.86-1.21;0.009

1,15 (0.94-1.40) 0.17

Death/PCa Increase IAD Increase IAD

1. SEUG/EORTC, Eur Urol. 2009 Jun;55(6):1269-77. 2. NCIC CTG PR.7. J Clin Oncol 29: 2011 (suppl 7; abstr 3) 3. Finnprostate study VII, J Urol. 2012 Jun;187(6):2074-81.

Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial. Hussain et al., J Clin Oncol 30, 2012 (suppl; abstr 4)

3040 hormone naïve M1 PCa pts with performance status (PS) 0-2, PSA ≥ 5 ng/ml were treated with 7 months (m) of goserelin + bicalutamide.

1535 pts achieving PSA ≤4 ng/ml on m 6 and 7 were randomized to CAD or IAD. Primary objective: To assess if OS with IAD is non-inferior to CAD Median FUp 10 y.

IAD (770) CAD (765)

Age (yrs) Median (range) 70 (39,97) 70 (39,92)

Disease extent Extensive 49% 47%

Minimal 51% 53%

Visceral disease 7.1% 6.3%

Bone Pain Present 28% 28%

Gleason score ≥8 27% 27%

Characteristic of the patients at randomization

Overall survival

10 years survival rate

HR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24).

+ 6 m.

Courtesy of B.Tombal and F. Lecouvet, CUSL, UCL, Brussels

Steve, 72 y.o, PSA 375 ng/ml, multiple bone metastases, T/goserelin + CPA 6 wks.

Neoadjuvant androgen pathway suppression prior to prostatectomy. Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520)

35men with localized PCa treated for 3 months prior to prostatectomy with Goserelin (G), and 5α-reductase inhibiteur dustasteride (D) 3.5 mg QD, antiandrogen

bicalutamide (B) 50 mg QD, and androgen synthesis inhibitor ketoconazole (K) 200 mg TID


Treatment testosterone DHT

ng/g (SD) nM ng/g (SD) nM

Untreated 0.21 (0.08) 0.7 4.38 (0.99) 15

G+B 0.07 (0.08) 0.3 0.92 (0.49) 3.2

G+D 0.32 (0.17) 1.1 0.02 (0.02) 0.06

G+B+D 0.33 (0.23) 1.1 0.04 (0.07) 0.15

G+B+D+K 0.24 (0.23) 0.8 0.02 (0.02) 0.08


G+B G+D G+B+D G+B+D+K

Nadir PSA < 0.2 71% 27% 90% 77%

Pathologic response

CR 0 0 10% 8%

Near CR (≤ 0.2cc) 0 18% 20% 23%

From Ryan and Tindall, J Clin Oncol 29:3651-3658. 2011

Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. ME Taplin al., J Clin Oncol 30, 2012 (suppl; abstr 4521)

58 men ≥ 3 positive biopsies and Gleason ≥ 7 (4+3), T3, PSA ≥ 20 ng/mL or PSA velocity > 2 ng/mL/year.

First 12 wks randomized to LHRHa or LHRHa/AA/prednisone (P) 5mg qd. After 12 wks and a PBx 12 more wks of LHRHa/AA/P followed by RP

Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. ME Taplin al., J Clin Oncol 30, 2012 (suppl; abstr 4521)

12 wks AA/ 24 wks LHRHa

24 wks AA/ 24 wks LHRHa

p

Pathological CR 4% 10% 0.6120

Near CR (≤5mm)

11% 24% 0.2992

pT3 59% 48%

Positive nodes 11% 28%

“Very high-risk cancers localized to the prostate are rarely cured by prostatectomy alone,” Dr. Taplin said. “Therapies that combine surgery with older androgen-inhibiting drugs have not historically improved outcomes. This unmet need has given rise to efforts to develop new drugs capable of more completely reducing androgen levels within the prostate tumors

Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer. Briganti A, et al. Predict consortium. Eur Urol. 2012 Mar;61(3):584-92.

CR

PC

Metastasis

67000+

Symptoms

Available options in CRCP

Docetaxel

Abiraterone acetate +P Cabazitaxel Enzalutamide (MDV3100)

Sipuleucel-T alpharadin-T

COU-AA-302 (Abiraterone)

PREVAIL (enzalutamide)

P: prednisone

1. de Bono, et al. N Engl J Med 2011;364:1995–2005; 2. Medivation Press Release AFFIRM 3rd November 2011; study stopped early following

favourable interim results 95 % CI not stated; 3. Tannock, et al. N Engl J Med 2004;2351:1502–12; 4. de Bono, et al. Lancet 2010; 76:1147–545

; 5. Kantoff, et al. N Engl J Med 2010;363:411–22; 6. Bayer Press Release ALSYMPCA 24th September 2011


Increase in

median

survival

Relative

reduction in

risk of death

Hazard ratio

(95% CI; P-value)

Abiraterone/P vs. placebo/P1 3.9 months 35% 0.65

(0.540.77; P<0.001)

MDV3100 vs. placebo 2* 4.8 months 37% 0.63†

(P<0.0001)

Docetaxel(q3w)/P vs.

Mitoxantrone/P3 2.4 months 24%

0.76

(0.620.94; P=0.009)

Cabazitaxel/P vs. mitoxantrone/P4 2.8 months 30% 0.70

(0.590.83; P<0.0001)

Sipuleucel T vs. placebo5 4.1 months 22% 0.78

(0.61 to 0.98; P:0.03)

Alpharadin vs. placebo6 2.8 months 31% 0.70

(0.55-0.88; P:0.00185)

Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

Patients Progressive chemo-naïve CRCP patients N=1088 Asymptomatic or mildly symptomatic

RA

ND

OM

IZED

1:1

AA 1000 mg daily Prednisone 5 mg BID

(Actual= 546)

Placebo daily Prednisone 5 mg BID

(Actual= 542)

Efficacy endpoints

Co-primary rPFS by central review OS Secondary Time to opiate used Time to

chemotherapy Time to ECOG-PS

deterioration TTPP

Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries: USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs 1

COU-AA-302 Statistical Plan

IA = interim analysis. Ho, HR=1.0.

Overall Assumption rPFS OS

α 0.01 0.04

Power 91% 85%

HR 0.67 0.80

Expected events 378 773

IA3

(55% OS events)

425 Events

= 0.0034

IA2

(40% OS Events)

311 Events

= 0.0005

Planned OS Analysis

IA1

(~15% OS Events)

116 Events

< 0.0001

1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12

Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

Population characteristics AA +P

(n=546) Placebo + P

(n=542)

Median age, years (range) 71(44-95) 70 (44-90)

Median time from initial diagnosis 5.5 5.1

Median PSA (ng/ml) 42.0 37.7

Median alkaline phosphatase (IU/L) 93.0 90.0

Median hemoglobin (g/dl) 13.0 13.1

Gleason ≥8 at initial diagnosis 53.9% 50.0%

Extent of disease

Bone metastases 83% 80%

> 10 bone metastases 48% 47%

Soft tissue or nodes 49.1% 50%

Pain (BPI short form)

0-1 66% 64%

2-3 32% 33%

Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)



AA +P Median

(months)

Placebo + P Median

(months) HR(95%CI) p

Time to opiate use NR 23.7 0.69 (0.57-

0.0.83) 0.0001

Time to chemotherapy initiation

25.2 16.8 0.58 (0.49-

0.69) <0.0001

Time to ECOG PS deterioration

12.3 10.9 0.82 (0.71-

0.94) 0.0053

Time to PSA progression 11.1 5.6 0.49 (0.42-

0.57) <0.0001

Other secondary endpoints



AA +P (n=546)

N(%)

Placebo + P (n=542)

N(%)

No. with selected subsequent therapy for CRPC

242 (44.3) 327 (60.3)

Docetaxel 207 (37.9 287 (53.0)

Cabazitaxel 45 (8.2) 53 (9.6)

Ketoconazole 39 (7.1) 63 (11.6)

Sipuleucel-T 27 (4.9) 24 (4.4)

Abiraterone acetate 26 (4.8) 54 (10.0)

Subsequent therapies


AA +P (n=546)

N(%)

Placebo + P (n=542)

N(%) RR(95%CI) p

PSA decline ≥50% 62% 24% NA <0.0001

N=220 N=218

RECIST defined objective response

36% 2.273

(1.591-3.247)

< 0.0001

Complete response 11% 4%

Partial response 25% 12%

Stable disease 61% 39%

Progressive disease 2% 15%

Serologic and clinical responses


AA +P (n=546)

%

Placebo + P (n=542)

%

All grades Grade 3/4 All gardes Gradde 3/4

Fatigue 39 2 34 2

Fluid retention 28 0.7 24 1.7

Hypokalemia 17 2 13 2

Hypertension 22 4 13 3

Cardiac disorders 19 6 16 3

Atrial fibrillation 4 1.3 5 0.9

ALT increased 12 5.4 5 0.8

AST increased 11 3 5 0.9

Side-Effects

Using PFS in Prostate Cancer

A risky IDMC decision

What about the overall results

Abiraterone pre-chemotherapy, a true paradigm shift ?

Prerequisites for accepting PSA as a valid co-primary

Clearly defined and specified in advance YES

Capable of being ascertained as completely as possible

YES

Measured in the same way for all subjects YES

Capable of unbiased assessment YES

Reflect tangible clinical benefit? Unknown

COU-AA-302 Statistical Plan

Price You Pay: Biased Estimate of Clinical Benefit

Adrenals androgens inhibitor

Total Drug

Patient

s

(n)

% > 50% PSA

response

Duration

(months)

Small et al., 19971 Ketoconazole (400 mg tid) +

hydrocortisone 50 63 3.5

Small et al.,19972 Ketoconazole (400 mg tid) +

hydrocortisone + AAW 20 55 8.5

Small et al., 20043 Ketoconazole (400 mg tid) +

hydrocortisone + AAW 128 27 8.6

Harris et al, 20024 Ketoconazole (200 mg tid) +

hydrocortisone 28 46 7.5

Millikan et al., 20015 Ketoconazole (400 mg tid) +

hydrocortisone + AAW 45 31 NA

Taplin et al., 20096 Ketoconazole (400 mg tid) + dutasteride

(0,5 mg sid) + hydrocortisone 57 56 20

Ryan et al., 2012 Abiraterone AA + P 546 62% 11,1

% PSA response: % of patients achieving 50% decrease in PSA; AAW = anti-androgen withdrawal

1) J Urol. 1997 157(4):1204-7; 2) Cancer 1997 80(9):1755-9; 3) JCO 2004 22(6):1025-33; 4) J Urol. 2002

168(2):542-5; 5) Urol Oncol. 2001 6(3):111-115; 6) Clin Cancer Res. 2009 15(22):7099-105: 7) JNCI 1994 86(3):222-7; 8) Anticancer Drugs 2004 15(9):843-7.

P: prednisone

1. de Bono, et al. N Engl J Med 2011;364:1995–2005; 2. Medivation Press Release AFFIRM 3rd November 2011; study stopped early following

favourable interim results 95 % CI not stated; 3. Tannock, et al. N Engl J Med 2004;2351:1502–12; 4. de Bono, et al. Lancet 2010; 76:1147–545

; 5. Kantoff, et al. N Engl J Med 2010;363:411–22; 6. Bayer Press Release ALSYMPCA 24th September 2011


Increase in median survival

Relative reduction in risk of death

Hazard ratio (95% CI; P-value)

Abiraterone/P vs. placebo/P1 3.9 months 35% 0.65

(0.540.77; P<0.001)

MDV3100 vs. placebo 2* 4.8 months 37% 0.63†

(P<0.0001)

Docetaxel(q3w)/P vs. Mitoxantrone/P3 2.4 months 24% 0.76

(0.620.94; P=0.009)

Cabazitaxel/P vs. mitoxantrone/P4 2.8 months 30% 0.70

(0.590.83; P<0.0001)

Sipuleucel T vs. placebo5 4.1 months 22% 0.78

(0.61 to 0.98; P:0.03)

Alpharadin vs. placebo6 2.8 months 31% 0.70

(0.55-0.88; P:0.00185)

Abiraterone + P vs.P ? NR in AA 25% 0,75

(0.61-0.93); P 0.0097

Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)


Quality of life response by FACT-P

Side effects of interest

All grades Grade ≥ 3

MDV3100 Placebo MDV3100 Placebo

Fatigue 33.6 29.1 6.3 6.3

Cardiac disorders 6.1 7.5 0.9 0.9

Myocardial infarction 0.3 0.5 0.3 0.3

LFT abnormalities 1.0 1.5 0.4 0.4

Seizure 0.6 0.0 0.6 0.6


Prostate

Kidney


New agent timelines

2005 2006 2007 2008 2009 2010 2011 20012

Sorafenib(1)

Sunitinib(2) Everolimus(4)

pazopanib(6)

temsirolimus(3) Bevacizumab

+Ifα(5)

1. Motzer RJ, et al. N Engl J Med. 2007;356(2):115-124. 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. 4. Escudier B, et al. Lancet.

2007;370(9605):2103-2211. 5. Rini BI, et al. J Clin Oncol. 2008;26(33):5422-5428. 6. Motzer RJ, et al. Lancet. 2008;372(9637):449-456. 7.

Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068.

Axitinib)

Results 1st line targeted therapies

Agent N ORR(%) Median PFS

months Median OS

months

Sunitinib vs. INFα(1,2) 750 47 vs. 12 P< 0,001

11,0 vs. 5 P< 0,001

26,4 vs. 21,8 P=0.051

Temsirolimus vs. INFα(3) 626 8,6 vs. 4.8

NS 5,5 vs. 3,1 P<0,0001

10,9 vs. 7,1 P=0,008

Bevacizumab + INFα vs. INFα(4) 649 31 vs. 13 P= 0,0001

10,2 vs 5,4 P=0,0001

INFα 19,8 B/INFα NR P 0,0267

Bevacizumab + INFα vs. INFα(5) 732 26 vs. 13 P<0,0001

8,5 vs. 5,2 P<0,0001

NR

Sorafenib vs INFα(6) 189 5 vs. 9 5,7 vs 5,6 P=0,504

NR

Pazopanib vs. placebo 435 30 vs. 3 P<0,001

9,2 vs 4,2 P<0,001

21,1 vs. 18,7 P 0,02

1. Motzer RJ et al. NEJM 2007; 2 Motzer RJ et al. JCO 2007; 3. Hudes et al. NEJM 2007; 4. Escudier et al. Lancet 2007; 5. Rini et al. JCO 2008; Escudier et al. JCO 2006; Sternberg C JCO 2010

Results 2nd line targeted therapies

Agent ORR(%) Median PFS

months Median OS

months

Sorafenib vs. placebo(1) 10 vs. 2 P< 0,001

5,5 vs. 2,8 P< 0,001

17,8 vs 15,2

Everolimus vs. placebo(2) 5 vs. 0 NS

4,9 vs. 1,9 P<0,0001

14,8 vs. 14,4

Axitinib vs. sorafenib(3) 6,7 vs. 4,7 P < 0.001

1. B. Escudier et al., NEJM 2007; 2. RJ Motzer et al., The Lancet 2008 3 BI Rini et al., The Lancet 2011

New agent timelines

2005 2006 2007 2008 2009 2010 2011 20012

Sorafenib(1)

Sunitinib(2) Everolimus(4)

pazopanib(6)

temsirolimus(3) Bevacizumab

+Ifα(5)

1. Motzer RJ, et al. N Engl J Med. 2007;356(2):115-124. 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. 4. Escudier B, et al. Lancet.

2007;370(9605):2103-2211. 5. Rini BI, et al. J Clin Oncol. 2008;26(33):5422-5428. 6. Motzer RJ, et al. Lancet. 2008;372(9637):449-456. 7.

Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068.

Axitinib)

tivozanib

Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. R. Motzer et al., J Clin Oncol 30, 2012 (suppl; abstr 4501)

Key eligibility criteria Advanced RCC Clear cell histology Measurable disease Prior nephrectomy 0-1 prior therapy but

no VGEF or mTOR therapy

ECOG PS 0-1 R

AN

DO

MIZ

ED 1

:1 Tivozanib 1.5 mg/day po

3 weeks on/1 week off N=260

Sorafenib 400mg po bid Continuous

N=257

TIVO-1 Phase 3 superiority of tivozanib vs. sorafenib as first-line targeted therapy for mRCC

Tivozanib (n=260) Sorafenib (n=257) HR p

Independent

11.9 (9.3-14.7)

9.1 (7.3-9.5)

0.797 0.042

Investigator 14.7

(10.4-16.6) 9.6

(9.0-11.0) 0.722 0.003

PFS assessment Median PFS (95%CI)

Tivozanib (n=260) Sorafenib (n=257)

Best overall response, %

Complete response 1 1

Partial response 32 23

Stable disease 52 65

Progressive disease 13 7

ORR 33 23

95%CI 27-39 18-29

p 0,014

Tivozanib (n=259,%) Sorafenib (n=257,%)

All grade Grade 3(4) All grade Grade 3(4)

Hypertension 44 24(2) 34 17(<1)

Diarrhea 22 2 32 6

Dysphonia 21 0 5 0

Fatigue 18 5 16 4

Weight loss 17 <1 20 3

Asthenia 15 4(<1) 16 3

Hand-foot S. 13 2 54 17

Back pain 14 3 7 2

Nausea 11 <1 8 <1

Dyspnea 10 2 8 2

Decrease appetite 10 <1 9 <1

Alopecia 2 0 21 0

Treatment emergent AEs

Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC). NB Haas et al., J Clin Oncol 30, 2012 (suppl; abstr 4500)

ECOG 2805 (ASSURE)

Stratify

Risk by TNM Stage/Grade

Intermediate Risk

High Risk

Histologic Subtype

Clear cell

Non-clear cell

Performance status

Surgery

Open vs laparoscopic

Arm B Sorafenib daily continuously for 1 year

Arm C Placebo Daily continuously for 1 year

RANDOMIZE

Non-Metastatic

Kidney Cancer

That meets radiologic criteria to

be clinically T1bNany (resectable) M0 disease

N

E

P

H

R

E

C

T

O

M

Y

Arm A Sunitinib daily for 4 of 6 weeks for 1 year

R

E

G

I

S

T

R

A

T

I

O

N

1

To determine if patients treated with sunitinib or sorafenib experience clinically significant decreases in left ventricular ejection fraction.

Primary endpoint of interest was LVEF decline within 6 months, defined as LVEF below the institutional lower limit of normal, where the drop is at least 16% from baseline.

MUGA MUGA MUGA MUGA

Treatment with Sorafenib, Sunitinib or Placebo

Randomization

3 mo 6 mo

End of study

12 mo

MUGA

Completion of therapy

Frequency of clinically significant congestive

heart failure (CHF)

Timepoint Sunitinib Sorafenib Placebo

2 Months - 1 (16%) -

3 Months 6 (16 to 21%) 1 (21%) 2 (19 & 32%)

4 Months 2 (23 & 24%) - -

6 Months 1 (18%) 5 (16 to 19%, 37%) 3 (17 to 19%)

Pts Assessed 397 394 502

Events 9 7 5

Rate 2.3% 1.8% 1.0%

90% CI 1.2 – 3.9% 0.8 – 3.3% 0.4 – 2.1%

Patients with Other Events

Type of Event Sunitinib Sorafenib Placebo

LVEF decline >=16% 5 2 3

Grade 2 LV Event 5 6 8

Grade 3 LV Event 2 3 -

Pts Assessed 510 507 572

Events (Combined) 21 18 16

Rate 4.3% 5.3% 3.7%

90% CI 2.8 – 5.9% 2.3 – 5.2% 1.8 – 4.2%

Other LVEF events defined as one of the following: LVEF decline >=16%

occurring after 6 months, or a grade 2 or 3 left ventricular systolic or

diastolic dysfunction reported via AdEERS or on a case report form

Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. B.Rini et al., J Clin Oncol 30, 2012 (suppl; abstr 4503)

Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. B.Rini et al., J Clin Oncol 30, 2012 (suppl; abstr 4503)

Primary objective To compare the objective response rate (ORR) in patients receiving axitinib plus dose titration (Arm A) vs. axitinib plus placebo (Arm B)80% power to detect ≥ 25% improvement in ORR

Secondary objectives

Progression-free survival

Axitinib plasma pharmacokinetics

Blood pressure measurements

…

Clinical Efficacy of Axitinib for First-line Metastatic RCC

Total (n=213)

Arm C Not eligible for dose titration

(n=91)

Arm A+B Eligible for

dose titration (n=112)

mPFS (months) (95% CI)

14.5 (11.5-17.4)

16.4 (11.0-19-0)

14.5 (11.0-19.3)

ORR (95%CI)

48% (41%-55%)

59% (49%-70%)

43% (34%-53%)

Patient preference between pazopanib (Paz) and sunitinib (Sun): Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. B.Escudier et al., J Clin Oncol 30, 2012 (suppl; abstr CRA4502)

2-week washout Period 2 Period 1 Off study

Randomisation Patient choice of treatment

to progression n=169

Sunitinib 50 mg 4/2, 10 weeks

Pazopanib 800 mg once daily,

10 weeks

Pazopanib 800 mg once daily,

10 weeks

Sunitinib 50 mg 4/2, 10 weeks

1:1 randomisation, Patients on sunitinib received placebo during 2-week ‘off-period’

Time (weeks) 0 12 22 10

Double-blind

Assessment: Questionnaire time points1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Placebo

Placebo

Weeks

Period 1

Sunitinib

Pazopanib

Sunitinib

Sunitinib

Pazopanib

Sunitinib

Period 2 Washout

Patient preference: End of study EQ-5D: Baseline, washout, end of study FACIT-Fatigue: Every 2 weeks SQLQ: Every 2 weeks

Primary endpoint: Patient preference for study treatments (Primary analysis population) 1

0

10

20

30

40

50

60

70

80

90

100

Preferred pazopanib Preferred sunitinib No preference

Pati

ents

(%

)

90% CI (for difference): 37.0-61.5; p<0.001

70% (n=80)

22% (n=25)

8% (n=9)

Most common adverse events (>10%; cont’d) 1

Adverse event Pazopanib (n=153) Sunitinib (n=148)

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Hair colour changes 17% 0 0 14% 0 0

Mucosal inflammation 16% 0 0 22% 1% 0

Rash 8% <1% 0 11% 0 0

Dysgeusia 16% 0 0 27% 0 0

Headache 14% <1% 0 11% 0 0

Hypertension 23% 8% 0 26%) 9% 0

Epistaxis 5% 0 0 11% <1% 0

Decreased appetite 20% 0 0 19% <1% 0

• Compared with sunitinib, pazopanib was associated with a lower incidence of asthenia, stomatitis and hand-foot syndrome, and a greater incidence of diarrhoea

Note: The electronic case report form collected relationship to IP without distinguishing which treatment period the adverse event (AE) was related to. An AE which spanned more than one period was considered to be an AE for the period during which the AE increased in grade. There is only one label for relationship for the whole event. As such, it is not always possible to determine which period treatment the AE was related to.

1. GSK data on file.

Which reasons influenced their choice?1

0 10 20 30 40 50 60 70

Better quality of life

Less fatigue

Less taste change

Less mucositis/stomatitis

Less nausea/vomiting

Less hand-foot syndrome

Better appetite

Less stomach pain

Less diarrhoea

Other

Less hair colour change

Pazopanib preferred (n=80)

Sunitinib preferred (n=25)

Number of patients 1. Escudier B, et al. ASCO 2012 oral presentation; abstract 4502.

Assumption of equivalent efficacy

Continuous vs. intermittent treatment

Patient preference, a key driver of treatment choice ?

Prostate

Kidney


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