Negative Trials in RCC:Where Did We Go Wrong?

Can We Do Better?

Tim Eisen

9th European Kidney Cancer Symposium, Dublin, April 2014

Tim Eisen - Disclosures

Company Research Support

Advisory Board

Trial Management

Group

Honoraria

Astra Zeneca + + +Astellas + +Aveo + + +Bayer + + + +GSK + + + +Immatics +Pfizer + + +Roche + +

Appraisal

40 Years of Developing mRCC Treatments

1980 1990 2000 2010 2020

CytokinesIL-2 and IFN-α High-dose IL-2

FDA approvalbased on phase II data

Sunitinib

Sorafenib

Temsirolimus

Bevacizumab+IFN-α

Everolimus Axitinib

Pazopanib

Chromatin Remodelling Gene Mutations

VHL tumour suppressor gene isolated

Failed studies – a BIG issue

935 / 7776 Phase II / III studies did not complete– Accrual 38.7%

– Sponsor decision 10.7%

– Interim analysis 9.9%

– Toxicity 8.2%

– Funding 5.6%

Stensland et al., GU ASCO 2014

Nephrectomy in mRCC:Key Questions in the TKI Era

Is cytoreductive nephrectomy benefical?

If so, should nephrectomy or TKI come first?

CARMENA V SURTIME

There are many ongoing Phase III studies of adjuvant targeted therapy in RCC...

Trial Treatment arms andduration

Patients N

SORCE1 Sorafenib (3 years)Sorafenib (1 year) then

placebo (2 years)Placebo (3 years)

Resected clear-cell/non-clear-cell RCC and intermediate- or high-risk disease

1656

ASSURE2 Sorafenib SunitinibPlacebo

Resected clear-cell/non-clear-cell RCC and intermediate-high- or very-high-risk disease

1923

S-TRAC3 SunitinibPlacebo

Resected predominantly clear-cell RCC and high-risk disease

720

PROTECT4 PazopanibPlacebo

Resected (predominantly) clear-cell RCC with high or moderately high risk of recurrence

1500

EVEREST5 EverolimusPlacebo

Resected clear-cell/non-clear-cell RCC and intermediate-high- or very-high-risk disease

1218

1 year

1 year

1 year

54 weeks

1. www.clinicaltrials.gov. NCT00492258; 2. www.clinicaltrials.gov. NCT00326898;3. www.clinicaltrials.gov. NCT00375674; 4. www.clinicaltrials.gov. NCT01235962; 5. www.clinicaltrials.gov. NCT01120249.

Adjuvant studies in RCC:Divided we fall?

Placebo / control 3143Sorafenib ≥1yr (SORCE)1242Pazopanib (PROTECT) 750

Sorafenib (ASSURE) 641

Sunitinib (ASSURE) 641Everolimus (EVEREST) 609Sunitinib (S-TRAC) 300

ARISER (G250 v Placebo)

Risk Group Staging % of total Leibovich Score1 T3/4; N0/X; M0 75% 4 - 92 Any T; N+; M0 8% 2 – 113 T1b/2; N0/NX; M0; G>3 17% 3 - 8

• Metastases at baseline in 11%• Median DFS 71 months• 5 year OS 78%

Belldegrun et al., ASCO 2013

MAMS vs traditionalTraditional Approach

Phase II

Phase III

T1

C T1

T2T3

C T3

T4

C T4

Multi-arm, Multi-stage

T2 T3T1C T4

Phase II

Phase III

Predictors of Successful Phase III Trials

Strong Phase II signal / scientific rationale

Predictive marker

Robust outcome – magnitude and relevance

Efficient and effective design

Clin Cancer Res. 2010 Dec 15;16(24):5951-5. doi: 10.1158/1078-0432.CCR-10-2632.Translating clinical trials into meaningful outcomes.LoRusso PM1, Schnipper LE, Stewart DJ, Boerner SA, Averbuch SD, Wolf W.

Recent Negative Trials in mRCC

Study Setting ExperimentalArm

StandardArm

Comment

INTORSECT 2nd line Temsirolimus SorafenibINTORACT 1st line Bev/Tem Bev/IFNRECORD 2 1st line Bev/Evero Bev/IFNGOLD 3rd line Dovitinib SorafenibAGILE 1st line Axitinib SorafenibTIVO 1 1st line Tivozanib Sorafenib

INTORSECT Phase III Study Design1

aDose reductions were allowed: temsirolimus (to 20 mg then 15 mg); sorafenib (to 400 mg/day, then every other day) 1. Hutson TE et al ESMO 2012; abstract LBA22_PR

N = 512

Key eligibility criteria:• mRCC• PD on 1st-line sunitinib

Stratification factors:• Duration of sunitinib

therapy (≤ or > 6 mos)• MSKCC risk group• Histology (clear cell or

non clear-cell)• Nephrectomy status

Primary end point: PFS (IRC)Secondary end points: OS, PFS (investigator), PFS at 12, 24, and 36 weeks, ORR, duration of response

Temsirolimus25 mg IV weeklya

n = 259

Sorafenib400 mg oral BIDa

n = 253

RANDOM I ZATION1:1

Prospective Data: INTORSECT Phase III Study Efficacy1

No significant difference in PFS between temsirolimus and sorafenib

OS significantly longer with sorafenib (P=0.014)

1. Hutson TE et al ESMO 2012; abstract LBA22_PR

1.00.90.80.70.60.50.40.30.20.1

00 5 10 15 20 25

PFS

(pro

babi

lity)

Time (months)Patients at risk, nSorafenibTemsirolimus

252259

7296

2228

119

65

00

TemsirolimusSorafenib

Median PFS,months 95% CI

4.283.91

4.01, 5.432.80, 4.21

P=0.1933 (log-rank)Stratified HR: 0.87(95% CI: 0.71, 1.07)

Progression-Free Survival(IRC Assessment)

CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; OS, overall survival; PFS, progression-free survival

1.00.90.80.70.60.50.40.30.20.1

00 10 20 30 40 50

Ove

rall

Surv

ival

(pro

babi

lity)

Time (months)Patients at risk, nSorafenibTemsirolimus

253259

158132

7454

3422

138

00

TemsirolimusSorafenib

Median OS,months 95% CI

12.2716.64

10.13,14.8013.55, 18.72

P=0.014 (log-rank)Stratified HR: 1.31(95% CI: 1.05, 1.63)

Overall Survival

Prospective Data: INTORSECT Phase III Study Efficacy1

No significant difference in PFS between temsirolimus and sorafenib

OS significantly longer with sorafenib (P=0.014)

1. Hutson TE et al ESMO 2012; abstract LBA22_PR

1.00.90.80.70.60.50.40.30.20.1

00 5 10 15 20 25

PFS

(pro

babi

lity)

Time (months)Patients at risk, nSorafenibTemsirolimus

252259

7296

2228

119

65

00

TemsirolimusSorafenib

Median PFS,months 95% CI

4.283.91

4.01, 5.432.80, 4.21

P=0.1933 (log-rank)Stratified HR: 0.87(95% CI: 0.71, 1.07)

Progression-Free Survival(IRC Assessment)

CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; OS, overall survival; PFS, progression-free survival

1.00.90.80.70.60.50.40.30.20.1

00 10 20 30 40 50

Ove

rall

Surv

ival

(pro

babi

lity)

Time (months)Patients at risk, nSorafenibTemsirolimus

253259

158132

7454

3422

138

00

TemsirolimusSorafenib

Median OS,months 95% CI

12.2716.64

10.13,14.8013.55, 18.72

P=0.014 (log-rank)Stratified HR: 1.31(95% CI: 1.05, 1.63)

Overall Survival

Recent Negative Trials in mRCC

Study Importantquestion?

Strong rationale?

Predictive marker?

Good design?

INTORSECT Yes Yes No YesINTORACTRECORD 2GOLDAGILETIVO 1

www.esmo2012.org

Rationale for Bevacizumab / Temsirolimus combination

Merchan ASCO 2007

Phase I study: N = 12, all ECOG 0-1

Prior therapy: n = 7, cytokines in 6/7

RR: NO CR PR=7 (60 %) SD = 3 (25 %)

PFS: n/a

Combination feasible with both agents given at full dose

High response rate further testing recommended

www.esmo2012.org

Rationale for Everolimus/Bevacizumab combination

Whorf et al ASCO 2008; Hainsworth et al JCO 2010

Phase II study: N = 30 untreated patients in preliminary reportN = 50 untreated patients in final report

Median PFS: 12 months in ASCO 2008 presentation (9 months in abstract) 9.1 months in the final report (JCO 2010)

RR: NO CR PR=23 % SD = 53 %

Combination feasible with both agents given at full dose

Very active (“12 months PFS”) further testing recommended

Recent Negative Trials in mRCC

Study Setting ExperimentalArm

StandardArm

Comment

INTORSECT 2nd line Temsirolimus Sorafenib PositiveINTORACT 1st line Bev/Tem Bev/IFN Ph I signal RECORD 2Large Ph II

1st line Bev/Evero Bev/IFN Ph II signal +/-

GOLD 3rd line Dovitinib Sorafenib True negativeAGILE 1st line Axitinib SorafenibTIVO 1 1st line Tivozanib Sorafenib

AGILE Study Design*

Previously untreated metastatic RCC

RANDOMIZE

Axitinib 5 mg BID†

(n=192)

2:1

Sorafenib 400 mg BID(n=96)

Primary endpoint: PFSRandomization stratified by ECOG PS (0 vs 1). * ClinicalTrials.gov: NCT00920816.† Titrated stepwise to 7 mg BID and then 10 mg BID in patients without grade 3 or 4 (CTCAE v3.0) axitinib-related AEs for a consecutive 2-week period, unless BP >150/90 mmHg. 22

Progression-free Survival (IRC Assessment)

* Stratified by ECOG PS; assuming proportional hazards, HR <1 indicates a reduction in favor of axitinib and HR >1 indicates a reduction in favor of sorafenib.IRC = independent radiology committee; mPFS = median progression-free survival

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10Time (months)

12 14 16 18 20

PFS

(pro

babi

lity)

22 24

1-sided P=0.038

Stratified HR, 0.77*(95% CI 0.56–1.05)

Axitinib Sorafenib

No. events (%)111 (58)60 (63)

192 154 132 114 91 78 63 54 19 6 096 73 60 43 34 24 20 19 10 0 0

Patients at risk, nAxitinib

Sorafenib3413

10

= censored for axitinib= censored for sorafenib

23

mPFS, mo (95%CI)10.1 (7.2–12.1)

6.5 (4.7–8.3)

Statistical Design• Primary endpoint for first-line comparison was PFS, assessed by

independent radiology committee (IRC)− 90% power to detect a 78% improvement in mPFS from 5.5 mo with sorafenib

to 9.8 mo with axitinib, corresponding to an HR of 0.56 (overall 1-sided α=0.025)

− An estimated 247 treatment-naïve patients were needed to observe the required 148 IRC-assessed PFS events

− One interim futility analysis was planned at 74 (50%) investigator-assessed PFS events; independent data monitoring committee (DMC) could adjust number of IRC-assessed PFS events based on conditional power at interim analysis

− Number of PFS events was increased to 169 by DMC

24

Recent Negative Trials in mRCC

Study Setting ExperimentalArm

StandardArm

Comment

INTORSECT 2nd line Temsirolimus Sorafenib True negativeINTORACT 1st line Bev/Tem Bev/IFN Ph I signal RECORD 2Large Ph II

1st line Bev/Evero Bev/IFN Ph II signal +/-

GOLD 3rd line Dovitinib Sorafenib True negativeAGILE 1st line Axitinib Sorafenib StatisticsTIVO 1 1st line Tivozanib Sorafenib

26

TIVO-1: Phase III superiority study of tivozanib vs sorafenib as first-line targeted therapy for advanced RCC

Motzer et al. J Clin Oncol 2012; 30(Suppl): Abstract 4501 (Oral presentation)

RANDOMISED

1:1Stratification factors• Geographic region• Prior treatments for mRCC • Number of metastatic lesions

Key eligibility criteria• Advanced RCC • Clear cell histology• Measurable disease • Prior nephrectomy• 0–1 prior therapy for mRCC• No prior VEGF or mTOR therapy• ECOG PS 0–1

Tivozanib 1.5 mg/day p.o., 3 weeks on/1 week off

(N=260)

Sorafenib 400 mg p.o. b.d., continuous

(N=257)

Crossover to tivozanib via separate protocol

Progression

27

HR=0.797; P=0.042

Median PFS, months (95% CI)

Tivozanib 11.9 (9.3–14.7)

Sorafenib 9.1 (7.3–9.5)

100

0

40

20

0 5 10 15Time since randomisation (months)

20

Prob

abili

ty o

f PFS

(%)

60

80

No. at riskTivozanib 260 257 217 210 181 179 164 163 144 140 126 117 109 100 94 68 65 29 29 2 2 0Sorafenib 257 253 218 212 184 183 146 144 120 113 91 84 73 68 64 46 44 19 18 2 2 0

TivozanibSorafenib

Tivozanib is superior to sorafenib for PFS (primary endpoint, independent radiological review)

ITT population

Data on file, AVEO/Astellas Pharma 2012, Study 301 CSR, Table 17 and Figure 3 Motzer et al. J Clin Oncol 2012; 30(Suppl): Abstract 4501 (Oral presentation)

28

Use of next-line treatments confounds the OS comparison

Still on tivozanib

treatment

Still on sorafenib

treatment

Randomised to tivozanib arm (n=260)

Randomised to sorafenib arm (n=257)

27%(n=71)

12%(n=31)

Discontinued initial

therapy 73%

(n=189)

Discontinued initial

therapy 88%

(n=226)

64%18%

10%8%

26%

3%

2%

70% (156/158 patients received

tivozanib)

VEGF (n=18)mTOR (n=16)No therapy (n=121)Other*(n=34)

VEGF (n=158)mTOR (n=4)No therapy (n=58)Other* (n=6)

Motzer et al. J Clin Oncol 2013; 31(Suppl 6): Abstract 350 (Poster)

*Other includes radiotherapy and cytokinesDue to rounding, total does not equal 100%

28

29

TIVO-1: final OS analysisMedian OS,

months (95% CI)

Tivozanib 28.8 (22.5–NR)

Sorafenib (includes patients who crossed over)

29.3 (29.3–NR)

Surv

ival

(%) HR=1.25; P=0.105

Tivozanib armSorafenib arma

No. at riskTivozanib 260 256 241 227 211 198 183 170 159 148 142 133 125 89 39 2 0Sorafenib 257 249 241 232 218 208 194 181 170 167 157 151 137 98 43 3 0

Time (months)

100

0

40

20

60

80

0 6 10 18 262 8 12 20 284 1614 22 3024 32

aincludes patients who crossed over to tivozanib after progression on sorafenibMotzer et al. J Clin Oncol 2013; 31(Suppl 6): Abstract 350 (Poster)

29

Recent Negative Trials in mRCC

Study Setting ExperimentalArm

StandardArm

Comment

INTORSECT 2nd line Temsirolimus Sorafenib PositiveINTORACT 1st line Bev/Tem Bev/IFN Ph I signal RECORD 2Large Ph II

1st line Bev/Evero Bev/IFN Ph II signal +/-

GOLD 3rd line Dovitinib Sorafenib True negativeAGILE 1st line Axitinib Sorafenib StatisticsTIVO 1 1st line Tivozanib Sorafenib Design

Conclusions

Perspective

Help ourselves in difficult situations

Minimise Risk & Maximise Efficiency:– How persuasive will the data be?

– Try to foresee consequences of design

– Strength of Phase II / scientific rationale

– Realistic statistical design

– Novel designs

Phase II: Use RECIST as a continuous variable

Multi-Arm Multi-Stage