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Eugen Von Hippel Arvid Lindau

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Imagine…!!!

A Clinical CaseSearching the sequence

Clinical Case:Presentation and InitialTreatment

Initial presentation 55-year-old male History of smoking and

hypertension In good physical condition

Upon presentation: Right abdominal flank pain ECOG performance status 1 Test results Hb: 14.1 g/dL Corrected calcium level:

9.2 mmol LDH: 372 IU/L

Imaging revealed a 5-cm mass inright kidney

CT scan revealed no furthermetastasis

Initial treatment: Patient had a nephrectomy Adrenal gland and lymph nodes

free of tumour Pathological examination

showed clear cell histology Stage pT1bN0M0, high grade

OSOS

EFSEFS

Thick line IFN

Acronym Intervention Status Estimatedcompletion

ARISER girentuximab completed completed

ASSURE sorafenib/sunitinib

activenot recruiting 4/2016

ATLAS axitinib recruiting 5/2019

PROTECT pazopanib activenot recruiting 4/2017

SORCE sorafenib recruiting ?

S-TRAC sunitinib activenot recruiting 6/2017

SWOG-S0931 everolimus recruiting nk

New drugs

Clinical Case:Diagnosis of MetastaticDisease

• 2 years after surgery, patient returned to clinic for routinephysical examination, blood tests, and chest x-ray

• ECOG performance status 0

• Test results–Hb: 12.0 g/dL–Corrected calcium level: 9 mmol–LDH: 362 IU/L

• Imaging revealed multiple nodules (<1. 5 cm) in both lungs

• MSKCC status: intermediate

Delayed start of treatment?

Median PFS 2m 10% pts had not progressed in 12 m Identical RR to IFN (15%)

RT Oliver et al. BJU 1989

% ofprogression in 1 m 3 m 12 m

Surveillance(n=73) 40 74 90

TreatmentIFN(n=52)

29 50 86

Surveillance vs IFNin 73 mRCC pts

Delayed start of treatment

Patients with good PS

Asymptomatic disease

Low burden, "slow growing" tumor

Discussion !

52 pts - median age 67

m-f: 75% - 25%

94% PS 0

96% clear cell histology

8% prior metastasectomy

Heng risk: favorable-intermediate 26%-74%

Baseline tumor burden 32 mm

Rini et al. ASCO 2014

Delayed start of treatment

Median time on observation until treatment initiation 14.1 m

Estimated 12 & 24 months rates of continued surveillance 58 & 33% respectively

Median change in tumor burden 8 mm & median growth rate of 1.4 mm/month

31 pts came off observation - 25 received treatment

Pts with tumor burden <15 mm vs. >15 mm: median observation period 31.6 m vs. 13.8 m

No impact of location/number of metastases on observation period

Anxiety & depression stable

Rini et al. ASCO 2014

Results

Delayed start of treatment

Median time on observation until treatment initiation 14.1 m

Estimated 12 & 24 months rates of continued surveillance 58 & 33% respectively

Median change in tumor burden 8 mm & median growth rate of 1.4 mm/month

31 pts came off observation - 25 received treatment

Pts with tumor burden <15 mm vs. >15 mm: median observation period 31.6 m vs. 13.8 m

No impact of location/number of metastases on observation period

Anxiety & depression stable

Rini et al. ASCO 2014

Results

When ?

Increased rhythm of growth

New mets

Symptoms

Patient or physician stress

Clinical Case:Further progression

• 10 months later - Restaging–Presented with mild, flu-like symptoms, asthenia

• ECOG performance status 1

• Test results–Hb: 11.5 g/dL–Corrected calcium level: 9.9 mmol–LDH: 367 IU/L

• Imaging revealed multiple nodules (1.75-2 cm) in both lungsand maybe mediastinal adenopathy

• Cytological examination confirmed RCC recurrence

• MSKCC status: intermediate

Mainstream in 1st line

HR=0.647(95% CI: 0.483–0.870)P=0.0033 (log-rank)

Sunitinib (n=193)Median 28.1 months(95% CI: 19.5–NA)IFN-α (n=162)*Median: 14.1 months(95% CI: 9.7–21.1)

*Includes 20 patients whocrossed over to sunitinib on study Motzer RJ, et al. J Clin Oncol 2009; Figlin RA, et al. ASCO 2008

1.00.90.80.70.60.50.40.30.20.1

0

Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36

Prob

ab

ility

of su

rviv

al

Exploratory Analysis to Assess Impactof Sunitinib Crossover Treatment

OS in patients who did not receive any post-study treatment

1st line

2nd line

Phase III COMPARZ Trial:First-line Pazopanib vs Sunitinib

Motzer RJ et al. N Engl J Med. 2013;369:722-731.

Eligibility Criteria• mRCC with clear-cell

histology

• Measurable disease

Pazopanib800 mg/day

Sunitinib 50 mg/day(schedule 4/2)

Primary end point: PFSSecondary end points: OS, ORR, PRO, safety and QoL

N = 1110

RANDOMIZE n = 553

n = 557

26

Clinical Case: First-lineTreatment

Sunitinib 50 mg once daily (4 weeks on/2 weeks

off schedule) initiated

Response observed, but accompanied by AEs:

Grade 2 asthenia (chronic)

Grade 2 hand-foot syndrome (managed with topical

creams)

Grade 2 hypertension (managed with antihypertensive

therapy)

Clinical Case: First-lineTreatment

Sunitinib dose reduced to 37.5 mg once daily(4/2 schedule)After 2 cycles: Lung CT showed slight progression in size of metastases no increase in size of target lesion (stable disease per

RECIST) Continued moderate fatigue and hand-foot syndrome,

which were difficult for the patient

Treatment break?EAT – BEACH – SLEEP - REPEAT

• m/f 75%/25%

• 95% RCC

• 19% pts had prior systemic treatment

• 48% favorable - 48 intermediate-4% poor (HENG)

• All patients with break >/= 3 m

Break do to toxicity/AEs(57%) - physician choice(26%)CR prior breakassociated with longersurveillance period

Mittal et al. ASCO 2014

Tx no of ptsstarting tx

medianduration tx

no of ptson break

mediandurationbreak

A 112 13.5 112 16.8

B 68 16.1 24 9.5

C 43 14.8 10 7.1

D 15 13.8 3 15.9

Wood et al ASCO 2012

No priortreatment

Sunitinib 50mg (4/2)

Tumor decrease(<10%) Continue until PD

Tumor decrease(<10%)

Hold &restart(>10%

increase from pre-break burden)

Sunitinib for 2cycles

A Phase II Study of Intermittent Sunitinib inPreviously Untreated Patients with Metastatic RenalCell Carcinoma

37 pts (20 eligible -

17

progressed/consent

issues)

16 pts >10% after 1st

period

4 pts no increase

Aggregate Tumor Burden Changes for 8 Patients in the Intermittent Phase for theEquivalent of > 3 “Stop-Start” Periods

2nd line treatment…myths, legends…and COMMON SENSE!

Mechanisms of resistanceto VEGF(R)-targeted therapy

VEGFR-TKI mTOR

Phase III Prospective Studies:VEGFr-TKI → mTOR Sequencing

1. Motzer RJ et al. Cancer. 2010;116:4256-65. 2. Calvo E et al. Eur J Cancer. 2012;48:333-9. 3. Hutson TE et al. J Clin Oncol. 2014;32:760-7.

Study Pt Population (N) Treatment mPFS, mo mOS, mo

RECORD-11,2 Sunitinib- and/or sorafenib-refractory (416)

Previous treatment with1 VEGFr-TKI (308)

EverolimusPlacebo

EverolimusPlacebo

4.91.9

5.41.9

14.814.4

Notreported

INTORSECT3 Sunitinib-refractory (512) TemsirolimusSorafenib

4.33.9

12.316.6

43

Phase III RECORD-1: Study Design

1. Motzer RJ et al. Lancet. 2008;372:449-56.2. Motzer RJ et al. Cancer. 2010;116:4256-65.

Upon DiseaseProgression

N = 416

Everolimus 10 mg/d + BSC(n = 277)

Placebo + BSC(n = 139)

Key eligibility criteria:• mRCC with clear-cell

histology• Measurable disease per

RECIST• Progression during or after

sunitinib and/or sorafenib• KPS ≥70%

Stratified by:• Number of previous VEGFr-

TKIs (1 vs 2)• MSKCC risk group

(favourable vs intermediatevs poor)

Primary end points: PFSSecondary end points: Safety, OS,ORR, QoL

RANDOMISE

2:1

44

RECORD-1: PFS

Motzer RJ et al. Cancer. 2010;116:4256-65.

100

80

60

40

20

00 2 4 6 8 10 14

Prob

abili

ty, %

Time, mo12

mPFS, mo 95% CIEverolimusPlacebo

4.91.9

P < .001 (log-rank)

HR: 0.3395% CI: 0.25–0.43

4.0–5.51.8–1.9

RECORD-1: PFS by Number of Previous VEGFr-TKIs

Everolimus significantly improved PFS regardless of the specific VEGFr-TKI or the number of previousVEGFr-TKIs

Calvo E et al. Eur J Cancer. 2012;48:333-9.

Everolimusn = 277

Placebon = 139 Treatment Effect

mPFS, mo mPFS, mo HR (95%) CI P

1 prior VEGFr-TKI 5.4 1.9 0.32 (0.24–0.43) < .001

2 prior VEGFr-TKIs 4.0 1.8 0.32 (0.19–0.54) < .001

Sunitinib as only prior VEGFr-TKI 3.9 1.8 0.34 (0.23–0.51) < .001

Sunitinib as only prior anti-neoplastic therapy 4.6 1.8 0.22 (0.09–0.55) < .001

Sorafenib as only prior VEGFr-TKI 5.9 2.8 0.25 (0.16–0.42) < .001

Sorafenib as only prior anti-neoplastic therapy 3.8 1.9 0.35 (0.14–0.88) .010

47RECORD-1: Grade 3/4 AEsand Laboratory Abnormalities1

No difference in toxicity when given after 1 or 2 previous VEGFr-TKIs2

1. Motzer RJ et al. Cancer. 2010;116:4256-65 --2. Calvo E et al. Eur J Cancer. 2012;48:333-9.

Everolimus + BSC (n = 274)

AE, % Grade 3 Grade 4Infection 7 3

Dyspnoea 6 1

Fatigue 5 0

Stomatitis 4 <1

Asthenia 3 <1

Pneumonitis 4 0

Laboratory Abnormality, %Lymphocytes decreased 16 2

Glucose increased 15 <1

Haemoglobin decreased 12 1

Phosphate decreased 6 0

Phase III INTORSECT: Study Design

aDose reductions were allowed: temsirolimus (to 20 mg then 15mg);sorafenib (to 400 mg/day, then every other day)

Hutson TE et al. J Clin Oncol. 2014;32:760-7.

N = 512

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

Stratification factors:• Duration of sunitinib

therapy (≤ or >6 mo)• 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 wk, ORR, duration of response

Temsirolimus25 mg IV weeklya

n = 259

Sorafenib400 mg oral BIDa

n = 253

RANDOMISE

INTORSECT: PFS and OS

No significant difference in PFS between temsirolimus andsorafenib

OS significantly longer with sorafenib (P = .014)

Hutson TE et al. J Clin Oncol. 2014;32:760-7.

1.00.90.80.70.60.50.40.30.20.1

00 5 10 15 20 25

PFS,

pro

babi

lity

Time, mo

TemsirolimusSorafenib

mPFS,months 95% CI

4.33.9

4.0–5.42.8–4.2

P = .19 (two sided log-rank)Stratified HR: 0.87(95% CI: 0.71–1.07)

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, mo

mOS,months 95% CI

12.3 10.1–14.813.6–18.7

P = .01 (two sided log-rank)Stratified HR: 1.31(95% CI: 1.05–1.63)

16.6TemsirolimusSorafenib

Progression-free Survival (IRC) Overall Survival

Retrospective Study: Improved OS with Everolimus vsTemsirolimus After Sunitinib Failure

Targeted Therapy mPFS with First DrugMos (95% CI)

mPFS with SecondDrug

Mos (95% CI)

mOSMos (95% CI)

Sunitinib to sorafenib (n = 257) 7.6 (6.5-8.2) 3.6 (2.9-4.1) 23.0 (20.2-23.0)

Sorafenib to sunitinib (n = 152) 7.3 (6.2-8.5) 5.2 (4.2-6.8) 26.5 (20.2-29.4)

Sunitinib to temsirolimus (n = 115) 7.2 (5.7-9.3) 3.2 (2.6-5.0) 27.7 (18.2-31.4)

Sunitinib to everolimus (n = 130) 8.6 (6.6-10.7) 3.7 (2.8-5.3) 43.3 (33.4-60.9)

Heng DYC, et al. Presented at: ASCO-GU Symposium; 2–4 February 2012; San Francisco, CA, USA. Abstract 387.

VEGFR-TKI

VEGFR-TKI

Phase III AXIS Trial: Study Design

*Sunitinib, bevacizumab + IFN-α, temsirolimus or a cytokine.†Option for dose titration to 10 mg bid if tolerated.Rini BI et al. Lancet. 2011;378:1931-1939.

N = 723

Axitinib 5 mg bid†

(n = 361)

Sorafenib 400 mg bid(n = 362)

Eligibility Criteria• mRCC with clear-cell

histology

• Measurable diseaseper RECIST

• Failed 1 prior systemicfirst-line regimen*

• ECOG PS 0-1 Primary end points: PFSSecondary end points: OS, ORR, durationof response, safety and tolerability, kidney-specific symptoms, HRQoL

RANDOMIZE

Stratified by ECOG PSand prior treatment

• 723 patients were enrolled– 361 randomized to axitinib– 362 randomized to sorafenib

• Median age = 61 years• Prior therapy:

– 54% sunitinib– 35% cytokines– 8% bevacizumab– 3% temsirolimus

Sunitinib

Cytokines

Bev.

Phase III AXIS Trial:Patients by Prior Therapy

Rini BI et al. Lancet. 2011;378:1931-1939.

AXIS: Overall PFS

Rini BI et al. Lancet. 2011;378:1931-1939.

mPFS, mo 95% CI

0.00 2 4 6 8 10

Time, months

AxitinibSorafenib

6.74.7

P < .0001 (log-rank)

Stratified HR: 0.66595% CI: 0.544-0.812

6.3-8.64.6-5.6

PFS,

pro

babi

lity

12 14 16 18 20

0.10.20.30.40.50.60.70.80.91.0

*One-sided log-rank test stratified by ECOG PS.Rini BI et al. Lancet. 2011;378:1931-1939.

AXIS: PFS by Prior Treatment1

Prior TreatmentRegimen Axitinib, months Sorafenib, months HR P*

Cytokines n = 126 n = 125IRC 12.1 6.5 0.464 < .0001Investigator 12.0 8.3 0.636 .005Sunitinib n = 194 n = 195IRC 4.8 3.4 0.741 .011Investigator 6.5 4.5 0.636 .0002Temsirolimus n = 12 n = 12IRC 10.1 5.3 0.511 .142Investigator 2.6 5.7 1.210 .634Bevacizumab n = 29 n = 30IRC 4.2 4.7 1.147 .637Investigator 6.5 4.5 0.753 .213

Cumulative Toxicity WithSequential VEGFr-TKI →VEGFr-TKI terapy

0 10 20 30 40 50 60 70

Mucosal inflammation

Constipation

Asthenia

Vomiting

Hypertension

Nausea

Decreased appetite

Diarrhoea

Prior Cytokines Prior Sunitinib

0 10 20 30 40 50 60 70

Lipase increasedMucosal inflammation

AstheniaHFS

VomitingHypertension

NauseaFatigue

Decreased appetiteDiarrhoea

Prior Cytokines Prior Sunitinib

PercentPercent

AEs shown are those with a >10% difference in incidence between subgroups.1. Pfizer Inc. FDA Oncologic Drugs Advisory Committee Briefing Document (NDA 202324). Axitinib (AG-013736) For the Treatment ofPatients With Advanced Renal Cell Carcinoma. 2011. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ucm282284.htm.

Axitinib ArmSorafenib Arm

Post sunitinib Post cytokines

Phase II RECORD-3 Trial: Study Design

*At randomisation, patients were stratified by MSKCCprognostic factors.†4 weeks on and 2 weeks off.

Motzer RJ et al. Presented at: ASCO Annual Meeting; 31 May–4June 2013;Chicago, IL: abstract 4504.

Everolimus10 mg/day

2nd LineC

rossover uponprogression

1 : 1

RANDOMISE

1st LineN = 471

Primary• PFS – 1st line

Secondary• PFS –

combined• ORR – 1st line• OS• Safety

Studyend pointsEligibility

Criteria• mRCC (clear

or non-clearcell histology)

• No priorsystemictreatment

*

Everolimus10 mg/day

Sunitinib50 mg/day†

Sunitinib50 mg/day†

Non-inferiority study

RECORD-3: First-line PFS and Overall Survival* *Data are not mature. Final analysis expected.

Kaplan-Meier Median PFS (mo)

Everolimus Sunitinib7.85 10.71

Hazard Ratio = 1.432-Sided 95% CI [1.15–1.77]

Kaplan-Meier Median OS (mo)

EVE then SUN SUN then EVE22.41 32.03

Hazard Ratio = 1.242-Sided 95% CI [0.94–1.64]

Time, months

100

Cum

ulat

ive

Even

t-fre

e Pr

obab

ility

, %

908070605040302010

00 3 6 9 12 15 18 21 24 27 30 33

Time, months

Everolimus (n/N = 182/238)Sunitinib (n/N = 158/233) TT

TTTT

TTTTTTTTTTTTTTTT

TTTTTTTTT

TTTT

T

T

TT

TTTTT

TT

T

T

TTTTTTTTTTTT

TTTTT

T

T

T

TT

T

TT

36

100

Cum

ulat

ive

Even

t-fre

e Pr

obab

ility

, %

908070605040302010

00 3 6 9 12 15 18 21 24 27 30 33

Everolimus then sunitinib (n/N = 108/238)Sunitinib then everolimus (n/N = 96/233)

TT

TT

TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

TTTTTTTTT

TTTTTTTTTTTTTTTTT

TT

TTTTTT

TT

TT

TTT

TT T

T

T TT TTTTT TTTTT TTT TTTT TTTTTTTTT TTTT

TTTT T TTTT TTTTTTTT TT TT TTT TTT TTTTTT T T

Motzer RJ et al. J Clin Oncol. 2013;31(suppl):abstract 4504.

Clinical Case: Second-lineTreatment

Everolimus 10 mg/day initiated

AEs observed after 5 months of treatmentGrade 1 hypercholesterolemiaCholesterol-lowering drug was added to

treatment regimenNo everolimus dose adjustment requiredGrade 2 pneumonitis Patient showed symptoms of pneumonitis,

including a persistent, slight cough Radiologic evidence suggested pneumonitis

Everolimus interrupted, course ofsteroids administeredCoughing stopped Imaging showed complete resolution of

pneumonitis

Clinical Case: Second-lineTreatment

After resolution of pneumonitis, everolimus resumed atfull dose of 10 mg once dailyNo recurrence of pneumonitis

After 8 months of stable disease on everolimus:Patient experienced increased fatigue, and ECOG PS score

increased to 1

Clinical Case: Second-lineTreatment

RJ Motzer, C Szczylik, N Vogelzang, CN Sternberg, C Porta,J Zolnierek, C Kollmannsberger, SY Rha, GA Bjarnason,

B Melichar, U De Giorgi, G Urbanowitz, C Cai, M Shi, B Escudier

Phase 3 Trial of Dovitinib vs Sorafenib inPatients With Metastatic Renal Cell

Carcinoma After 1 Prior VEGF PathwayTargeted and 1 Prior mTOR Inhibitor Therapy

European Cancer Congress 2013Abstract 34LBA

Study Design

StratificationMSKCC risk group: favorable, intermediate, poorGeographic region: Japan, Asia Pacific, Europe/Middle East, Americas

Key Eligibility Criteria

• Metastatic RCC with clear cellcomponent

• 1 prior VEGF-targeted therapyand 1 prior mTOR inhibitor

• Other anticancer therapiespermitted (cytokines)

• Progressive disease within 6months of last targetedtherapy

• Measurable disease

Sorafenib

400 mg

twice daily

Dovitinib

500 mg/day

5 days on/2 days off

RANDOMIZATI

ON

1:1

Progression-Free Survival (Central)

100

80

60

40

20

0

0 3 6 9 12 15 18 21

Months

Prob

abili

ty (%

) eve

nt-fr

ee

284 148 41 20 3 1 1 0Dovitinib286 152 42 12 2 1 0 0Sorafenib

n/N Median, months(95% CI)

Hazard Ratio(95% CI)

Dovitinib 209/284 3.7 (3.5-3.9) 0.86 (0.72-1.04)P = .063aSorafenib 231/286 3.6 (3.5-3.7)

Patients at risk

a1-sided based onstratified log-rank

test

Months

Progression-Free Survival (Investigator)

DovitinibSorafenib

Patients at risk

n/N Median, months(95% CI)

Hazard Ratio(95% CI)

Dovitinib 212/284 3.9 (3.7-5.1) 1.00 (0.82-1.21)P = .494aSorafenib 214/286 3.9 (3.7-5.0)

284 169 56 30 5 1 0 0286 177 59 24 6 2 0 0

100

80

60

40

20

0

0 3 6 9 12 15 18 21

a1-sided based onstratified log-rank

test

Prob

abili

ty (%

) eve

nt-fr

ee

RCC treatmentThe Sequence!

Loukas Kontovinis, medical oncology

www.oncomedicare.com