PowerPointstatic.livemedia.gr/livemedia/documents/al17240_us63... · 2015-06-14 · Stomatitis 4
Transcript of PowerPointstatic.livemedia.gr/livemedia/documents/al17240_us63... · 2015-06-14 · Stomatitis 4
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www.oncomedicare.com
The Sequence
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Evolution
Eugen Von Hippel Arvid Lindau
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Pathways
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Imagine…!!!
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A Clinical CaseSearching the sequence
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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
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OSOS
EFSEFS
Thick line IFN
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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
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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
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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
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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
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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
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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
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When ?
Increased rhythm of growth
New mets
Symptoms
Patient or physician stress
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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
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Mainstream in 1st line
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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
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1st line
2nd line
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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
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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)
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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
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Treatment break?EAT – BEACH – SLEEP - REPEAT
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• 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
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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
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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
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2nd line treatment…myths, legends…and COMMON SENSE!
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Mechanisms of resistanceto VEGF(R)-targeted therapy
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VEGFR-TKI mTOR
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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
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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
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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
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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
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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
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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
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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
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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.
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VEGFR-TKI
VEGFR-TKI
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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
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• 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.
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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
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*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
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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
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Post sunitinib Post cytokines
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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
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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.
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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
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Everolimus interrupted, course ofsteroids administeredCoughing stopped Imaging showed complete resolution of
pneumonitis
Clinical Case: Second-lineTreatment
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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
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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
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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
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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
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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
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RCC treatmentThe Sequence!
Loukas Kontovinis, medical oncology
www.oncomedicare.com