Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
www.oncomedicare.com
The Sequence
Evolution
Eugen Von Hippel Arvid Lindau
Pathways
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