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Johannes EttlInterdisziplinäres Brustzentrum und Frauenklinik rechts der Isar,Technische Universität München Direktorin: Prof Dr M Kiechle
MBCA: Neues aus San Antonio
Technische Universität München, Direktorin: Prof. Dr. M. Kiechle
Projektgruppensitzung am 24. Januar 2012 MBCA: Neues aus San Antonio
OsteoporosisOsteoporosis CenterCenter PerinatalPerinatal CenterCenter
Frauenklinik rechts der Isar der Technischen Universität MünchenDirektorin Prof. Dr. Marion Kiechle
Überblick:• Kombinierte endokrine Therapie: CDK 4/6-Inhibitor und Le• Her2pos: Überlebensvorteil der dualen Blockade 1st-Line• Vergleich Eribulin-Capecitabine
OsteoporosisOsteoporosis CenterCenter PerinatalPerinatal CenterCenter
Frauenklinik rechts der Isar der Technischen Universität MünchenDirektorin Prof. Dr. Marion Kiechle
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Abstract S1-6
Results of a Randomized Phase 2 Study of PD 0332991, a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole vs ,
Letrozole Alone for First-Line Treatment of ER+ HER2– Advanced Breast Cancer (TRIO-18)ER+, HER2 Advanced Breast Cancer (TRIO 18)
RS Finn,1 JP Crown,2 I Lang,3 K Boer,4 IM Bondarenko,5 SO Kulyk,6 J Ettl,7 R Patel,8T Pinter,9 M Schmidt,10 Y Shparyk,11 AR Thummala,12 NL Voitko,13 A Breazna,14
ST Kim 15 S Randolph 15 DJ Slamon1ST Kim, S Randolph, DJ Slamon
1University of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research Group, Dublin, Ireland; 3Orszagos Onkologiai Intezet, Budapest, Hungary; 4Szent Margit Korhaz, Onkologia, Budapest, Hungary; g g p g y g g p g y
5Dnipropetrovsk City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine; 6Municipal Treatment-and-Prophylactic Institution, Donetsk, Ukraine; 7Technical University of Munich, Munich,
Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA, USA; 9Petz Aladar Megyei Oktato Korhaz, G H 10U i it H it l M i M i G 11L i St t O l i R i l T t t d Di ti
3This presentation is the intellectual property of Richard S. Finn. Contact at [email protected].
Gyor, Hungary; 10University Hospital Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV, USA; 13Kyiv City Clinical Oncology
Center, Ukraine; 14Pfizer Oncology, New York, NY, USA; 15Pfizer Oncology, La Jolla, CA, USA Presented at SABCS 2012; December 5, 2012; San Antonio, TX, USA
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Rb M t R l t f th R i tRb as Master-Regulator of the R-point
4This presentation is the intellectual property of Richard S. Finn. Contact at [email protected]. 4
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Phase 2 Design:Previously untreatedPhase 2 Design:Previously untreated for metastatic/advanced disease
Part 1
RR PD 0332991
Part 2
RRRRAANNDD
PD 0332991 125 mg QDa +
Letrozole 2.5 mg QD ER+, HER2–
RRAANNDD
PD 0332991 125 mg QDa +
Letrozole 2 5 mg QD
1:1ER+, HER2–
BC
OOMMIIZZ
g
1:1
ER , HER2BC with
CCND1 amp and/or
loss of p16
OOMMIIZZ
2.5 mg QD
ZZAATTIIOO
Letrozole 2.5 mg QD
loss of p16 ZZAATTII
Letrozole 2.5 mg QD
N = 66
OONN
N = 99
OONN
N = 66 N = 99
Stratification Factors
5This presentation is the intellectual property of Richard S. Finn. Contact at [email protected].
• Disease Site (Visceral vs Bone only vs Other)• Disease-Free Interval (>12 vs ≤12 mo from end of
adjuvant to recurrence or de novo advanced disease)a Schedule 3/1.
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Baseline Characteristics (ITT)Baseline Characteristics (ITT)PD 991 + LET
(n = 84)LET
(n = 81)
Median Age, years (range) 62 (41 – 89) 64 (38 – 84)
ECOG PS, n (%)0 46 (55) 45 (56)1 38 (45) 36 (44)
Disease StageStage IIIBStage IV
3 (4)80 (95)
6 (7)75 (93)Stage IV
Other80 (95)1 (1)
75 (93)0
Disease SiteVisceralB l
37 (44)18 (21)
43 (53)12 (15)Bone only
Other (Non-Visceral)18 (21)29 (34)
12 (15)26 (32)
Disease-Free Interval, n (%)>12 mos from adjuvant to recurrence 24 (29) 30 (37)j≤12 mos from adjuvant to recurrence
or de novo advanced disease
24 (29)60 (71)
30 (37)51 (63)
Prior Systemic Treatment, n (%)None 44 (52) 37 (46)NoneChemotherapyHormonal
TamoxifenAnastrozole
44 (52)34 (40)26 (31)23 (27)8 (10)
37 (46)37 (46)28 (35)24 (30)11 (14)
6This presentation is the intellectual property of Richard S. Finn. Contact at [email protected].
AnastrozoleLetrozoleExemestane
8 (10)2 (2)4 (5)
11 (14)1 (1)2 (2)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
B t O ll R (ITT)Best Overall Response (ITT)PD 991 + LET LETPD 991 + LET
(n = 84)LET
(n = 81)
All randomized patients, n 84 81
Objective Response Rate, % (95% CI)Complete Response, n (%)Partial Response n (%)
34 (24, 46)0
29 (34)
26 (17, 37)1 (1)
20 (25)Partial Response, n (%) 29 (34) 20 (25)
Patients with measurable disease, n (%)
Objective Response Rate, % (95% CI)
64 (76)
45 (33, 58)
65 (80)
31 (20, 43)Objective Response Rate, % (95% CI)Complete Response, n (%)Partial Response, n (%)
45 (33, 58)0
29 (45)
31 (20, 43)0
20 (31)
Stable Disease ≥24 weeks, n (%) 30 (36) 15 (18)
Clinical Benefit Rate, n (%)* 59 (70) 36 (44)
Stable Disease <24 weeks, n (%) 14 (17) 22 (27)
Progressive Disease, n (%) 3 (4) 17 (21)
7This presentation is the intellectual property of Richard S. Finn. Contact at [email protected].
Indeterminate, n (%) 8 (10) 6 (7)
* Complete response + partial response + stable disease ≥24 weeks.
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
P i F S i lProgression-Free SurvivalPD 991 + LET
( 84)LET
( 81)(n = 84) (n = 81)
Number of Events (%) 21 (25) 40 (49)
Median PFS, months(95% CI)
26.1(12.7, 26.1)
7.5(5.6, 12.6)0.9
1.0
abili
ty
(95% CI) (12.7, 26.1) (5.6, 12.6)
Hazard Ratio(95% CI)
0.37(0.21, 0.63)
P value <0.0010.7
0.8
0.9
val P
roba
0.5
0.6
e Su
rviv
0.3
0.4
ion-
Free
0.1
0.2
rogr
essi
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
0Pr
8This presentation is the intellectual property of Richard S. Finn. Contact at [email protected].
Time (Month)84 75 60 53 43 35 25 18 15 14 9 5 3 1PD991+LET81 57 38 29 22 17 11 6 5 4 3 3 1 1LET
Number of patients at risk
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Most Common AEs ≥10% (AT)Most Common AEs ≥10% (AT)PD 991 + LET
(n = 83)LET
(n = 77)(n = 83) (n = 77)Grade 1/2 Grade 3 Grade 4 Grade 1/2 Grade 3 Grade 4
Neutropenia 19 46 5 3 1 0
Leukopenia 24 14 0 1 0 0
Fatigue 29 2 2 21 1 0
Anemia 20 4 1 3 1 0
Nausea 19 2 0 10 1 0
Hot flush 19 0 0 12 0 0
Alopecia 18 0 0 3 0 0Alopecia 18 0 0 3 0 0
Arthralgia 18 0 0 14 1 0
Diarrhea 14 4 0 8 0 0
Nasopharyngitis 13 0 0 9 0 0Nasopharyngitis 13 0 0 9 0 0
Vomiting 12 1 0 3 1 0
Thrombocytopenia 11 1 0 0 0 0
Constipation 11 0 0 8 0 0
Cough 11 0 0 5 0 0
Decreased appetite 10 1 0 5 0 0
9This presentation is the intellectual property of Richard S. Finn. Contact at [email protected].
Asthenia 10 0 0 3 0 0
Bone pain 7 1 1 5 0 0
OsteoporosisOsteoporosis CenterCenter PerinatalPerinatal CenterCenter
Frauenklinik rechts der Isar der Technischen Universität MünchenDirektorin Prof. Dr. Marion Kiechle
OsteoporosisOsteoporosis CenterCenter PerinatalPerinatal CenterCenter
Frauenklinik rechts der Isar der Technischen Universität MünchenDirektorin Prof. Dr. Marion Kiechle
OsteoporosisOsteoporosis CenterCenter PerinatalPerinatal CenterCenter
Frauenklinik rechts der Isar der Technischen Universität MünchenDirektorin Prof. Dr. Marion Kiechle
OsteoporosisOsteoporosis CenterCenter PerinatalPerinatal CenterCenter
Frauenklinik rechts der Isar der Technischen Universität MünchenDirektorin Prof. Dr. Marion Kiechle
A Phase III, Open-label, Randomized, Multicenter Study Of Eribulin MesylateMulticenter Study Of Eribulin Mesylate Versus Capecitabine In Patients With
Locally Advanced Or Metastatic Breast Cancer Previously Treated WithCancer Previously Treated With
Anthracyclines And TaxanesPeter A. Kaufman,1 Ahmad Awada,2 Christopher Twelves,3
Louise Yelle,4 Edith A. Perez,5 Jantien Wanders,6Martin S Olivo 7 Yi He 7 Corina E Dutcus 7 Javier Cortes8Martin S. Olivo,7 Yi He,7 Corina E. Dutcus,7 Javier Cortes8
1Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 2Medical Oncology Clinic, Jules Bordet Institute, Brussels, Belgium; 3Leeds Institute of
Molecular Medicine and St James’s Institute of Oncology, Leeds, UK; 4Department of Medicine, University of Montreal, Montreal, Canada; 5Mayo Medical Clinic, Jacksonville, FL, USA;
6Eisai Ltd, Hatfield, UK; 7Eisai Inc., Woodcliff Lake, NJ, USA; 8Vall D’Hebron University Hospital Barcelona SpainVall D Hebron University Hospital, Barcelona, Spain
Study DesignSan Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Study Design
Global randomized open label Phase III trial (Study 301)Global, randomized, open-label Phase III trial (Study 301)
Co-primary endpointOS d PFS
Co-primary endpointOS d PFS
Patients (N=1102)L ll d d MBCPatients (N=1102)L ll d d MBC Eribulin mesylate
1.4 mg/m2† 2- to 5-min IVDay 1 & 8 q21 days
• OS and PFS
Secondary endpoints
• OS and PFS
Secondary endpoints
Locally advanced or MBC• ≤3 prior chemotherapy
regimens (≤2 for advanced disease)
Locally advanced or MBC• ≤3 prior chemotherapy
regimens (≤2 for advanced disease)
Randomization 1:1• Quality of life• ORR• Duration of response
• Quality of life• ORR• Duration of response
advanced disease)• Prior anthracycline and
taxane in (neo)adjuvant setting or for locally
advanced disease)• Prior anthracycline and
taxane in (neo)adjuvant setting or for locally
Capecitabine1250 mg/m2 BID orally
• 1-, 2- and 3-year survival• Tumor-related symptom
assessments • Safety parameters
• 1-, 2- and 3-year survival• Tumor-related symptom
assessments • Safety parameters
g yadvanced or MBC
g yadvanced or MBC
1250 mg/m BID orallyDays 1-14, q21 days
• Safety parameters • Population PK (eribulin
arm only)
• Safety parameters • Population PK (eribulin
arm only)
Stratification:G hi l i HER2 t t– Geographical region, HER2 status
†Equivalent to 1.23 mg/m2 eribulinThis presentation is the intellectual property of the author.
Patient and Disease CharacteristicsSan Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Patient and Disease CharacteristicsEribulin (n=554) Capecitabine (n=548)
M di ( ) 54 0 (24 80) 53 0 (26 80)Median age (range) 54.0 (24-80) 53.0 (26-80)ECOG performance, % 0 45 42
1 53 55
2+ 2 3Number of prior chemotherapy regimens for advanced disease, %
0 21 19
1 50 53for advanced disease, %2 28 27
>2 1 1Sites of disease†, % Visceral 84 88
Non-visceral only 15 11
HER2 status‡, % Positive 16 15
Negative 68 69g
ER status‡, % Positive 47 51
Negative 42 39
PR status‡ % Positive 41 43
ITT l ti
PR status‡, % Positive 41 43
Negative 47 45
Triple (ER/PR/HER2) negative, % 27 25
ITT population†Determined by independent assessment; missing patients for sites of disease were 1% for eribulin and 1% for capecitabine ‡Assays carried out and defined locally Unknown patients for eribulin and capecitabine were: HER2 status 17% and 16% ; ER status 11% and 10%; PR status 12% and 12%, respectively
This presentation is the intellectual property of the author.
Overall SurvivalSan Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Overall Survival
Median OS1.0
Median OS (months)
Eribulin (n=554) 15.9
bilit
y
0.8
HR† 0.879 (95% CI 0.770, 1.003)
Capecitabine (n=548) 14.5
l pro
bab
0.6HR 0.879 (95% CI 0.770, 1.003)
p value‡=0.056
Surv
iva
0.4
0.2
Time (months)0
0.056524844403632282420161284
Time (months)ITT population; †HR Cox model including geographic region and HER2 status as strata‡p value from stratified log-rank test based on clinical database
This presentation is the intellectual property of the author.
Progression-free SurvivalSan Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Investigator ReviewIndependent Review
Progression free Survival
Investigator ReviewIndependent Review
1 0 1 0
Median (months)
Eribulin (n=554) 4 1
Median (months)
E ib li ( 554) 4 21.0
0.8
ity
1.0
0.8
lity
Eribulin (n=554) 4.1
Capecitabine (n=548) 4.2
Eribulin (n=554) 4.2
Capecitabine (n=548) 4.1
HR† 0.977 (95% CI 0.857, 1.114) p value‡=0.736
HR† 1.079 (95% CI 0.932, 1.250) p value‡=0.3050.6
prob
abili
0.6
al p
roba
bi
0.4
0.2Surv
ival
0.4
0.2
Surv
iva
0.2
0.00 4 8 12 16 20 24 28 32 36 40 44 0 4 8 12 16 20 24 28 32
0.2
0.036 40 44
Time (months)Time (months)
ITT population; †HR Cox model including geographic region and HER2 status as strata‡p value from stratified log-rank test based on clinical database
This presentation is the intellectual property of the author.
Study Medication ExposureSan Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Study Medication Exposure
Eribulin Capecitabine(n=544) (n=546)
Median duration of treatment 4 1 3 9Median duration of treatment, months (range)
4.1 (0.7-45.1)
3.9 (0.7-47.4)
Median number of cycles (range)
6 (1-65)
5 (1-61)
Relative dose intensity (%) 87 86
Safety populationThis presentation is the intellectual property of the author.
Hematologic Adverse Events†
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Hematologic Adverse Events
Eribulin( 544)
Capecitabine( 546)(n=544) (n=546)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4% % % % % %
Neutropenia 54 25 21 16 4 <1Leukopenia 31 13 2 10 2 <1Anemia 19 2 0 18 <1 <1Thrombocytopenia 5 <1 0 6 <1 <1Febrile neutropenia 2 2 <1 <1 <1 <1Febrile neutropenia 2 2 <1 <1 <1 <1
S f t l tiSafety population†Incidence >10% (all grades) or 1% (Grade 3 or higher) in either armIf a subject had two or more AEs in the same system organ class or with the same preferred term with different CTCAE grades, then the event with the highest grade was used for that subject
This presentation is the intellectual property of the author.
Non-Hematologic Adverse Events†Non Hematologic Adverse Events
Eribulin CapecitabineEribulin(n=544)
Capecitabine(n=546)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4% % % % % %
Hand-foot syndrome <1 0 0 45 14 0Alopecia 35 - - 4 - -Diarrhea 14 1 0 29 5 <1Nausea 22 <1 0 24 2 0Vomiting 12 <1 <1 17 2 0F ti 17 2 0 15 2 1Fatigue 17 2 0 15 2 <1Asthenia 15 4 <1 15 4 0Decreased appetite 13 <1 0 15 2 0P i h l th 13 4 0 7 <1 0Peripheral sensory neuropathy 13 4 0 7 <1 0Pyrexia 13 <1 0 6 <1 0Headache 13 <1 0 10 <1 <1Dyspnea 10 2 <1‡ 11 3 <1‡
S f l i
Dyspnea 10 2 <1‡ 11 3 <1‡
Back pain 10 2 0 8 <1 0
Safety population†Incidence >10% (all grades) or 1% (Grade 3 or higher) in either arm; ‡Grade 5 events also occurred in 0.7% and 0.5% of patients, respectivelyIf a subject had two or more AEs in the same system organ class or with the same preferred term with different CTCAE grades, then the event with the highest grade was used for that subject
This presentation is the intellectual property of the author.
Overall Survival By Receptor StatusSan Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012
Subgroup HR (95% CI) Eribulin CapecitabineMedian (months)
Overall Survival By Receptor Status
Overall 0.879 (0.770, 1.003) 15.9 14.5
HER2 status
Median (months)
Positive 0.965 (0.688, 1.355) 14.3 17.1
Negative 0 838 (0 715 0 983) 15 9 13 5n=755Negative 0.838 (0.715, 0.983) 15.9 13.5
ER status
n=755
Positive 0.897 (0.737, 1.093) 18.2 16.8
Negative 0.779 (0.635, 0.955) 14.4 10.5n=449
Triple negative
Yes 0.702 (0.545, 0.906) 14.4 9.4n=284
No 0.927 (0.795, 1.081) 17.5 16.6
ITT population
0.2 0.5 1.0 2 5Favors eribulin Favors capecitabine
This presentation is the intellectual property of the author.
Was Bleibt?
• CDK4/6- Inhibition: Phase III hoffentlich erfolgreich
• Pertuzumab: neuer Standard in der firstlineHer2pos
• Eribulin: Alternative in der 2nd/3rd line, insbesondere TNBC