MBCA: Neues aus San Antonio - tumorzentrum-muenchen.de€¦ · MBCA: Neues aus San Antonio...

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



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


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


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


• 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.


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)


AnastrozoleLetrozoleExemestane

8 (10)2 (2)4 (5)

11 (14)1 (1)2 (2)


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)


Indeterminate, n (%) 8 (10) 6 (7)

* Complete response + partial response + stable disease ≥24 weeks.


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


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


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


Asthenia 10 0 0 3 0 0

Bone pain 7 1 1 5 0 0

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


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





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


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


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


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


Was Bleibt?

• CDK4/6- Inhibition: Phase III hoffentlich erfolgreich

• Pertuzumab: neuer Standard in der firstlineHer2pos

• Eribulin: Alternative in der 2nd/3rd line, insbesondere TNBC

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