Everolimus más exemestano en pacientes con cáncer de mama avanzado RE+HER2-: Estudio BALLET E....

Everolimus más exemestano en pacientes con cáncer de mama avanzado RE+HER2-:

Estudio BALLET

E. CiruelosServicio Oncología Médica

Hospital 12 de OctubreMadrid

XVII Simposio de Revisiones en CáncerMadrid, 11 a 13 de Febrero de 2015

PFS Based on Local Assessment at 18-mo Follow-up in BOLERO-2 Confirms Earlier Reports

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.Yardley DA, et al. Adv Ther. 2013;30:870-884.

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Time (months)

121086420

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146

485

239

EVE+EXE

PBO+EXE

No. at risk

HR = 0.45 (95% CI, 0.38-0.54)Log-rank P < .0001

Kaplan-Meier mediansEVE+EXE: 7.8 monthsPBO+EXE: 3.2 months

Censoring timesEVE+EXE (n/N = 310/485)PBO+EXE (n/N = 200/239)

Jerusalem G. P5-19-02. SABCS 2014

Overview

• Study Design• Baseline

– Patient Characteristics

– Prior Treatment and Experimental Treatment Disposition

• Safety Profile – AEs Description and Stomatitis and Non-infectious Pneumonitis (NIP)

Time–course

– Treatment Exposure: Discontinuation and Dose Changes

• Subsequent Treatment• BRAWO trial

Overview





Time–course


• Subsequent Treatment

Study Design (BOLERO-2-like)

Patient population• Postmenopausal women • HR+, HER2– unresectable

locally advanced or metastatic BC

• Recurrence or progression after NSAI

Treatment continues until: • Disease progression• Unacceptable toxicity• Death• Discontinuation from the study

for any other reason• Drug locally reimbursed or LPLV

TREATMENT PHASEEverolimus (RAD001) 10 mg/day

+ Exemestane 25 mg/day

Primary objective• To evaluate the safety of everolimus (RAD001) in postmenopausal women with hormone receptor-positive locally

advanced or metastatic breast cancer after recurrence or progression following NSAIs treatment

Secondary objective• To evaluate adverse events grade 3 and 4 in the routine practice

Study Design (diferences with Bolero 2)

Patient population• Postmenopausal women • HR+, HER2– unresectable

locally advanced or metastatic BC

• Recurrence or progression after NSAI

Treatment continues until: • Disease progression• Unacceptable toxicity• Death• Discontinuation from the study

for any other reason• Drug locally reimbursed or LPLV

TREATMENT PHASEEverolimus (RAD001) 10 mg/day

+ Exemestane 25 mg/day

Primary objective• To evaluate the safety of everolimus (RAD001) in postmenopausal women with hormone receptor-positive locally

advanced or metastatic breast cancer after recurrence or progression following NSAIs treatment

Secondary objective• To evaluate adverse events grade 3 and 4 in the routine practice

Any prior CT linesPrior exemestane permited

Recruitment and Key DatesN

umbe

r of p

atie

nts

trea

ted

Austria

Belgium

Bulgaria

Finland

Denmark

HungaryIta

ly

Netherla

nds

Norway

Poland

Romania

SlovakiaSpain

Sweden0

200

400

600

800

1000

1200

1400

4

237

35 10 867

1154

7120 47 26 20

429

6

14 countries, 317 sites

2134 treated patients

Key dates:

Actual FPFV: 16 May 2012 LPLV: 1 Sep 2014

Planned DBLock: 1 Dec 2014

Ad Hoc Analysis - Method

• The population includes those patients enrolled up to Oct 1st 2013 (considering 1st RAD intake) and all visits occurred by Oct 6th 2014

All screened patients Full analysis set* Safety population**

2067 2066 2064

* The full analysis set (FAS) consists of all enrolled patients who received at least one dose of everolimus (RAD001) and exemestane.**The safety analysis set (SAS) includes all patients who received at least one dose of study treatment and had at least one post-baseline safety assessment.

Overview





Time–course



Patient Characteristics Patients(N = 2066)

Age, median (min–max), y 63.0 (28–90)

<65 y; n (%) 1133 (54.8) 65–70 y; n (%) 380 (18.4)≥ 70 y; n (%) 553 (26.8)

Body mass index at baselineNBMI, median (min–max)

189925.7 (14.7–54.6)

Body mass index at EOT*NBMI, median (min–max)

145724.8 (14.9–51.7)

ECOG Performance Status; n (%) Patients(N = 2066)

0 1348 (65.2)1 640 (31.0)2 55 (2.7)Missing* 23 (1.1)

EOT, end of trial.*based on all screened patients (N=2067).

Patient Characteristics

Disease status at study entry, n (%) Patients(N = 2064)

Metastatic (stage IV) 1703 (82.5)

Locally advanced 358 (17.3)Missing 3 (0.1)

Time from first diagnosis, n (%) Patients(N = 2039)

Median (min, max); years 8.02 (0.21, 44.4)

Number of metastatic sites, n (%) Patients(N = 2064)

1 424 (20.5)

2 486 (23.5)

3 421 (20.4)

4 274 (13.3)

≥5 456 (22.1)

Patient Characteristics

Metastasis Patients, n (%) (n = 2064)

Visceral* 1231 (59.6)Visceral and bone 896 (43.4)Visceral only 196 (9.5)

Bone only 524 (25.4)Others** 750 (36.3)

Metastasis location Patients, n (%)(n = 2064)

Lung 581 (28.1)Bone 1594 (77.2)Liver 755 (36.6)CNS 57 (2.8)Lymph nodes 602 (29.2)Other localization 705 (34.2)Missing 3 (0.1)

Patient Characteristics (similar to Bolero 2)

Most Frequent Comorbidities at BaselineComorbidity; n (%) N = 2064Overall 1557 (75.4)Cardiovascular disorders 906 (43.9)

Hypertension 710 (34.4)Lymphoedema 31 (1.5)Atrial fibrillation 23 (1.1)

Metabolism and nutrition disorders 645 (31.3)Dyslipidemia 482 (23.4)Diabetes mellitus 189 (9.2)

Psychiatric disorders 396 (19.2)Depression 170 (8.2)Anxiety 152 (7.4)Sleep disorder 124 (6.0)

Gastrointestinal disorders 252 (12.2)Bone pain 188 (9.1)Hypothyroidism 144 (7.0)Osteoporosis 143 (6.9)Dyspnea 57 (2.8)Fatigue 52 (2.5)Asthenia 51 (2.5)

Most Frequent Concomitant Therapies

Concomitant therapy; n (%) N = 2064Overall 309 (15.0)

Bisphosphonates 188 (9.1%)Glucocorticoids 19 (0.9%)

Proton pump inhibitors 8 (0.4%)Benzodiazepines 7 (0.3%)Gonadotropin releasing hormone analogues 6 ( 0.3%)Heparin group (LMWH) 6 ( 0.3%)

LMWH, low molecular weight heparin.

Patients without chemo in mBC; %

Patients with ≥1 chemo in mBC; %

BALLET 39.9 60.1

BOLERO 2 74 26

Type of Prior Antineoplastic Therapy – Overall

Type of Prior Antineoplastic Therapy – OverallPrior antineoplastic therapy; n (%)

Overall (%) BALLET (N = 2064)

Bolero 2 (EE arm)

AntiestrogensFulvestrantTamoxifen

1528 (74.0)868 (42.1)

1296 (62.8)17%47%

Aromatase inhibitorsExemestane

2050 (99.3)510 (24.7)

100%0

Taxanes 1184 (57.4)

Pyrimidine analoguesFluorouracilCapecitabine

1357 (65.7)1024 (49.6)692 (33.5)

Anthracyclines 1415 (68.6)Cyclophosphamide 1438 (69.7)Vinorelbine 515 (25.0)Platinum compounds 145 (7.0)Bevacizumab 228 (11.0)

Data are based on the Safety Analysis Set (SAS). N = 2064. Chemo, chemotherapy; mBC, metastatic breast cancer.

Line of Treatment with Everolimus + Exemestane

Missing

≥4th line

3rd line

2nd line

1st line

0 100 200 300 400 500 600 700 800 900 1000

Number of patients

212 (10.3%)

489 (23.7%)

469 (22.7 %)

887 (43.4%)

7 (0.3%)

BOLERO-2: 282 (39%)

BOLERO-2: 306 (42%)

BOLERO-2: 137 (19%)

Line of Treatment with Everolimus + Exemestane

Missing

≥4th line

3rd line

2nd line

1st line

0 100 200 300 400 500 600 700 800 900 1000

Number of patients

212 (10.3%)

489 (23.7%)

469 (22.7 %)

887 (43.4%)

7 (0.3%)

BOLERO-2: 282 (39%)

BOLERO-2: 306 (42%)

BOLERO-2: 137 (19%)

Patients in the BALLET trial were more pre-treated (66% of BALLET patients in ≥ 3rd line vs 39 % of patients in BOLERO-2)

Patients with Prior Non-steroidal Aromatase Inhibitors as

last treatment

0%

10%

20%

30%

40%

50%

60%

70%

80%

0.371

74.0%

BALLETBOLERO-2

Pati

ents

wit

h pr

ior

NSA

I as

last

trea

tmen

t (%

)

Chemo, chemotherapy; EVE, everolimus; EXE, exemestane, NSAI, non-steroidal aromatase inhibitor; HT; hormone therapy; TAM, tamoxifen.

Details on Prior Treatment by Lines (Until 3rd Line)

• Chemo NSAI (61%)• Chemo TAM NSAI

(22%)• NSAI only

(16%)

Adjuvant

Patients receive EVE + EXE in

1st line (n = 212, 10,3%)

• Chemo (31%)• HT only (64%)

1st line • Chemo NSAI

(14%)• Chemo TAMNSAI (19%)• NSAI only (7%)• No adjuvant setting

(22%)

Adjuvant

Patients receive EVE + EXE in

2nd line (n = 489, 23,7%)

• Chemo (35%)• HT only (59%)

1st line

• Chemo NSAI (9%)• Chemo NSAI TAM (11%)• NSAI only (6%)• No adjuvant setting

(30%)

• Chemo (31%)• HT only (64%)

Adjuvant 2nd linePatients receive

EVE + EXE in 3rd line

(n = 469, 22,7%)

Overview





Time–course



Safety Profile – Adverse Events

≥1 pneumonitis related to everolimus

≥1 stomatitis related to everolimus

≥1 AE related to everolimus

≥1 AE regardless of everolimus relationship

0 500 1000 1500 2000 2500

Number of patients

182 (8.8%)

Overall(N = 2064)

1st line (n = 212)

≥2nd line(n = 1845)

BOLERO-2(n = 720)1

≥1 AE, % 94.7 95.3 94.6 100

≥1 AE EVE-related, % 86.2 85.4 86.3 –

≥1 stomatitis, % 51.2 45.8 51.9 67

≥1 pneumonitis, % 8.8 7.5 9.0 20

1955 (94.7%)

1779 (86.2%)

1057 (51.2%)

AE, adverse event; EVE, everolimus1. Rugo et al. Ann Oncol 2014; 25:808–15.

Most Frequent Drug-Related AEs – Overall vs First Line

StomatitisRash

Asthenia

Decreased appetite

Diarrhea

Fatigue0

10

20

30

40

50

6051.2

15 14.810.8 10.6 10.4

45.8

12.3 10.85.2

9 9

Overall (N = 2064) 1st line (n = 212)

Patie

nts

(%)

Treatment-emergent AEs related to everolimus are shown (>10% in overall SAS population).AE, adverse event.1. Rugo et al. Ann Oncol 2014; 25:808–15.

This is comparable with the AEs in the everolimus + exemestane arm in BOLERO-2 (stomatitis, rash, fatigue, diarrhea and decreased appetite)1

Most Frequent Drug-related AEs – G3/G4

Stomatitis

Asthenia

Hyperglycaemia

PneumonitisFatigue

Rash0

1

2

3

4

5

6

7

8

9

10 9.5

2.5

3.9

1.81.1 0.9

8.5

2.81.9

1.4

2.4

0.5

Overall (N = 2064) 1st line (n = 212)

Patie

nts

(%)

G3/G4 drug-related AEs, % patients ,

Overall (N = 2064) 30.2

1st line (n = 212) 25

AE, adverse event; G3/G4, Grade 3/Grade 4.1. Rugo et al. Ann Oncol 2014; 25:808–15.

Bolero 2: 8%Bolero 2: 6%

Bolero 2: 4%Bolero 2: 4%

Bolero 2: 1%

Bolero 2: 53%

Stomatitis: Time to Onset

BALLETMost events occurred within the first 4 weeks of treatment

with no major differences among grades

BOLERO-2>1/3 of stomatitis events

(≥Grade 2) occurred in the first 2 weeks of treatment

All-grade

Grade 1

Grade 2

Grade 3

Grade 4

Pneumonitis: Time to Onset

BALLETMost events occurred within first 3 months of treatment, with no major differences

among grades

BOLERO-2~25% of pneumonitis events

(≥Grade 2) occurred in the first 12 weeks

of treatment

All-grade

Grade 1Grade 2

Grade 3Grade 4

Overview





Time–course



Median Duration of TreatmentTreatment lines N

Median treatment duration; days (weeks)Everolimus Exemestane

Overall 2064 111 (15.8) 115 (16.4)1st line 212 127 (18.1) 140 (20.0)≥ 2nd line 1852 110 (15.7) 117 (16.7)No stomatitis 964 97 (13.8) 103 (14.7)At least 1

stomatitis1100 123 (17.5) 132 (18.8)

FUP, follow up.The duration of treatment is defined as the difference between last dosing date and first dosing date (includes the periods of temporary interruption).1. Piccart M, et al. SABCS 2012, poster P6-04-02; 2. Yardley DA, et al. Adv Ther. 2013;30:870-884.

Duration of exposure; weeks

BOLERO -2Everolimus

BOLERO -2Exemestane

Median (range)1,2 23.9 (1.0 – 123.3) 29.5 (1.0 – 123.3)

Disease progression

EVE reimbursed

Adverse eventSubject withdrew

consentProtocol violation

Death

Other*

0 100 200 300 400 500 600 700 800

Number of patients

Discontinued Patients and Reasons for Discontinuation

*Reasons include: natural end, subject’s condition no longer requires study drug, loss to follow up, abnormal laboratory values, unsatisfactory therapeutic effect, administrative problems, abnormal test procedure result, among others.

(1.7%)

(3.4%)

(1.4%)

(6.4%)

(36.3%)

(34.5%)

(16.2%)BOLERO-2:

9.1%

Most Frequent AEs Leading to Permanent Discontinuation

AE

EVE (N = 2064) BOLERO-2 (EVE + EXE; n = 482)1

All Grades; n (%)

Grade 3/4; n (%)

All Grades, % Grade 3/4, %

Overall 605 (29.3) 286 (13.9) 26 –

Pneumonitis* 64 (3.1) 19 (0.9) 5.6 1.9

Oral mucositis/stomatitis

41 (2.0) 21 (1.0) 2.7 0.8

Asthenia 34 (1.6) 18 (0.9) 0.8 0.4

Dyspnea 26 (1.3) 12 (0.6) 2.3 1.5

Anemia 17 (0.8) 9 (0.4) – –

Pyrexia/fever 17 (0.8) 3 (0.1) – –

Vomiting 16 (0.8) 8 (0.4) – –

Hyperglycemia 15 (0.7) 8 (0.4) 0.2 0.2

Diarrhea 13 (0.6) 6 (0.3) – –

Nausea 12 (0.6) 3 (0.1) – –

Reason for Discontinuation per Month of Treatment

First intake <= 1 month 2–3 months 4–6 months 7–9 months >10 months0

50

100

150

200

250

300

AEPD

Months of treatment

Nu

mb

er

of p

atie

nts

Close follow up during the first months of treatment should lead to early identification of AEs

Dose Changes EVE dose reduction and interruption N = 2064 (%) BOLERO-2

(n = 482)1,2

Duration of treatment at 10 mg; median, days 83 –

Dose change; % 59.6 62.41a

AEs as reason for change; % 56 62.42

Stomatitis; % 39.3 23.71,2

Pneumonitis; % 8.6 7.51,2

Dose interruption; % 56.2 66.21b

Duration of dose interruption; median, days 17.5 71

Median time to first dose modification; days (range) 32 (1- 441) –

Analyses performed on the SAS output. The BOLERO-2 results shown are from the EVE + EXE arm of the study (n = 482).a301 out of 482 patients in the EVE + EXE arm of BOLERO-2 required dose interruptions or reductions (1065 events).b750 events out of 1065 events of EVE dose interruption/reduction.

AE, adverse event; EVE, everolimus; EXE, exemestane.1. Rugo H.S et al. Annals Oncol 2014; 25: 808–815.2. Yardley D.A. et al. Adv Ther. 2013; 30:870–84.

Relative Dose Intensity

Everolimus relative dose intensity

BALLET (no stomatitis)

(n = 964)

BALLET (stomatitis)(n = 1100)

BALLET(overall)

(N = 2064)

BOLERO-21

Relative dose intensitya

Mean SD Median Range

0.910.1591.00

0.1 – 1.0

0.830.1890.92

0.3 – 1.1

0.870.1800.98

0.1 – 1.1

0.760.2540.87

0.0 – 1.0

Relative dose intensity, n (%)a,b

0.00 – < 0.60 0.60 – < 0.80 0.80 – < 0.90 ≥ 0.90

87 (9.0)104 (10.8)

78 (8.1)693 (71.9)

202 (18.4)201 (18.3)122 (11.1)575 (52.3)

289 (14.0)305 (14.8)200 (9.7)

1268 (61.4)

87 (18.0)82 (17.0)91 (18.9)

222 (46.1)

SD, standard deviation.aRelative dose intensity = dose intensity/planned dose intensity.bDose intensity thresholds for BOLERO-2 are 0 - < 0.50, 0.50 - < 0.70, 0.70 - < 0.90, ≥ 0.90. 1. Rugo H, et al. IMPAKT 2012 Breast Cancer Conference. Abstract 288.

Overview





Time–course



n (%) BALLET (n = 2064)

BOLERO-2 (n = 485)

Hormonal therapy 851 (41.2) 228 (47)Chemotherapy 645 (31.2) 257 (53)

Antineoplastic Therapy Following Study Treatment Discontinuation

Antineoplastic Therapy Following Study Treatment Discontinuation

Antineoplastic therapy; n (%) N = 2064Overall 1436 (69.6)Aromatase inhibitors

Exemestane LetrozolecAnastrozole

711 (34.4)693 (33.6)

11 (0.5)10 (0.5)

Selective immunosuppressantsEverolimus

568 (27.5)567 (27.5)

Pyrimidine analoguesCapecitabine

238 (11.5)166 (8.0)

TaxanesPaclitaxel Docetaxel

178 (8.6)119 (5.8)22 (1.1)

Anti-estrogensFulvestrant Tamoxifen

140 (6.8)121 (5.9)

8 (0.4)Anthracyclines

Doxorubicin122 (5.9)15 (0.7)

VincalkyloidsVinorelbine

107 (5.2)68 (3.3)

Breast cancer treatment with everolimus and exemestane for ER+ women results of the 2nd interim

analysis of non-interventional trial, BRAWO

Peter A. Fasching, Thomas Decker, Andreas Schneeweis, Christoph Uleer, Frank Förster, Pauline Wimberger, Christian Kurbacher, Nadia Harbeck, Oliver Tomé, Bettina Müller, Christoph Mundhenke, Sherko Kümmel, Mathias Muth, Julia Kreuzeder, Wilhelm Bloch, Hans Tesch, Diana Lüftner, Christian Jackish, Florian Schütz, Eva-Maria Grischke.

Poster presented at ESMO 2014. Abstract LBA9.

BRAWO

Mediana PFS 8 meses

Conclusions (I)

• Compared with BOLERO-2, patients in the BALLET trial were predominantly treated in later lines ( ≥3rd), with a higher proportion of patients pre-treated with chemotherapy – Overall, duration of therapy in BALLET was slightly shorter than that in

BOLERO-2

• The combination of everolimus and exemestane in the real world setting has a manageable and tolerable safety profile: – No new safety concerns were identified– Everolimus + exemestane resulted in fewer G3/G4 AEs as first-line

treatment compared with overall study population– Early assessment of toxicity (3 months)

Conclusions(II)

• BRAWO expanded access: 1st and 2nd – line patients

• Confirms:- patients´ characteristics- median dose intensity and dose reductions- overall better toxicity profile than Bolero 2- better tolerability if 1st line

Conclusions(III)

• BALLET Efficacy data to be presented in 2015 (ESMO?)

• Planned efficacy sub-analysis: - nº of prior CT lines- elderly (> 70y)- obesity- diabetes- prior fulvestrant / exemestane- bone only / visceral only- efficacy and toxicity correlation- …

Everolimus más exemestano en pacientes con cáncer de mama avanzado RE+HER2-: Estudio BALLET E....

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