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BREAK-3: A Phase III randomized, open-label study comparing dabrafenib to DTIC in previously untreated subjects with BRAF mutated metastatic (Stage III/IV) melanoma A. Hauschild,1 J-J. Grob,2 L.V. Demidov,3 T. Jouary,4 R. Gutzmer,5 M. Millward,6 P. Rutkowski,7 C.U. Blank,8 B. Mirakhur,9 M. Guckert,9 S. Swann,9 P. Haney,9 A-M. Martin, 9 D. Ouellet,9 K. Grotzinger,9 V. Goodman,9 P.B. Chapman10 on behalf of the entire BREAK-3 trial Group University Hospital, Schleswig-Holstein, Dep. of Dermatology, Kiel, Germany Aix-Marseille University, APHM, Hopital Timone, Marseille, France 3 N.N.Blokhin Russian Cancer Research Center, Moscow, Russia 4 Skin Cancer Unit, Dermatology Department, Hôpital Saint André, Bordeaux, France 5 Department of Dermatology and Allergy, Skin Cancer Center, Hannover Medical School, Germany 6 Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia 7 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 8 Division of Medical Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital (NKI–AVL), Amsterdam, The Netherlands 9 GSK, Oncology, Philadelphia, PA, USA 10Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 1 2


Disclosures •  A. Hauschild: Received grant from GSK compensated consultant/ advisor to GSK and Roche, travel grants from GSK and Roche •  P.B. Chapman: Compensated consultant to GSK and Genentech •  J-J. Grob, M. Millward, C.U. Blank : Compensated consultant to GSK •  L.V. Demidov: Compensated consultant to, and support for travel from, GSK •  T. Jouary: Support for travel from GSK •  R. Gutzmer: Received grants and travel grants from Roche, is a compensated consultant/advisor/lecturer to GSK and Roche •  P. Rutkowski: No disclosures •  B. Mirakhur, M. Guckert, S. Swann, P. Haney, A-M. Martin, D. Ouellet, K. Grotzinger, V. Goodman: Employees of GSK; stock ownership-GSK


Background •  Dacarbazine (DTIC) was the reference drug for randomized clinical trials although it never demonstrated overall survival benefits (response rates: 5–15%; PFS: 1.5–3 months; OS: 6–11 months) •  Emerging and newly approved treatments in 2011/2012 •  Overall survival benefits in Phase III trials for: –  ipilimumab –  vemurafenib (in BRAFV600E mutated patients)

F S Hodi et al. NEJM 2010; P B Chapman et al. NEJM 2011; C Robert et al, NEJM 2011


BREAK-2 on dabrafenib (Phase II trial) Maximum percent change in baseline target lesions

Investigator-assessed maximum change in target lesions: V600E population

•  Confirmed response rate, 59% (95% CI: 48.2%, 70.3%) •  Median PFS, 6.3 months Trefzer et al, presented at SMR 2011


BREAK-3: A Global Study

Enrollment per country Germany France USA Italy Spain Canada Poland Russia Australia The Netherlands Ireland Hungary

57 36 32 22 21 18 17 17 16 8 4 2


BREAK-3: study design •  Primary endpoint: Investigator-assessed PFS •  > 95% power to detect HR of 0.33 Screened N=733

Dabrafenib 150 mg twice daily n=187

3:1 randomization Enrolled n=250

Stratification factors: unresectable stage III, stage IV; M1a+M1b vs M1c

DTIC 1000 mg/m2 IV every 3 weeks n=63 • 

Cross-over allowed at radiologic PD

Dabrafenib 150 mg twice daily n=28 (68% of PD patients)

Secondary objectives: OS, ORR in both groups and after cross-over, PFS2 (after cross-over), duration of response, safety/tolerability and BRAF mutation assay validation


Key eligibility criteria •  Unresectable stage III/IV metastatic melanoma •  Treatment-naïve (except for IL-2, surgery, radiotherapy) •  ECOG performance status: of 0–1 •  CNS metastases stable for >3 months after surgery or stereotactic radiosurgery •  BRAFV600E mutation detected by allele-specific PCR assay •  No other serious underlying diseases


Demographic and clinical baseline characteristics Dabrafenib n=187 (%)

DTIC n=63 (%)

53

50

Female

75 (40%)

26 (41%)

ECOG = 0 ECOG ≥1 Unknown

124 (66%) 62 (33%) 1 (<1%)

44 (70%) 16 (25%) 3 (5%)

Stage III, Stage IV (M1a + M1b) Stage IV (M1c)

63 (34%) 124 (66%)

23 (37%) 40 (63%)

≤ULN LDH >ULN LDH Unknown

119 (64%) 67 (36%) 1 (<1%)

43 (68%) 19 (30%) 1 (2%)

Age, median (years)


Primary endpoint: PFS Proportion Alive Without Progression

Investigator-assessed (cut-off: 19 December 2011) Hazard ratio 0.30 (95% CI: 0.18, 0.51); p<0.0001

1.0 0.9 0.8

Dabrafenib: median PFS 5.1 mos

0.7 0.6 0.5 0.4

DTIC: median PFS 2.7 mos

0.3 0.2 0.1 0.0 0

1

2

3

4

5

6

7

8

9

31 4

5 2

3 0

0 0

Time from Randomization (Months) Number at risk 187 63

184 53

173 31

113 14

100 11

41 6

On randomized study treatment at cut-off: dabrafenib 57%, DTIC 27% Median follow-up time: 4.9 months (dabrafenib 5.1 mos, DTIC 4.8 mos.)


PFS: Independent reviewer-assessed Proportion Alive Without Progression

(cut-off: 19 December 2011)

Hazard ratio 0.35 (95% CI 0.20, 0.61)

1.0 0.9 0.8

Dabrafenib: median PFS 6.7 mos

0.7 0.6 0.5

DTIC: median PFS 2.9 mos

0.4 0.3 0.2 0.1 0.0 0

1

2

3

4

5

6

7

8

9

28 4

7 2

4 0

0 0

Time from Randomization (Months) Number at risk 187 63

182 53

167 32

112 16

98 12

39 5


Hazard ratios for PFS by subgroups Investigator-assessed ECOG status 0

Hazard ratio (95% Cl)

No. of patients 168

0.27 (0.14, 0.51)

≥1 LDH levels

78

0.38 (0.15, 0.93)

≤ ULN

156

0.23 (0.12 0.47)

> ULN

83

0.36 (0.15, 0.86)

<65 years

197

0.31 (0.18, 0.55)

≥65 years Gender

53

0.34 (0.10, 1.14)

101

0.29 (0.13, 0.67)

149

0.30 (0.15, 0.58)

86

0.26 (0.10, 0.68)

164

0.32 (0.17 0.60)

250

0.30 (0.18, 0.51)

Age

Female Male Disease stage III, IV (M1a+ M1b) IV (M1c) All patients (Primary analysis)

0.1

0.5 Dabrafenib better

1

1.2 DTIC better


Best confirmed response Investigator-assessed Dabrafenib CR

6 (3%)

PR

ORR (CR + PR)

DTIC

Independent review Dabrafenib

DTIC

0

6 (3%)

1 (2%)

93 (50%)

12 (19%)

87 (47%)

3 (5%)

99 (53%)

12 (19%)

93 (50%)

4 (6%)


Maximum percent change in baseline target lesions

Dabrafenib: Maximum tumor percent change from baseline investigator-assessed


Maximum percent change in baseline target lesions

DTIC: Maximum tumor percent change from baseline investigator-assessed


Treatment-related AEs: ≥ 5% of patients Dabrafenib, n (%) AE

Skin

GI

Hematologic

Other

All

DTIC, n (%)

Grade 3

Grade 4

All

Grade 3

Grade 4

Hyperkeratosis

95 (51)

1 (<1)

1 (<1)

Palmar-plantar hyperkeratosis

39 (21)

4 (2)

1 (2)

SCC/KA

13 (7)

9 (5)

Nausea

18 (10)

21 (36)

Vomiting

8 (4)

12 (20)

Neutropenia

2 (1)

1 (<1)

9 (15)

3 (5)

4 (7)

Thrombocytopenia

1 (<1)

1 (<1)

5 (8)

1 (2)

2 (3)

Leukopenia

1 (<1)

3 (5)

1 (2)

Arthralgia

30 (16)

1 (<1)

Fatigue

32 (17)

2 (1)

13 (22)

Headache

32 (17)

2 (3)

Pyrexia

28 (15)

5 (3)

Asthenia

26 (14)

7 (12)

Photosensitivity: dabrafenib (3%), DTIC (5%)


Safety: Serious AEs occurring in >1 patient Serious Adverse Event Any event

Dabrafenib n=187 (%) 43 (23%)

DTIC n=59 (%) 13 (22%)

Squamous cell carcinoma (SCC)

9 (5%)

0

Pyrexia

7 (4%)

0

New primary melanoma

3 (2%)

0

Vomiting

2 (1%)

1 (2%)

Atrial fibrillation

2 (1%)

0

Ejection fraction decreased

2 (1%)

0

Hypotension

2 (1%)

0

Anemia

1 (<1%)

1 (2%)

Constipation

1 (<1%)

1 (2%)

0

2 (3%)

Abdominal pain


Dose modifications due to AEs

Treatment modification Treatment discontinuation

Dabrafenib n=187 (%)

DTIC n=59 (%)

5 (3%)

2 (3%)

Dose reduction

34 (18%)

10 (17%)

Dose interruption/delay

51 (27%)

16 (27%)


Conclusions •  BREAK-3 showed a 70% decrease in the risk of progression or death compared with DTIC in BRAF-mutated melanoma •  Dabrafenib induced significant anti-tumor response in 53% (INV) and 50% (IRC) of patients, respectively •  Few serious AEs and treatment-related discontinuations (3%) with dabrafenib and DTIC •  SCC/KA were seen in 7% and photosensitivity in 3% of dabrafenib-treated patients •  Next steps: BRAF/MEKi (dabrafenib/trametinib) combination studies for stage IV and in the adjuvant setting –  Phase I/II update by Weber et al, CSE Mutated Melanoma June 4th, 3:30pm


Thanks to the GSK team, additional investigators, patients and their families!!! Australia M.P. Brown, A. Hill, R. Kefford. Canada S. Ellard, D. Hogg, W. Miller, T. Petrella, M.G.B. Smylie. France M.-F. Avril, F. Grange, J.-P. Lacour, E. Maubec, L. Mortier, C. Robert. Germany C. Bayerl, T. Bieber, E. Dippel, H. Gollnick, C. Hafner, J. Hassel, R. Herbst, M. Huber, M. Kaatz, E. Kaempgen, C. Loquai, C. Mauch, J. Norgauer, A. Roesch, R. Rompel, D. Schadendorf, E. Schultz, J. Thomalla, A. Tsianakas.

The Netherlands J.B.A.G. Haanen Poland B. Karaszewska, P. Kurczab, Z. Stojcev, M. Ziobro. Russia A.M. Karachun, N.V. Kovalenko, E.V. Levchenko, G.M. Manikhas, G.Z. Mukhametshina, M.V. Shomova.

Hungary Z. Battyáni, G. Liszkay, T. Pintér, É. Remenyik, Á. Wéber.

Spain S. M. Algarra, A. Arance ,Fernández, E. Calvo Aller, J.L. Gonzalez Larriba, P. Lopez Criado, J.A. López Martín, J.L. Manzano Mozo, I. Márquez Rodas, E. Muñoz Couselo, M. Ochoa de Olza Amat, P. Sancho Márquez, A. Soria Rivas.

Ireland O. Breathnach, J.P. Crown, D. Gallagher, J. McCaffrey, K.J. O Byrne, P. Donnellan, H.P. Redmond.

United States B. Chmielowski, R.M. Conry, G.A. Daniels, M. Ernstoff, L. Fehrenbacher, B. Heller, C.D. Lao, D.R. Minor, G.K. Pennock, T.F. Logan.

Italy V. Chiarion-Sileni, P.F Conte, V. Ferraresi, M. Maio, P. Marchetti, A. Minisini, P. Queirolo, F. Roila, A. Santoro.

GSK BREAK-3 study team M. Mattox, J. Van Buskirk , S. Lane, D. Foose, N. Hyland.

Funding for this study NCT01227889 (BRF113683) was provided by GlaxoSmithKline

BREAK-3  

cancer, tratamiento para el cancer

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