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Investor science conference call from
ESMO 2012
Vienna, 2 October 2012
2
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results to differ materially in the future from those reflected in forward-looking statements
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9 litigation;
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to mean that Roche’s earnings or earnings per share for this year or any subsequent period will
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Introduction
Dr. Karl Mahler, Head of Investor Relations, Roche
4
Key assets / newsflow Event
Date /
location
4 June 2012
Chicago, USA
ASCO (American Society of Clinical
Oncology)
T-DM1: EMILIA pretreated HER2+ mBC
Avastin: TML treatment through multiple
lines in mCRC, AURELIA platinum resistant
ovarian cancer
Actemra: ADACTA RA monotherapy head to
head versus adalimumab
8 June 2012
Berlin, Germany
EULAR (Annual European Congress of
Rheumatology )
4/5 September 2012
London, GB
Investor Day R&D strategy and pipeline
Growth opportunities
Innovation and efficiency
2 October 2012
Vienna, Austria
ESMO (European Society for Medical
Oncology)
Herceptin: HERA HER2+ early BC final
analysis; T-DM1: EMILIA pretreated HER2+
mBC updated OS data; Zelboraf early data
from MEK combo and brain mets study
Investor events 2012
R&D and strategy updates
Phase II
(23 NMEs)
Phase III
(9 NMEs)
Registration
(2 NMEs)
Oncology
Immunology
Virology
Perjeta (pertuzumab)* HER2+ mBC 1L
Erivedge* advanced BCC
mericitabine HCV
rontalizumab SLE
danoprevir HCV
mGluR5 antag TRD
LT alpha MAb RA
P selectin MAb ACS/CVD
M1 prime MAb asthma
11 beta HSD inh metabolic diseases
etrolizumab ulcerative colitis
anti-factor D Fab geograph. atrophy
EGFL7 MAb solid tumors
crenezumab Alzheimer‘s
gantenerumab Alzheimer’s
MAO-B inh Alzheimer’s
EGFR MAb solid tumors
mGluR2 antag depression
PI3K/mTOR inh solid & hem tumors
setrobuvir HCV
PI3K inh solid tumors
glypican-3 MAb liver cancer
HER3/EGFR m. epithelial tumors
onartuzumab (MetMAb) solid tumors
bitopertin schizophrenia
aleglitazar CV risk reduction in T2D
obinutuzumab (GA101) hem. tumors
T-DM1 HER2+ mBC
ocrelizumab MS
tofogliflozin (SGLT2) type 2 diabetes
lebrikizumab severe asthma
Oncology represents 60% of new molecules in
R&D pipeline
5
PCSK9 MAb metabolic diseases
arbaclofen fragile X syndrome (FXS)
oxLDL MAb sec prev CV events
CIF/MEK inh solid tumors
Raf & MEK dual inh solid tumors
PD-L1 MAb solid tumors
MEK inh solid tumors
AKT inhibitor solid tumors
MEK inh solid tumors
CD22 ADC hem malignancies
anti-angiogenic solid tumors
PI3K inh solid tumors
Steap 1ADC prostate ca.
ADC heme tumors
ADC ovarian ca.
CD44 MAb solid tumors
ALK inhibitor NSCLC
PI3K inh solid tumors
Bcl-2 inh CLL and NHL
ADC oncology
ChK1 inh solid tum & lymphoma
Tweak MAb oncology
ADC multiple myeloma
WT-1 peptide cancer vaccine
MDM2 ant solid & hem tumors
HER3 MAb solid tumors
CSF-1R MAb solid tumors
MDM2 ant solid & hem tumors
ADC oncology
ADC metastatic melanoma
PI3k inh glioblastoma 2L
ChK1 inh(2) solid tumors BRAF inh (2) BRAF mut melanoma
BACE inh Alzheimer’s
GABRA5 NAM cogn. disorders
GIP/GLP-1 dual ago type 2 diabetes
V1 receptor antag autism
IL-6 MAb RA
IL-17 MAb autoimmune diseases
TLR7 agonist HBV
- infectious diseases
Phase I
(38 NMEs)
CardioMetabolism
Neuroscience
Ophthalmology
As of June 30 2012; * Approved in US, filed in EU
Reference:
Weisgerber-Kriegl, U. et al. 2008. J Clin Oncol; ASCO Annual Meeting Proceedings: 26:15S
Incidence of HER2-positive mBC without Herceptin
No. of women expected to be prevented from breast cancer recurrence
Herceptin to prevent breast cancer recurrences
in 28,000 women
Over 10 years in 5 major EU countries alone
6
7
Agenda
Introduction
Dr. Karl Mahler, Head of Investor Relations
Update on HER2 breast cancer and skin cancer franchises
Stefan Frings MD, Global Head Medical Affairs Oncology, Roche
T-DM1: Updated overall survival results from EMILIA
Herceptin optimal duration of treatment in early breast cancer
• Final analysis of HERA: 2 years versus 1 year of trastuzumab after adjuvant
chemotherapy
• PHARE: 6 months versus 1 year of trastuzumab in adjuvant early breast cancer
Metastatic melanoma
• BRIM7 phase Ib data of Zelboraf in combination with MEK inhibitor RG7421
• Phase I Zelboraf single-arm study in patients with brain metastases
Stefan Frings MD, Global Head Medical Affairs Oncology, Roche
Redefine the standard of care
Reshape the biologics market for HER2-positive breast cancer
9
Adjuvant
BC
Herceptin
+ chemo
Herceptin subcutaneous + chemo
(HannaH)
Herceptin & Perjeta + chemo (APHINITY)
1st line
mBC
Herceptin
+ chemo T-DM1 & Perjeta (MARIANNE)
Herceptin & Perjeta +
chemo (CLEOPATRA)
2nd line
mBC
Xeloda +
lapatinib T-DM1 (EMILIA)
2016 2012 2013 2014 2015 2011
Filing timelines
Established standard of care Potential new standard of care Potential future standard of care
2017 2019 2018 2020
T-DM1 & Perjeta + chemo
10 www.esmo2012.org 10
Updated Overall Survival Results From EMILIA,
a Phase 3 Study of Trastuzumab Emtansine (T-DM1)
vs Capecitabine and Lapatinib in HER2-Positive
Locally Advanced or Metastatic Breast Cancer
S Verma,1 D Miles,2 L Gianni,3 IE Krop,4 M Welslau,5
J Baselga,6 M Pegram,7 D-Y Oh,8 V Diéras,9 E
Guardino,10 L Fang,10 MW Lu,10 S Olsen,10 K Blackwell11
1Sunnybrook Odette Cancer Center, Toronto, Canada; 2Mount Vernon Cancer
Center, Northwood, UK; 3San Raffaele Hospital, Milan, Italy; 4Dana-Farber Cancer
Institute, Boston, MA, USA; 5Medical Office Hematology, Aschaffenburg, Germany; 6Massachusetts General Hospital, Boston, MA, USA; 7University of Miami Sylvester
Comprehensive Cancer Center, Miami, FL, USA; 8Seoul National University College
of Medicine, Seoul, Korea; 9Institut Curie, Paris, France; 10Genentech, Inc, South
San Francisco, CA, USA; 11Duke Cancer Institute, Durham, NC, USA
11 www.esmo2012.org 11
EMILIA Study Design
• Stratification factors: World region, number of prior chemo regimens for MBC or
unresectable LABC, presence of visceral disease
• Primary endpoints: PFS by independent review, OS, and safety
• Key secondary endpoints: PFS by investigator, ORR, DOR
• Statistical considerations: Hierarchical statistical analysis was performed in pre-specified
sequential order: PFS by independent review → OS → secondary endpoints
PFS analysis: 90% power to detect HR=0.75; 2-sided alpha 5%
OS analyses: 80% power to detect HR=0.80; 2-sided alpha 5%
1:1
HER2-positive LABC
or MBC (N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic treatment
or within 6 months of
adjuvant treatment
PD
T-DM1
3.6 mg/kg q3w IV
Capecitabine
1000 mg/m2 PO bid, days 1–14, q3w
+
Lapatinib
1250 mg/day PO qd
PD
12 www.esmo2012.org 12
Progression-Free Survival
by Independent Review
496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0
495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0
Cap + Lap
T-DM1
No. at risk by independent review:
Median
(months)
No. of
events
Cap + Lap 6.4 304
T-DM1 9.6 265
Stratified HR=0.650 (95% CI, 0.55, 0.77)
P<0.0001
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Pro
po
rtio
n p
rog
ress
ion
-fre
e
Time (months)
Unstratified HR=0.66 (P<0.0001).
13 www.esmo2012.org 13
Overall Survival: First Interim Analysis
496 469 438 364 296 242 195 155 129 97 74 52 31 17 7 3 2 1 0
495 484 461 390 331 277 220 182 149 123 96 67 46 29 16 5 2 0 0
Cap + Lap
T-DM1
No. at risk: Time (months)
Pro
po
rtio
n s
urv
ivin
g
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
77.0% 65.4%
47.5%
84.7%
Median (months) No. of events
Cap + Lap 23.3 129
T-DM1 NR 94
Stratified HR=0.621 (95% CI, 0.48, 0.81); P=0.0005
Efficacy stopping boundary P=0.0003 or HR=0.617
Unstratified HR=0.63 (P=0.0005).
NR, not reached.
14 www.esmo2012.org 14
Overall Survival: Second Interim Analysis
(confirmatory analysis)
496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4
495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5
Cap + Lap
T-DM1
No. at risk: Time (months)
78.4% 64.7%
51.8%
85.2%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n s
urv
ivin
g
Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).
Median (months) No. of events
Cap + Lap 25.1 182
T-DM1 30.9 149
Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006
Efficacy stopping boundary P=0.0037 or HR=0.727
15 www.esmo2012.org 15
Conclusions
In the EMILIA study, T-DM1 achieved:
• Significant improvement in PFS
– Median PFS: Cap + Lap 6.4 mos; T-DM1 9.6 mos
– HR=0.650; P<0.0001
• Significant improvement in OS
– Median OS: Cap + Lap 25.1 mos; T-DM1 30.9 mos
– HR=0.682; P=0.0006
Key secondary efficacy endpoints including time to symptom
progression1 were also significantly improved with T-DM1
The safety profile of T-DM1 was favorable to that of Cap + Lap
T-DM1 should offer an important therapeutic option in the treatment
of HER2-positive metastatic breast cancer
1Welslau et al. ESMO 2012, Poster 329P.
Herceptin in adjuvant HER2-positive breast
cancer
Herceptin 1 year is the regulatory and clinical
standard endorsed by guidelines for early BC
17
1 year of treatment SOC
• Based on 4 large phase
III studies*
• Adjuvant setting
approved in 2006
• Overall, more than 1.2
million patients treated
Herceptin optimal duration of use in adjuvant setting
Longer duration trial
HERA
• 2 years vs. 1 year
Shorter duration trials
PHARE, PERSEPHONE
and others
• 6 months vs. 1 year
*HERA, NCCTG N9831, NSABP B-31, BCIRG006
HERA TRIAL: 2 years versus 1 year of
trastuzumab after adjuvant chemotherapy
in women with HER2-positive early breast
cancer at 8 years of median follow up
Aron Goldhirsch, Martine J. Piccart-Gebhart, Marion Procter,
Evandro de Azambuja, Harald A. Weber, Michael Untch, Ian Smith, Luca Gianni,
Christian Jackisch, David Cameron, Richard Bell, Mitch Dowsett, Richard D. Gelber,
Brian Leyland-Jones, and José Baselga on behalf of the HERA Study Team
ESMO Congress, Vienna – 1 October 2012
OBSERVATION n=1698
Women with locally determined HER2-positive invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%
Randomization
1 year Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule
n=1703
2 years Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule
n=1701
After ASCO 2005, option of switch to Trastuzumab
HERA TRIAL DESIGN 2001 – 2005 (n=5102)
CT, chemotherapy; RT, radiotherapy 19
Dis
ease
-fre
e s
urv
ival
(%)
Years from randomization
89.1%
86.7% 81.0%
81.6%
75.8%
76.0%
DFS FOR 2 YEARS VS. 1 YEAR
TRASTUZUMAB AT 8 YRS MFU
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9
No. at risk
Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194
Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205
Trastuzumab 1 year
Trastuzumab 2 years
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 367 0.99 (0.85-1.14) 0.86
1 year 1552 367
20
• No evidence of long-term benefit of 2 years compared to
1 year trastuzumab when administered as sequential
treatment following chemotherapy.
• Short term DFS gain for the 2 years arm in the hormone
receptor negative cohort raises hypotheses, and
illustrates need to evaluate results by receptor status.
• Secondary cardiac endpoints and other adverse events
are increased in the 2 years trastuzumab arm.
SUMMARY: ANALYSIS OF 2 YEARS
VS. 1 YEAR TRASTUZUMAB
confidential
21
Median follow-up
(% follow-up time after
selective crossover) DFS benefit
No. of DFS events
1 year trastuzumab
vs observation
2005 (0%)
1 yr MFU 127 vs 220 P<0.0001
2006 (4.3%)
2 yrs MFU 218 vs 321 P<0.0001
2008 (33.8%)
4 yrs MFU 369 vs 458 P<0.0001
2012 (48.5%)
8 yrs MFU 471 vs 570 P<0.0001
SUMMARY OF DFS AND OS ANALYSES FOR
1 YEAR TRASTUZUMAB VS. OBSERVATION
ACROSS ANALYSIS TIME POINTS
Extended from Gianni et al, 2011
Favours 1 year trastuzumab Favours observation 0 1 2
HR (95% CI)
0.54
0.64
0.76
0.76
Median follow-up
(% follow-up time after
selective crossover) OS benefit
No. of deaths
1 year trastuzumab
vs observation
2005 (0%)
1 yr MFU 29 vs 37 P=0.26
2006 (4.1%)
2 yrs MFU 59 vs 90 P=0.0115
2008 (30.9%)
4 yrs MFU 182 vs 213 P=0.1087
2012 (45.5%)
8 yrs MFU 278 vs 350 P=0.0005
Favours 1 year trastuzumab Favours observation 0 1 2
HR (95% CI)
0.76
0.66
0.85
0.76
confidential
22
• HERA results at 8 yrs MFU show sustained and
statistically significant DFS and OS benefit for 1 year
trastuzumab versus observation in ITT analyses despite
selective crossover.
• 1 year of trastuzumab remains the standard of care as
part of an adjuvant therapy for patients with HER2-
positive early breast cancer.
SUMMARY: ANALYSIS OF DFS AND OS
FOR 1 YEAR TRASTUZUMAB VS.
OBSERVATION AT 8 YRS MFU
confidential
23
www.esmo2012.org
PHARE* Trial results comparing 6 to 12 months of trastuzumab in
adjuvant early breast cancer
Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau,
Daniel Serin, Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany,
Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar.
Protocol of Herceptin®
Adjuvant with Reduced Exposure
*lighthouse in French
www.esmo2012.org
Study design
trastuzumab 6 months
trastuzumab up to 12 months
stop trastuzumab
Clinical exam LVEF
3
Mammography
6 9 12 15 18 21 24 30 mos
…
0
R
R: Randomization after informed consent
Up to 60 mos…
Stratification 1. ER pos / neg 2. Chemo: conco/ seq
25
www.esmo2012.org
Statistical Methods
• Non inferiority randomized trial
– 2% variation in terms of absolute difference of recurrence
– The 95% CI HR margins should not cross the 1.15 boundary
– 1040 DFS events required for 80% power at 5% level
or
4 years of accrual and at least 2 years of follow-up
– HR were estimated from the stratified Cox model
• Accrual target: 3400 patients
26
www.esmo2012.org
Study information
Trastuzumab 12 months 1690 patients
Activated: 30/05/2006
Trastuzumab 6 months 1690 patients
4 patients excluded from analysis 1 Informed consent not signed 1 Randomized twice 2 HER2 negative after FISH testing
Randomization 3384 patients
•May 28th 2010 – IDMC meeting
“After careful thought and lengthy debate we recommend that entry to the trial be suspended. We do not recommend, at this time, a crossover to a longer duration of intervention for the 6 month group but would reserve the option of such a recommendation for the future, dependent on how the data develop”
Closed: 09/07/2010 Database locked: 31/07/2012
27
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00
Pro
babili
ty
1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Disease Free Survival
* Cox model stratified by ER status and concomitant chemotherapy
95.5 91.2 87.8 84.9
97.0 93.8 90.7 87.8
Events HR 95%CI p-value H 12m 176 H 6m 219 1.28 (1.05 – 1.56) 0.29
28
www.esmo2012.org
DFS Forest plot
All patients (3380) 1.28 (1.05 - 1.56)
Chemotherapy1.39 (1.05 - 1.85)1.17 (0.89 - 1.54)
Estrogene Receptor1.32 (1.01 - 1.74)1.23 (0.92 - 1.65)
Tumour size (cm)1.00 (0.71 - 1.42)1.46 (1.09 - 1.95)1.23 (0.75 - 2.00)
Nodal status1.31 (0.93 - 1.84)1.27 (0.90 - 1.78)1.22 (0.85 - 1.75)
Age yrs1.78 (0.70 - 4.53)1.32 (0.95 - 1.84)1.38 (0.95 - 2.01)1.08 (0.75 - 1.54)
Sequential (1428)Concomitant (1952)
Negative (1412)Positive (1968)
0-2 (1771)2-5 (1294)>5 (242)
Negative (1842)1-3 pos. nodes (1008)>3 pos. nodes (497)
<35 (129)35-49 (1065)50-59 (1059)>60 (1128)
0 .5 1 1.5 2 2.5HR
Favors 12mo Favors 6mo
1.15
29
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00
Pro
bab
ility
1690 1645 1438 1016 566 25H 6m1690 1662 1463 1042 583 19H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Overall Survival
* Cox model stratified by ER status and concomitant chemotherapy
42.5mos. median FU
99.3 97.2 95.2 93.1
99.9 98.7 96.9 95.0
Events HR 95%CI p-value H 12m 66 H 6m 93 1.47 (1.07 – 2.02)
30
Summary
Discussant Sandra Swain, MD
Noninferiority Trials
• Null Hypothesis: Treatments differ by more than an
acceptable level, Δ
• Alternate Hypothesis: Treatments do not differ more
than Δ
• PHARE: Δ is 15% increase in DFS HR or HR of 1.15
• Hoping to reject the null and show the new treatment
(6 mo) is noninferior or not worse than standard
treatment (12 mo) by more than 15% increase in the
DFS HR
• This would be accomplished if the CI does not
include 1.15 and the upper limit is less than 1.15
Slides reproduced from presentation 32
PHARE conclusions
• Observed HR 1.28 (CI: 1.05-1.56) so inconclusive in
terms of noninferiority
• Since Lower CI > 1.0, conclude that 12 mo is better than
6 mo and increase in HR for 6 mo is at least 5%, not
sure if less than 15%
• 395 events much less than planned 1040 events, so if
trial had continued may have been able to statistically
show HR with 6 mo greater than 15% with tighter point
estimates
Slides reproduced from presentation 33
ADJUVANT TRASTUZUMAB
< 1 Year =
ONE YEAR ADJUVANT TRASTUZUMAB REMAINS STANDARD
2 Years 6 Months
Slides reproduced from presentation 34
HER2 franchise update
Stefan Frings MD, Global Head Medical Affairs Oncology, Roche
Improving standard of care in HER2-positive
breast cancer in all lines of treatment
36
• Perjeta (pertuzumab) approved in US, EMA approval
expected in 2013
• CLEOPATRA showed significant PFS and OS benefit, final OS
data to be presented at SABCS 2012
• T-DM1 EMILIA submitted globally with medically and
statistically significant PFS. Statistically significant superior
OS benefit observed in Aug 2012.
• US approval expected late 2012/early 2013
• PHARE and HERA confirm 1 year of Herceptin as SOC
• Subcutaneous Herceptin: HANNAH filed in 2012 (EU), device
in development
• Perjeta APHINITY trial ongoing
• Plans for T-DM1 adjuvant program moving forward
1st line mBC:
2nd line / pre-
treated BC:
Adjuvant BC:
Skin cancer franchise update
Stefan Frings MD, Global Head Medical Affairs Oncology, Roche
Zelboraf
Annual incidence of patients with BRAF mutated metastatic melanoma
38 * Source: Globocan epidemiology & reported Mortality Rates(2008) with assumption of 50% BRAF mutation rate
CEMAI: 7’700
APAC: 3’215
W-EU: 6’990
N-AM: 5’410
LATAM:1’910
28%
31%
13%
8%
21%
Zelboraf in melanoma and beyond
Targeting BRAF-driven cancers to suppress tumor formation
39
Metastatic melanoma
Vemurafenib monotherapy
• Patients with brain metastases (Ph2)
MEK combination
• Zelboraf + MEKi RG7421 BRIM7 (Ph1)
Phase 3: FPI expected Q4/2012
Other combinations
• Zelboraf + ipilimumab (Ph1)
• Zelboraf + anti PD-L1 RG7466
Phase1: FPI Q3/2012
Adjuvant melanoma
Vemurafenib monotherapy
BRIM8 Phase 3
FPI Q3/2012
Other tumor types
Vemurafenib monotherapy
• Papillary thyroid cancer (Ph2)
NEW
NEW
NEW
*RG7421=GDC-0973
BRAF-mutation positive tumors
Phase 1B Study of Vemurafenib in Combination
with the MEK inhibitor,
GDC-0973, in Patients with Unresectable or
Metastatic BRAFV600-Mutated Melanoma
(BRIM7)
Rene Gonzalez,1 Antoni Ribas, 2 Adil Daud,3
Anna Pavlick,4 Thomas F. Gajewski,5 Igor Puzanov,6
Melinda S.L. Teng,7 Iris T. Chan,7 Nicholas Choong,7
Grant McArthur8
1University of Colorado Comprehensive Cancer Center, Denver, CO, USA; 2The Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA;
3Hematology/Oncology Division, University of California, San Francisco, CA, USA;
4New York University Medical Center, New York, NY, USA; 5University of Chicago, Chicago, USA; 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 7Genentech, South San Francisco, CA, USA;
8Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
Acquired resistance to
BRAF inhibition
Corcoran RB, et al. Sci Signal 2010 23;3:ra84; Villanueva J et al. Cancer Cell 2010; Nazarian R et al. Nature 2010; Su F et al. Cancer Res 2011; Wagle N et al. J Clin Oncol 2011; Johannessen CM et al. Nature 2010;
Poulikakos PI et al. Nature 2011
NRAS mutations
COT overexpression
BRAFV600 mutation
truncation /
amplification
MEK mutations
MEK-dependent resistance MEK-independent resistance
RTK overexpression
RTK ligand
overexpression
Cell survival Cell survival
vemurafenib
RG7421
T
T
BRAFV600
mutation
ERK
MEK
RTK
PI3K
AKT
*RG7421=GDC-0973; in collaboration with Exelixis 41
BRIM7 Results: Cohort Assignment
and Dose-limiting toxicity (6 July 2012)
As of 6 July 2012, 6 out of 10 dose cohorts have met the protocol-specified criteria to
be declared safe (cohorts shown in green in figures below)
One DLT observed in Cohort 1B: Gr 3 QT interval prolongation, related to vemurafenib
GD
C-0
97
3 d
aily
(1
4/1
4)
60 mg
100 mg
80 mg
960 mg 720 mg
4 n=5
2 n=4
2A n=3
3 n=3
5
1 n=5
GD
C-0
97
3 d
aily
60 mg (21/7)
960 mg 720 mg
1D 1C n=3
1B n=6
1A n=8
60 mg (28/0)
Vemurafenib twice daily Vemurafenib twice daily
Dose-escalation cohorts with GDC-0973 dosed 14 days on/14 days off
Dose-escalation cohorts with GDC-0973 dosed 21 days on/7 days off or continuously
Exp 1B n=13
Exp 1A n=20
42
www.esmo2012.org
*Includes all patients reporting each of AE general terms, even for zero incidence.
aNon-acneiform rash includes MedDRA terms rash, rash generalised, rash maculo-papular, rash macular, rash papular,
rash erythematous, erythema, rash pruritic, dermatitis, skin exfoliation, dermatitis exfoliative, lividity bLFT elevation includes MedDRA terms alkaline phosphatase increased, bilirubin increased, hyperbilirubinaemia, AST
& ALT increased, transaminases increased, and gamma-glutamyltransferase increased. c Serous chorioretinopathy includes MedDRA terms chorioretinal disorder, chorioretinopathy, 1 pt with blurred vision
later diagnosed as serous choreoretinopathy.
BRIM-7 Results: AEs attributed to either
vemurafenib or GDC-0973 in all patients* (6 July 2012)
Most common AEs attributed to either vemurafenib or GDC-0973
n=70 Grade 3 or 4 Total
n % n %
Total number of patients with AEs 20 28.6 67 95.7
Non-acneiform rasha 5 7.1 37 52.9
Diarrhea 4 5.7 36 51.4
Photosensitivity / Sunburn 0 0 22 31.4
Fatigue 1 1.4 21 30.0
Nausea 1 1.4 20 28.6
Selected AEs attributed to either vemurafenib or GDC-0973
Creatine phosphokinase elevation 3 4.3 14 20.0
Liver function test elevationb 3 4.3 14 20.0
Arthralgia 1 1.4 9 12.9
Serous chorioretinopathyc 0 0 3 4.3
Cutaneous squamous cell carcinoma, KA 1 1.4 1 1.4
43
www.esmo2012.org
BRIM7 Results: Change in tumor size from
baseline to best response in BRAFi-naïve
patients
SLD, sum of longest diameters
-30
% C
hange fro
m B
aselin
e in S
LD
of T
arg
et
Lesio
ns
-100
-50
0
50
100
Individual Patients Treated with Vemurafenib and GDC-0973
Best Tumor Response for Each Patient (BRAFi-naïve)
Cohort 1A
Cohort 1B
Cohort 1C
Cohort 2A
Cohort 4
Exp. Cohort 1A
Exp. Cohort 1B
n=25 evaluable patients
44
BRIM7: Conclusions
GDC-0973 in combination with vemurafenib can be delivered
safely at the respective single-agent MTDs:
vemurafenib 960 mg BID, and
GDC-0973 60 mg QD 21 days on / 7 days off
Adverse events were tolerable and manageable
Preliminary anti-tumor activity in vemurafenib-naïve patients is
encouraging
Phase 3 study of vemurafenib + GDC-0973 is being initiated
45
Open-label Pilot Study of Vemurafenib in
Previously Treated Metastatic Melanoma (Mm)
Patients (Pts) With Symptomatic Brain Metastases (BM) Reinhard Dummer et al., Department of Dermatology, University Hospital of Zurich,
Switzerland
Responses in brain metastases
46
Conclusions
Vemurafenib therapy:
feasible in patients with advanced melanoma with
symptomatic brain metastases
induces tumor regression in brain metastases in addition to
other sites of involvement
strong indications of vemurafenib activity in cerebral
metastases; efficacy and safety will be further studied with
longer-term follow-up
47
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