Transcript Phase III Trial of vemurafenib followed by ipilimumab vs

Immunotherapy is the Preferred Initial
Treatment for Most Patients with
Metastatic BRAFV600 Mutant Melanoma
Michael B. Atkins, M.D.
Deputy Director
Georgetown-Lombardi Comprehensive
Cancer Center
The case for immunotherapy--Immunotherapy produces durable unmaintained
tumor responses
Immunotherapy works as well against
BRAFV600 mutant melanoma as WT tumors
Immunotherapy is getting better
 Better drugs
 Better patient selection
BRAF inhibitors work as well in patients with
prior immune therapy; the converse is not so
High Dose IL-2 Therapy*
 RR: 16% (43 / 270)
 Some large volume
and visceral
 Most soft tissue and
lung
 Durable responses
 Median 8.9 mos
 CR: not reached
 Survival
 Median 12 mos
 11% >@ 5yrs
*Atkins et al JCO, 1999 (N=270)
Pooled data from phase II studies CA184-008 and CA184-022:
ipilimumab monotherapy 10 mg/kg (N=227)
1.0
Proportion alive
0.8
0.6
mWHO CR/PR/SD = 27.8%
irRC CR/PR/SD
with WHO PD = 9.7%
Other PD or unknown = 62.6%
0.4
0.2
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Wolchok, Hodi et al
Overall survival for 51-patient cohort
Rx’d w/ 10 mg/kg x 4 + maintenance
~26% 2 yr OS estimate also seen in
165-pt cohort from expanded access trial
Kevin Heller, BMS—data presented in part at ESMO 2009, ASCO 2010, 2011 posters
Relationship of MAPKinase pathway mutations
and response to HD IL-2
Mutation
All
CR/PR
SD/PD
BRAF
60
14(23%)
46 (77%)
NRAS
15
7 (47%)
8 (53%)
WT
26
3 (12%)
23 (88%)
P-value
0.05
A significantly larger proportion of patients with BRAF or NRAS
mutant tumors achieved CR/PR compared to those with WT tumors.
Joseph, Sullivan et al- JIT 2011
Ipilimumab Therapy
 Produces durable unmaintained responses; not restricted by
BRAF status
 Activity powerful enough to work in the CNS and overcome
concurrent immunosuppression
 Activity seen in patients with prior IL-2
 Activity seen in patients with elevated LDH, liver
metastases, etc
 Treatment more widely applicable
BRAF inhibitor Therapy - Limitations
Median PFS of only 6-7 months
Median OS 13-16 months
Forrest plot suggests most of the benefit
confined to patients with M1c disease
Sosman et al NEJM 2012, Chapman et al ASCO 2012
Overall survival (February 01, 2012 cut-off) censored at
crossover
100
Vemurafenib (n=337)
Median f/u 12.5 months
Overall survival (%)
90
80
Hazard ratio 0.70
70
(95% CI: 0.57–0.87)
p<0.001 (post-hoc)
60
50
Dacarbazine (n=338)
Median f/u 9.5 months
40
30
20
BRIM2
10
9.7
0
0
13.6
6
12
15.9
18
24
Time (months)
No. at risk
Dacarbazine
Vemurafenib
338
337
244
326
173
280
111
231
79
178
50
109
24
44
4
7
0
1
Overall survival by baseline characteristic
(February 01, 2012 cut-off) censored at crossover
Number
of patients
Factor
All patients
Favors
vemurafenib
Favors
dacarbazine
675
Age:
<65 years
≥65 years
514
161
Sex:
Female
Male
294
381
ECOG status:
0
1
459
216
Disease stage: IIIc
M1a
M1b
M1c
33
74
127
441
LDH:
391
284
Normal
Elevated
0.2
0.4 0.6 1.0
2
4
6
10
Hazard ratio and 95% confidence interval
20
BRAF inhibitor Therapy - Limitations
Median PFS of only 6-7 months
Median OS 13-16 months
Forest plot suggests most of the benefit
confined to patients with M1c disease
Combination BRAF-MEK inhibition may offer
some advantages…
Sosman et al ASCO 2012, Chapman et al ASCO 2012
BRAF inhibitor Therapy - Limitations
Median PFS of only 6-7 months
Median OS 13-16 months
Forest plot suggests most of the benefit
confined to patients with M1c disease
Combination BRAF-MEK inhibition may offer
some advantages, but median PFS still only 710 months
Sosman et al ASCO 2012, Chapman et al ASCO 2012,
Weber et al, ASCO 2012
BRAF inhibitor Therapy - Limitations
Thus, BRAF (+/- MEK) inhibitor treatment
postpones but does not prevent the tragedy
of metastatic melanoma
Sosman et al ASCO 2012, Chapman et al ASCO 2012,
Weber et al, ASCO 2012
Treatment for BRAF Mutant Melanoma
1.0
0.9
Proportion Surviving
0.8
0.7
0.6
Which is preferred?
0.5
0.4
0.3
0.2
Ipilimumab
BRAFi
0.1
0.0
0
1
2
3
Years after stage IV diagnosis
PRESENTED BY: Michael B. Atkins
4
5
Immunotherapy is getting better
Clinical Activity of BMS-936558 in
Melanoma Patients
Pop
N
ORR
n (%)
All
MEL
106
33 (31)
17
6 (35)
18
5 (28)
Median Duration of Response
(95% CI)
[individual pt response]
SD 24 wk
n (%)
PFSR at
24 wk
(%)
Not Reached
Range: 1.8+ to 25.7
6 (6)
42
0
41
1 (6)
33
4 (12)
48
1 (6)
55
0
30
Not Reached
[3.7+, 4.2+, 5.6, 5.6, 5.6+, 11.2+]
Not Reached
[1.8+, 4.2, 7.4+, 7.6+, 9.2+]
24 months (22.9- NR)
MEL
34
11 (32)
[1.9+, 5.5+, 7.5, 7.5, 11.1+, 13.4+,
18.4+, 22.9, 23.2+, 24, 24.9+]
Not Reached
17
7 (41)
20
4 (20)
[9.2+, 9.3, 11.1, 12.9, 18.8+, 22+,
22.4+]
25.7 months (17.0-25.7)
[17, 18+, 24.6+, 25.7]
3mg/kg
 4 melanoma patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not
classified as responders for the ORR calculation
Changes in Target Lesions Over Time in
Melanoma Patients (3mg/kg)
Dose Group: 3mg/kg
60
% Change From Baseline In Target Lesions Tumor Burden
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
0
10
20
30
40
50
60
70
80
90
100
110
120
Weeks Since Initiation Of Treatment
On Study Status(On/Off)
Off
On
+: 1st Occurence of New Lesion
 Of 33 patients with OR (all dose levels)
 29 were treated 1 year (before July 3, 2012) and 14 had responses of 1 year
 4 were treated <1 year and 4 had responses ranging from 1.8-5.3 months
130
MK-3475 (Unconfirmed + Confirmed Responses)
in Advanced MEL Patients
Complete
Response
(N, 95% CI)
Objective Response
(N, 95% CI)
Disease Control
Rate
(N, 95% CI)
All MEL
N=83
5%
(4; 2%-13%)
47%
(39; 34% - 56%)
60%
(50; 48%- 70%)
IPI Naïve
N=58
7%
(4; 2%-18%)
50%
(29; 35% -61 %)
67%
(39; 51%-76%)
IPI Treated
N=25
0%
40%
(10; 17% -59%)
44%
(11; 24%-68%)
All patients were dosed at 10 mg/kg
Includes all patients who received first dose as of April 25, 2012.
Centrally available response information as of Oct 19, 2012
Objective response= confirmed and unconfirmed complete and partial response
Disease control rate= objective response + stable disease
Hamid SMR 11/11/12
Clinical Activity in a Melanoma Patient-1
Baseline: 13/Apr/2012
27/July/2012
Courtesy of A. Ribas M.D.
• 72 yrs old male with melanoma after progressing on bio-chemotherapy, HD IL-2, and ipilimumab
• Patient was on oxygen support due to progressive lung disease burden and pleural effusion
• After 3 months of MK-3475, the patient is off the oxygen support and continues to respond
Clinical Activity in a Melanoma Patient-1
Baseline: 13/Apr/2012
27/July/2012
MK-3475 Characteristics of Responses (irRC):
Time to Respond & Duration for 43 Patients with Objective Response
IPI naive
IPI treated
Complete response
Partial Response
On Treatment
• Median duration of treatment,
• 7.6 months + (3.3-11+)
• one patients discontinued due to PD
and four patients discontinued due to
AEs
0
4
8
12
16
20
24
28
32
36
On Treatment Duration in Weeks
40
44
48
52
Immunotherapy for Melanoma
???
1.0
0.9
Proportion Surviving
0.8
0.7
0.6
Anti PD1 + x
0.5
Anti-PD1
0.4
0.3
0.2
Ipilimumab
0.1
IL-2
0.0
0
1
2
3
Years after stage IV diagnosis
PRESENTED BY: Michael B.
Atkins
4
5
Checkpoint blockade vs oncogenemutation targeted therapy for melanoma
Annual pt-years of remission
# Annual
Cases
Proportion % RR
c\ mutation
Median
Durability
of
remission
Pt years
BRAF +
cKIT
9000
0.5
0.5
0.6 yrs
1350 pt yrs
AntiCTLA4/Anti
-PD1
9000
N/A
0.33
2 years
6000 pt yrs
Adapted from Drew Pardoll
Treatment Selection Opportunities
Correlation of PD-L1 expression in pretreatment tumor biopsies
with clinical outcomes in Anti-PD-1 Therapy
Proportion of patients
42 pts include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC.
17/17
1
Melanoma
0.8
16*/25
0.6
PD-L1(+)
PD-L1(-)
9/25
0.4
p=0.006†
0.2
† analysis not pre-planned and
based on subset of subjects'.
0/17
0
PD-L1(+)
*2 pts still under evaluation
PD-L1(-)
*
RCC
Association Between Pretreatment Tumor PD-L1 Expression
and Clinical Response
Response Status
PD-L1 Positive
no. (%)
PD-L1 Negative
no. (%)
Total
no. (%)
CR/PR
9 (36)
0
9 (21)
Nonresponder
16* (64)
17 (100)
33 (79)
All Patients
25
17
42
Topalian S, et al. NEJM 2012;366:2443-2454.
NSCLC
Sequencing of Treatment
BRIM2- ORR by pre-defined subgroups
Overall response rate (%)
80
70
60
50
40
30
20
Overall ORR of 53% (IRC)
10
RR (size proportional to the number of patients in the subgroup)
95% Confidence intervals
0
All
treated
patients
<65 65
F
Age
Ribas et al ASCO 2011
M
Sex
0
1
ECOG PS
M1a/
M1b
M1c
Stage
1
>1
Yes
No
# prior Previous IL-2
therapies
Baseline characteristics
Normal 1.0–1.5x
ULN
>1.5x
ULN
LDH at enrollment
BRAF inhibition +/- prior immunotherapy
MAPKi PFS
MAPKi OS
IT initially PFS 6.7 mo (CI 4.3-9.1 mo)
MAPKi initially PFS 5.6 mo (CI 4.7-6.8 mo)
IT initially OS 19.6 mo (CI 10.0- mo)
MAPKi initially OS 13.4 mo (CI 10.1-17 mo)
p-value 0.43, log rank
OS (probability)
p-value 0.40, log rank
Time (mo)
Ackerman/Sullivan-BIDMC/MGH-SITC 2012
Immunotherapy following MAPKI:
DFHCC/MIA Retrospective Data
– 193 patients discontinued MAPKi therapy (176 with
disease progression)
• Median OS 2.9 mos (CI 1.8-4.4 mos) from last dose of MAPKi
• Single agent ipilimumab treatment (n=34 pts)
No tumor responses (2 SD)
Median PFS 2.7 mos, median OS 5 mos
50% of patients received < 4 doses
All Pts alive > 1 year- are back on MAPK inhibitors inhibitors
– Summary:
• Patients progressing on BRAFi appear unlikely to respond to
ipilimumab
• Those alive either had slow growing disease and short period
of RAFi treatment due to toxicity or are back on a RAFi
Ackerman/Sullivan-BIDMC/MGH-SITC 2012
Ipilimumab following BRAF inhibitor Therapy
OS 5.0 mo (CI 3.0-8.8 mo)
OS (probability)
PFS 2.7 mo (CI 1.8-3.1 mo)
long term survivors all
treated with additional MAPKi
Time (mo)
Ackerman/Sullivan-BIDMC/MGH-SITC 2012
Treatment Selection in Patients with
BRAF Mutant Melanoma: Conclusions
 Current data suggests that for many patients
with BRAFV600E melanoma (asymptomatic,
immune infiltrate), starting with
immunotherapy offers them a chance for
longterm benefit without compromising their
benefit from subsequent BRAFi therapy
Two shots on goal are better than one
E1612: Ipi vs Vemurafenib
Arm 1:
ECOG PS
1. 0
2. 1
Stage
1. St III or
M1a/b
2. M1c
Prior therapy
1. No prior Rx
2. Prior Rx
R
A
N
D
O
M
I
Z
E
PD
Ipi 3 or
10mg/kg q
3wks x 4 +/maint q12
wks
Vemurafenib
960mg BID
Arm 2:
Vemurafenib
960mg BID
PD
ECOG and SWOG protocol – Atkins, Chmielowski
Tumor measurements q12 wks
Ipi 3 or
10mg/kg q
3wks x 4 +/maint q12
wks
Treatment Selection in Patients with
BRAF Mutant Melanoma: Conclusions
 Current data suggests that for many patients
with BRAFV600E melanoma (asymptomatic,
immune infiltrate), starting with
immunotherapy offers them a chance for
longterm benefit without compromising their
benefit from subsequent BRAFi therapy
 Newer immunotherapies are approaching the
efficacy (RR and PFS) of BRAFi with more
durability
Immunotherapy may be the better of the
two shots