1. Two Year Estimate of Overall Survival in COMBI-v, a Randomized, Open-Label, Phase 3 Study Comparing the Combination of Dabrafenib and Trametinib With Vemurafenib as First-Line Therapy in Patients With Unresectable or Metastatic BRAF V600E/K Mutation-Positive Cutaneous Melanoma
C. Robert, B. Karaszewska, J. Schachter, P. Rutkowski, A. Mackiewicz, D. Stroyakovskiy, M. Lichinitser, R. Dummer, F. Grange, L. Mortier, V. Chiarion-Sileni, K. Drucis, I. Krajsova, A. Hauschild, B. Mookerjee, J. Legos, and D. Schadendorf

2. Disclosures
Consultancy: Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche

3. Key inclusion criteria
COMBI-v Study Design
N = 1645 screened
Interim OS Analysis
[202 events]
Final OS Analysis
[280 events]
Key inclusion criteria
BRAF V600E/K mutation
Stages IIIC or IV cutaneous melanoma
Treatment naive in advanced or metastatic melanoma
ECOG PS 0 or 1
No brain metastases, unless:
Treated
Stable ≥ 12 weeks
Stratification
BRAF mut V600E vs K
LDH (> ULN vs  ULN)
Dabrafenib + Trametinib
150 mg BID + 2 mg QD
n = 352
N = 704
Vemurafenib
960 mg BID
n = 352
Eligible patients were assigned in a 1:1 ratio to receive either a combination of dabrafenib (150mg orally twice daily) and trametinib (2mg orally once daily) or vemurafenib (960mg orally twice daily)
The primary endpoint was OS
Secondary endpoints included PFS, ORR, DoR and safety
Crossover was prohibited until the Independent Data and Safety Monitoring Committee recommended stopping the study early for efficacy. After the recommendation, the study protocol was amended to allow patients in the vemurafenib group to cross over to the combination therapy group
Primary Endpoint: OS
Secondary Endpoints: PFS, ORR, DOR, safety
BID, twice daily; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ORR, overall response rate; QD, once daily; ULN, upper limit of normal.

4. COMBI-v Updated Data Cut-off
Primary Cut-off:
April 2014
Updated Data Cut-off:
March 2015
Data analysed
COMBI-v: PFS, OS,
ORR, safety
COMBI-v: OS, safety
Robert C, et al.
NEJM 20151
Data on file.
ESMO 20152
Median follow-up: 11 months
Median follow-up: 19 months
Interim analysis (April 2014) demonstrated a significant increase in OS for the dabrafenib + trametinib arm
IDMC recommended stopping for efficacy at interim OS analysis
Patients receiving vemurafenib were permitted to crossover to dabrafenib + trametinib arm
Current analysis for COMBI-v estimated 2-year OS based on March 2015 data cutoff
1. Robert C, et al. N Engl J Med 2015;372:30-39; 2. Data on file.

5. COMBI-v: Overall Survival
Dabrafenib + Trametinib
Median OS = 25.6 mo (95% CI: 22.6–NR)
1.0
0.9
0.8
1-yr OS = 73%
0.7
1.5-yr OS = 60%
0.6
1-yr OS = 64%
2-yr OS = 51%
Proportion alive
0.5
0.4
1.5-yr OS = 50%
0.3
Vemurafenib
Median OS = 18.0 mo (95% CI: 15.6–20.7)
2-yr OS = 38%
0.2
0.1
HR 0.66 (95% CI: 0.53–0.81)
P < 0.001
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Time from randomisation, months
Patients at riska
Dabrafenib + Trametinib
352
342
336
311
286
260
245
230
217
198
173
128 68 38 16 5
Vemurafenib
341
315
252
231
201
187
166
152
129 88 46 28 7
a Data cut-off: March 2015.

6. COMBI-v: Overall Survival
Dabrafenib + Trametinib
Median OS = 25.6 mo (95% CI: 22.6–NR)
197 censored patients with 98 (50%) still on treatment
1.0
0.9
0.8
0.7
0.6
Proportion alive
0.5
0.4
0.3
Vemurafenib
Median OS = 18.0 mo (95% CI: 15.6–20.7)
158 censored patients with 33 (20%) still on treatment
Speaker note for disposition:
There were overall 197 patients censored on DT (56%) and 158 (45%) on Vem at time of cutoff
- 98 (49.7%) censored patients were on DT with follow-up ongoing and 33 (19.7%) were on Vem with follow-up ongoing
- 21 subjects on D+T and 39 for V that were “censored, follow-up ended”.  The reasons were (D+T vs V) “lost to follow-up” (5 vs 16), “physician decision” (4 vs 3), and withdrawal by subject (12 vs 20).
- Of the 176 D+T and 119 V who were “censored with follow-up ongoing”, 98 (55.7%) on D+T were still on combo (with another 5 on mono D), and 33 (27.7%) were still on V.
0.2
0.1
HR 0.66 (95% CI: 0.53–0.81); P < 0.001
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Time from randomisation, months
Patients at riska
Dabrafenib + Trametinib
352
342
336
311
286
260
245
230
217
198
173
128 68 38 16 5
Vemurafenib
341
315
252
231
201
187
166
152
129 88 46 28 7
a Data cut-off: March 2015.

7. COMBI-v: Investigator-Assessed Progression-Free Survival
Dabrafenib + Trametinib
Median PFS = 12.6 mo (95% CI: 10.7–15.5)
1.0
0.9
0.8
0.7
0.6
Proportion Alive and Progression Free
0.5
0.4
0.3
0.2
Vemurafenib
Median PFS = 7.3 mo (95% CI: 5.8–7.8)
0.1
HR 0.61 (95% CI: 0.51–0.73); P < 0.001
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Time from Randomisation, months
Patients at riska
Dabrafenib +
Trametinib
352
310
270
229
202
175
158
140
125
115 98 56 30 26 4
Vemurafenib
352
281
216
162
127
100 81 69 61 59 49 23 8 4
a Data cut-off: March 2015.

8. COMBI-v: Best Response
Best Confirmed Response
Dabrafenib + Trametinib
(n = 351)
Vemurafenib
(n = 350)
Complete response, n (%)
59 (17)
36 (10)
Partial response, n (%)
172 (49)
150 (43)
Stable disease, n (%)
87 (25)
102 (29)
Progressive disease, n (%)
22 (6)
39 (11)
Not evaluable, n (%)
12 (3)
25 (7)
Response rate, n (%)
[95% CI]
231 (66)
[60.4‒70.6]
186 (53)
[47.5‒58.2]
Difference in ORR, n (%) [95% CI]
13 [20.2–5.3]
P value
0.0008
DOR, months [95% CI]
13.8 [11.2‒18.1]
8.5 [7.4‒9.7]
Note: ORR There is now a net increase of 5 responders for both treatment arms each compared to April 2014 data cut, CR rates have increased from 13 to 17% on DT versus 8 to 10% on Vem
For DOR, there were 131 (56.7%) and 122 (65.5%) who have now progressed.  The median duration time is 13.8 months (11.2, 18.1) for D+T and 8.5 months (7.4, 9.7) for Vem; a month increase for Vem.
a Data cut-off: March 2015.

9. COMBI-v: OS and PFS for Patients With Baseline LDH ≤ ULN
OS, Baseline LDH ≤ ULN
PFS, Baseline LDH ≤ ULN
1.0
1.0
Dabrafenib + Trametinib
Median PFS = 17.5 mo (95% CI, 15.5‒21.4)
Dabrafenib + Trametinib
Median OS = NR (95% CI, NR‒NR)
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Proportion Alive
0.5
Proportion Alive and Progression Free
0.5
0.4
0.4
0.3
0.3
LDH is the variable which appears as the stronger predictor of survival in covariate and regression analysis.
Note: In patients who had a Baseline LDH ≤ ULN, mOS was not reached and mPFS was 17.5 months on DT while mOS was 21.5 months and PFS 9.2 months on Vem.
0.2
0.2
Vemurafenib
Median OS = 21.5 mo (95% CI, 18.3‒NR)
Vemurafenib
Median PFS = 9.2 mo (7.6‒11.0)
0.1
0.1
HR = 0.56 (95% CI, 0.42‒0.75)
HR = 0.55 (95% CI, 0.43‒0.70)
0.0
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Time from randomisation, months
Time from Randomisation, months
D + T
233
228
227
221
216
204
193
185
175
162
145
108 59 33 14 5
D + T
233
212
201
183
166
147
133
119
109
100 85 50 26 22 4
Vem
238
231
222
211
197
184
165
153
134
121
104 74 36 20 6
Vem
238
197
169
130
106 86 69 60 52 50 43 20 6 2

10. COMBI-v: Summary of Follow-Up Therapy (> 2% Any Arm)
Medication, n (%)
Dabrafenib + Trametinib
(n = 350)
Vemurafenib
(n = 349)
Any medication
119 (34)
178 (51)
Ipilimumab
75 (21)
102 (29)
31 (9)
34 (10)
Dabrafenib
18 (5)
47 (13)
Dacarbazine
39 (11)
Pembrolizumab
24 (7)
Carboplatin
10 (3)
9 (3)
Paclitaxel
7 (2)
Fotemustine
Nivolumab
4 (1)
Temozolomide
6 (2)
15 (4)
Trametinib
3 (< 1)
13 (4)
Any line

11. COMBI-v: AEs of Special Interest Leading to Permanent Discontinuation (≥ 1% of Patients)
Category, n (%)
April 2014 Data Cut-off
March 2015 Data Cut-off
Permanent Discontinuation of Dabrafenib or Trametinib
(n = 350)
Permanent Discontinuation of Vemurafenib
(n = 349)
Any category
34 (10)
33 (9)
43 (12)
35 (10)
Pyrexia
13 (4)
1 (< 1)
15 (4)
Hepatic disorder
7 (2)
14 (4)
9 (3)
Cardiac related events
10 (3)
12 (3)
Chills/rigors
---
2 (< 1)
Hypersensitivity
5 (1)
4 (1)
Arthralgia
6 (2)
QTc Prolongation
3 (1)
Rash
Skin related toxicities
Dabrafenib: ALT increased, AST increased, GCT increased, and hepatic enzyme increased (n = 2 each); ALP increased and hepatocellular injury (n = 1 each)
Vemurafenib: AST increased (n = 5); ALT increased (n = 4); bilirubin increased and hepatic enzyme increased (n = 3 each); ALP increased (n = 2); cholestasis (n = 1), GCT increased, hepatitis, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, and liver injury (n = 1 each)

12. Conclusions The combination of dabrafenib + trametinib showed
Improved OS vs vemurafenib
Median OS, 25.6 vs 18.0 months [HR 0.66; P < 0.001]; 2-year OS > 50%
Improved PFS, ORR, and DOR vs vemurafenib
Longest benefit in patients with LDH ≤ ULN with median OS not reached and median PFS of 17.5 months
AE profile manageable with no new safety signals with additional 8-month follow up
Overall results were comparable to those reported for COMBI-d
Dabrafenib + trametinib has demonstrated superiority over BRAFi monotherapy in 2 phase-3 trials, supporting its use as a standard of care therapy in patients with BRAF V600–mutant melanoma