The document discusses adjuvant therapy for malignant melanoma. It begins by providing background on ECOG 1684, a randomized controlled trial published in 1996 that found high-dose interferon alfa-2b prolongs relapse-free and overall survival compared to observation alone in high-risk resected melanoma patients. It then summarizes EORTC 18071, another randomized controlled trial from 2015 that found adjuvant ipilimumab improved relapse-free survival compared to placebo in patients with completely resected stage III melanoma. The document provides key details from these two important trials that established adjuvant therapies for reducing recurrence in high-risk melanoma.

1. 1
M E L A N O M A
A D J U V A N T T H E R A P Y
T O

2. 2
M A U R I C I O L E M A
M E D I N A
C l í n i c a d e O n c o l o g í a
A s t o r g a / C l í n i c a S O M A ,
M e d e l l í n
P O S I T I O N S T A T E M E N T
Am I right? Quizás, quizás, quizás!
WHO SHOULD NOT
GET ADJUVANT
THERAPY FOR
MALIGNANT
MELANOMA?

3. 3
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y

4. 4
5-yr relapse rate in
stage III melanoma
N o t a l l m e l a n o m a s a r e c r e a t e d e q u a l
W i d e r i s k s p r e a d i n s t a g e
I I I d i s e a s e .
A J C C 8 t h
37
68
89
IIIA IIIB IIIC
0
50
100
IIIA T1a/b, T2a N1a or N2a
IIIB T0
T1a/b, T2a
T2b, T3a
N1b, N1c
N1b/c, N2b
N1a/b/c, N2a/b
IIIC T0
T1a/b, T2a/b, T3a
T3b, T4a
T4b
N2b/c, N3b/c
N2c, N3a/b/c
Any N1+
N1a/b/c, N2a/b/c
IIID T4b N3a/b/c
5-yrRelapseRate(%)

5. 5
I F N A L P H A 2 B I P I L I M U M A B D A B R A F E N I B + T R A M E T I N I B
E C O G 1 6 8 4 ( 1 9 9 6 )
E C O G 1 6 9 0 ( 2 0 0 0 )
E C O G 1 6 9 4 ( 2 0 0 1 )
E C O G 2 6 9 6 ( 2 0 0 1 )
E O R T C 1 8 0 7 1 ( 2 0 1 5 ) C O M B I - A D ( 2 0 1 7 )
F O R V6 0 0 E / V6 0 0 K
ADJUVANT THERAPY IN MELANOMA
A L I T T L E H I S T O R Y
H i g h - r i s k d i s e a s e ( m o s t l y, s t a g e I I I )
A n t i P D 1
N i v o l u m a b
C H E C K M AT E 2 3 8 ( 2 0 1 7 )
P e m b r o l i z u m a b
K E Y N O T E 0 5 4 / 2 0 1 8 )

6. 6
I F N A L P H A 2 B I P I L I M U M A B D A B R A F E N I B + T R A M E T I N I B
E C O G 1 6 8 4 ( 1 9 9 6 )
E C O G 1 6 9 0 ( 2 0 0 0 )
E C O G 1 6 9 4 ( 2 0 0 1 )
E C O G 2 6 9 6 ( 2 0 0 1 )
E O R T C 1 8 0 7 1 ( 2 0 1 5 ) C O M B I -A D ( 2 0 1 7 )
F O R V6 0 0 E / V6 0 0 K
ADJUVANT THERAPY IN MELANOMA
A L I T T L E H I S T O R Y
H i g h - r i s k d i s e a s e ( m o s t l y, s t a g e I I I )
A n t i P D 1
N i v o l u m a b
C H E C K M AT E 2 3 8
( 2 0 1 7 )
P e m b r o l i z u m a b
K E Y N O T E 0 5 4 /
2 0 1 8 )

7. 7
ECOG 1684
K i r kw o o d , J C O, 1 9 9 6
IIB: Breslow >
4 mm (pT4)
IIIA: T1-3N1
ypN1
RANDOMIZED
.,1 : 1
-
Observation-
*20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three
times per week subcutaneously (SC) for 48 weeks
Primary end-points: RFS and OS
Secondary end-points: DMFS and OS, in all and in PD-L1 + tumors
HD IFN*

8. 8
Interferon alfa-2b adjuvant therapy of high-risk resected
cutaneous melanoma: the Eastern Cooperative Oncology
Group Trial EST 1684.
E v i d e n c e i n f o g r a m
K i r kw o o d J M , J C O, 1 9 9 6
287
T4 or N+ disease
PATIENTS
6.9
.,
MEDIAN FOLLOW-UP
(yr)
1.7 vs 1
p = 0.0023
RFS (yr)
3.8 vs 2.8
A company is an association or
collection of individuals,
OS (yr)
Grade 3 Toxicity: 63%, Grade 4 Toxicity: 9%,
Toxic deaths: 2 (Hepatotoxicity)

9. 9
ECOG 1684
I F N A L P H A 2 B
2 0 M U Q D X 2 0 o n M o n t h 1
1 0 M U /m 2 t i w x 1 1 m o
5 years 10 years
RFS
50%
Stratified logrank (1-sided) p-value = 0.0023
Median follow-up: 6.9 years

10. 10
T4N0M0 - IIB T1-4pN1M0 - IIIA
ECOG 1684: Kirkwood, JCO, 1996

11. 11
T4N0M0 - IIB T1-4pN1M0 - IIIA
ECOG 1684: Kirkwood, JCO, 1996

12. 12
T1-4cN1M0 - IIIA ypN1
ECOG 1684: Kirkwood, JCO, 1996

13. 13
T1-4cN1M0 - IIIA ypN1
ECOG 1684: Kirkwood, JCO, 1996

14. 14
ECOG 1684
I F N A L P H A 2 B
2 0 M U Q D X 2 0 o n M o n t h 1
1 0 M U /m 2 t i w x 1 1 m o
S t a n d a r d o f c a r e
IFN alpha-2b prolongs
the relapse-free
interval and overall
survival of high-risk
resected melanoma
patients.
5 years 10 years
RFS
50%
Stratified logrank (1-sided) p-value = 0.0023
Median follow-up: 6.9 years

15. 15
Ives, N. J., Suciu, S., Eggermont, A. M. M., Kirkwood, J.,
Lorigan, P., Markovic, S. N., … Wheatley, K. (2017). Adjuvant
interferon-α for the treatment of high-risk melanoma: An
individual patient data meta-analysis. European Journal of
Cancer, 82, 171–183. https://doi.org/10.1016/j.ejca.
2017.06.006
Meta-analysis: Adjuvant IFN vs No
Individual Patient Data
7744 patients
15 trials, 18 arms

16. 16
Ives, N. J., Suciu, S., Eggermont, A. M. M., Kirkwood, J.,
Lorigan, P., Markovic, S. N., … Wheatley, K. (2017). Adjuvant
interferon-α for the treatment of high-risk melanoma: An
individual patient data meta-analysis. European Journal of
Cancer, 82, 171–183. https://doi.org/10.1016/j.ejca.
2017.06.006
Meta-analysis: Adjuvant IFN vs No
Individual Patient Data
7744 patients
15 trials, 18 arms

17. 17
Ives, N. J., Suciu, S., Eggermont, A. M. M.,
Kirkwood, J., Lorigan, P., Markovic, S. N., …
Wheatley, K. (2017). Adjuvant interferon-α for
the treatment of high-risk melanoma: An
individual patient data meta-analysis.
European Journal of Cancer, 82, 171–183.
https://doi.org/10.1016/j.ejca.2017.06.006
Meta-analysis: Adjuvant
IFN vs No
Individual Patient Data
7744 patients
15 trials, 18 arms
Survival curve for Event-Free Survival

18. 18
“Most interestingly, there
was a statistically
significant benefit of IFN
upon overall survival (OS)
that translates into an
absolute benefit of at least
3% (CI 1-5%) at 5 years”
Kirkwood, Ascierto, J Transl Med, 2008

19. 19
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y
50
2514
100
High-dose Interferon

20. 20
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y
50
2528
100
High-dose Interferon

21. 21
EORTC 18071
E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5
Stage III cutaneous
melanoma (excluding lymph
node metastasis ≤1 mm or in-
transit metastasis) with
adequate resection of lymph
nodes
RANDOMIZED
.,1 : 1
-
Placebo-
10 mg/kg ipilimumab or placebo every 3 weeks for four doses,
then every 3 months for up to 3 years
Primary end-points: RFS
Ipilimumab
Eggermont, A. M. M., Chiarion-Sileni, V., Grob, J.-J., Dummer, R., Wolchok, J. D., Schmidt, H., … Testori, A. (2015). Adjuvant
ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised,
double-blind, phase 3 trial. The Lancet Oncology, 16(5), 522–530. https://doi.org/10.1016/S1470-2045(15)70122-1

22. 22
Inclusion Criteria
Stage IIIA melanoma
if N1a, at least 1 metastasis >1
mm),
Stage IIIB or stage IIIC,
with no in-transit metastasis.
The primary cutaneous
melanoma must
have been completely
excised with adequate
surgical
margins.
Complete regional
lymphadenectomy was
required within the 12 weeks
before randomisation.
Exclusion criteria
Unknown primary, ocular, or mucosal melanoma,
ECOG PS 1>1
Autoimmune disease
Uncontrolled infections
Cardiovascular disease
WBC count <2500
ANC <1000
Platelet count <75k
Hb <9gr/dL
Creatinine > 2.5 x ULN
Hepatic enzymes and LDH > 2 x ULN
Use of systemic steroids
Prior systemic therapy for melanoma
Eggermont, A. M. M., Chiarion-Sileni, V., Grob, J.-J., Dummer, R.,
Wolchok, J. D., Schmidt, H., … Testori, A. (2015). Adjuvant ipilimumab
versus placebo after complete resection of high-risk stage III
melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.
The Lancet Oncology, 16(5), 522–530. https://doi.org/10.1016/
S1470-2045(15)70122-1

23. 23
Adjuvant ipilimumab versus placebo after complete resection of
high-risk stage III melanoma (EORTC 18071): a randomised, double-
blind, phase 3 trial
E v i d e n c e i n f o g r a m
951
Stage III
PATIENTS
5.3
.,
MEDIAN FOLLOW-UP
(yr)
26.1 vs 17.1
p = 0.001
RFS (month
1%
Colitis
Myocarditis
Multiorgan failure
Toxic deaths
Grade 3-4 toxicity: gastrointestinal 16%, hepatic 11% and endocrine 8%.
Adverse events led to discontinuation of treatment in 245 (52%)
E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5
EORTC 18071
E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5

24. 24
EORTC 18071
A d j u v a n t t r i a l f o r s t a g e I I I M e l a n o m a :
I p i l i m u m a b v s P l a c e b o
5 years 10 years
Median Follow-up: 5.3 years
PFS
50%
E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5

25. 25
EORTC 18071
E g g e r m o n t ,
L a n c e t O n c o l , 2 0 1 5
RFS

26. 26
EORTC 18071
E g g e r m o n t ,
L a n c e t O n c o l , 2 0 1 5
RFS by type of LN status

27. 27
EORTC 18071
E g g e r m o n t ,
L a n c e t O n c o l , 2 0 1 5RFS by type of LN status and ulceration (post-hoc)

28. 28
EORTC 18071
E g g e r m o n t ,
L a n c e t O n c o l , 2 0 1 5
Toxicity

29. 29
EORTC 18071
E g g e r m o n t ,
L a n c e t O n c o l , 2 0 1 5
Toxicity

30. 30EORTC 18071 E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5
Immune-Related Adverse Events
Grade 1-2 Grade 3 Grade 4 Grade 5 Grade 1-2 Grade 3 Grade 4 Grade 5
Ipilimumab Placebo

31. 31EORTC 18071 E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5
Immune-Related Adverse Events
Grade 1-2 Grade 3 Grade 4 Grade 5 Grade 1-2 Grade 3 Grade 4 Grade 5
Ipilimumab Placebo

32. 32
EORTC 18071
A d j u v a n t t r i a l f o r s t a g e I I I M e l a n o m a :
I p i l i m u m a b v s P l a c e b o
L i m i t e d u p t a k e
Adjuvant ipilimumab significantly
improved recurrence-free survival for
patients with completely resected
high-risk stage III melanoma
5 years 10 years
Median Follow-up: 5.3 years
PFS
50%
The risk–benefit ratio of adjuvant
ipilimumab at this dose and schedule
requires additional assessment based
on distant metastasis-free survival and
overall survival endpoints to define its
definitive value
E g g e r m o n t , L a n c e t O n c o l , 2 0 1 5

33. 33
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y
20
2548
75
Ipilimumab

34. 34
CHECKMATE 238
After
complete
resection of
stage IIIB,
IIIC, or IV
melanoma
RANDOMIZED
.,1 : 1
Nivolumab
Ipilimumab
Nivolumab at a dose of 3 mg/kg every 2 weeks or ipilimumab at a dose
of 10 mg/kg every 3 weeks for four doses and then every 12 weeks.
Primary end-points: recurrence-f ree survival in the ITT
We b e r J , N E J M , 2 0 1 7

35. 35
Inclusion Criteria
15 years of age or older
Stage IIIB, IIIC, or IV melanoma
ECOG PS 0/1
Resected regional or distant
metastases
Complete regional
lymphadenectomy or resection
was required within
12 weeks before randomization.
Patients with resected brain
metastases were eligible
Exclusion criteria
Ocular or uveal melanoma
A history of autoimmune disease,
Another malignancy within 3 years of
randomization
Systemic use of glucocorticoids
Previous systemic therapy for melanoma.
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M.,
Cowey, C. L., … Ascierto, P. A. (2017). Adjuvant Nivolumab versus
Ipilimumab in Resected Stage III or IV Melanoma. New England Journal
of Medicine, 377(19), 1824–1835. https://doi.org/10.1056/
NEJMoa1709030

36. 36
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J.,
Arance, A. M., Cowey, C. L., … Ascierto, P. A. (2017).
Adjuvant Nivolumab versus Ipilimumab in Resected Stage
III or IV Melanoma. New England Journal of Medicine,
377(19), 1824–1835. https://doi.org/10.1056/
NEJMoa1709030

37. 37
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M.,
Cowey, C. L., … Ascierto, P. A. (2017). Adjuvant Nivolumab versus
Ipilimumab in Resected Stage III or IV Melanoma. New England Journal
of Medicine, 377(19), 1824–1835. https://doi.org/10.1056/
NEJMoa1709030
Nivo Ipi

38. 38
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M.,
Cowey, C. L., … Ascierto, P. A. (2017). Adjuvant Nivolumab versus
Ipilimumab in Resected Stage III or IV Melanoma. New England Journal
of Medicine, 377(19), 1824–1835. https://doi.org/10.1056/
NEJMoa1709030
Nivo Ipi

39. 39
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M.,
Cowey, C. L., … Ascierto, P. A. (2017). Adjuvant Nivolumab versus
Ipilimumab in Resected Stage III or IV Melanoma. New England Journal
of Medicine, 377(19), 1824–1835. https://doi.org/10.1056/
NEJMoa1709030
Nivo Ipi

40. 40
Adjuvant Nivolumab versus Ipilimumab in
Resected Stage III or IV Melanoma.
E v i d e n c e i n f o g r a m
906
Stage III and IV
PATIENTS
18
.,
MEDIAN FOLLOW-UP
(months)
70 vs 61
HR = 0..65
12-mo RFS (%)
0
2 toxic deaths int Ipilimumab
arm
Toxic deaths in the Nivo
Grade 3 or 4 adverse events were reported in 14.4% of the patients in the
nivolumab group and in 45.9% of those in the ipilimumab group
We b e r J , N E J M , 2 0 1 7

41. 41
CheckMate 238
A d j u v a n t t h e r a p y f o r s t a g e I I I a n d I V M e l a n o m a :
N i v o l u m a b v s I p i l i m u m a b
5 years 10 years
Minimum follow-up: 18 months
Hazard ratio, 0.65 (97.56% CI, 0.51–0.83)
P<0.001
Nivolumab: 154 events/453 patients
Ipilimumab: 206 events/453 patients
RFS
50%
We b e r J , N E J M , 2 0 1 7

42. 42
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H.
J., Arance, A. M., Cowey, C. L., … Ascierto, P. A.
(2017). Adjuvant Nivolumab versus Ipilimumab in
Resected Stage III or IV Melanoma. New England
Journal of Medicine, 377(19), 1824–1835. https://
doi.org/10.1056/NEJMoa1709030

43. 43
Weber, J., NEJM, 2017

44. 44
Weber, J., NEJM, 2017

45. 45
Weber, J., NEJM, 2017

46. 46
Weber, J., NEJM, 2017

47. 47
Weber, J., NEJM, 2017

48. 48
Weber, J., NEJM, 2017

49. 49
Weber, J., NEJM, 2017

50. 50
CheckMate 238
A d j u v a n t t h e r a p y f o r s t a g e I I I a n d I V M e l a n o m a :
N i v o l u m a b v s I p i l i m u m a b
5 years 10 years
Minimum follow-up: 18 months
Hazard ratio, 0.65 (97.56% CI, 0.51–0.83)
P<0.001
Nivolumab: 154 events/453 patients
Ipilimumab: 206 events/453 patients
RFS
50%
We b e r J , N E J M , 2 0 1 7
O n e s t a n d a r d o f c a r e
Adjuvant therapy with nivolumab
resulted in significantly longer
recurrence-free survival and a
lower rate of grade 3 or 4 adverse
events than adjuvant therapy
with ipilimumab

51. 51
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y
20
9368
75
Nivolumab

52. 52
EORTC 1325 / KEYNOTE 054
E g g e r m o n t , N E J M , 2 0 1 8
High risk,
resected,
stage III,
cutaneous
melanoma
RANDOMIZED
.,1 : 1
Pembrolizumab
200 mg IV q3w x18
Pembrolizumab
If recurrence after 6 mo
Placebo
IV q3w x18
Stratif ication factors: IIIA vs IIIB vs IIIC (1-3 LN) vs IIIC (4+ LN)
North America, Europe, New Zealand/Australia, other countries
Primary end-points: RFS and RFS in PD-L1 + tumors
Secondary end-points: DMFS and OS, in all and in PD-L1 + tumors

53. 53
Inclusion Criteria
18 years of age or older
Cutaneous melanoma with
metastasis to regional lymph nodes
Stage IIIA melanoma
(patients with stage N1a melanoma
had to have at least one
micrometastasis measuring >1 mm
in greatest diameter)
Stage IIIB or IIIC disease with no in-
transit metastases as
ECOG PS 0/1
Complete regional
lymphadenectomy or resection was
required within
13 weeks before randomization.
Exclusion criteria
Uncontrolled infections
A history of autoimmune disease,
Systemic use of glucocorticoids
Previous systemic therapy for melanoma.
Eggermont, A. M. M., Blank, C. U., Mandala, M., Long, G. V., Atkinson,
V., Dalle, S., … Robert, C. (2018). Adjuvant Pembrolizumab versus
Placebo in Resected Stage III Melanoma. New England Journal of
Medicine, NEJMoa1802357. https://doi.org/10.1056/
NEJMoa1802357

54. 54
E v i d e n c e i n f o g r a m
919
Stage III and IV
PATIENTS
15
.,
MEDIAN FOLLOW-UP
(months)
75.4 vs 61
HR = 0..57
12-mo RFS (%)
1
Myositis
Toxic deaths with Pembro
Grades 3 to 5 that were related to the trial regimen were reported in 14.7% of
the patients in the pembrolizumab group and in 3.4% of patients in the
placebo group
E g g e r m o n t A M M , N E J M , 2 0 1 8
Adjuvant Pembrolizumab versus Placebo in
Resected Stage III Melanoma

55. 55
EORTC 1325 / KN 054
A d j u v a n t t r i a l f o r s t a g e I I I M e l a n o m a :
P e m b r o l i z u m a b v s
P l a c e b o
5 years 10 years
RFS
50%
HR (98.4% CI): 0.57 (0.43–0.74), p<0.001
Median follow-up: 15 months

56. 56
EORTC 1325
P e m b r o l i z u m a b v s
P l a c e b o
A d j u v a n t t r i a l f o r s t a g e I I I M e l a n o m a :
PD-L1 negative tumors
also benefit from Anti-PD1
therapy

57. 57
Eggermont, A. M. M., Blank, C. U., Mandala, M., Long, G. V., Atkinson, V., Dalle, S., … Robert, C. (2018). Adjuvant
Pembrolizumab versus Placebo in Resected Stage III Melanoma. New England Journal of Medicine, NEJMoa1802357.
https://doi.org/10.1056/NEJMoa1802357

58. 58
Eggermont, A. M. M., Blank, C. U., Mandala, M., Long, G. V., Atkinson, V., Dalle, S., … Robert, C. (2018). Adjuvant
Pembrolizumab versus Placebo in Resected Stage III Melanoma. New England Journal of Medicine, NEJMoa1802357.
https://doi.org/10.1056/NEJMoa1802357

59. 59
EORTC 1325 / KN 054
A d j u v a n t t r i a l f o r s t a g e I I I M e l a n o m a :
P e m b r o l i z u m a b v s
P l a c e b o
T o o s o o n t o k n o w
Pembrolizumab
administered every 3
weeks for up to 1 year
resulted in significantly
longer recurrence-free
survival than placebo
5 years 10 years
RFS
50%
HR (98.4% CI): 0.57 (0.43–0.74), p<0.001
Median follow-up: 15 months

60. 60
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y
20
9368
75
Pembrolizumab

61. 61
COMBI-AD
L o n g G , N E J M , 2 0 1 7
Stage III
melanoma
with BRAF
V600E or
V600K
mutations
RANDOMIZED
.,1 : 1
Dabrafenib + Trametinib
Placebo
Dabrafenib at a dose of 150 mg twice daily plus trametinib at a
dose of 2 mg once daily
Primary end-points: RFS
Secondary end points included overall survival, distant
metastasis–f ree survival, f reedom f rom relapse, and safety

62. 62
Inclusion Criteria
118 years of age or older
Cutaneous melanoma with metastasis to regional lymph nodes
With BRAF V600E or V600K mutations
Stage IIIA melanoma (patients with stage N1a melanoma had to have at least
one micrometastasis measuring >1 mm in greatest diameter)
Stage IIIB or IIIC disease with no in-transit metastases as
ECOG PS 0/1
Complete regional lymphadenectomy or resection was required within
12 weeks before randomization.
Long, G. V., Hauschild, A., Santinami, M., Atkinson, V., Mandalà, M., Chiarion-Sileni, V., … Kirkwood, J. M. (2017).
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF -Mutated Melanoma. New England Journal of Medicine, 377(19),
1813–1823. https://doi.org/10.1056/NEJMoa1708539

63. 63
E v i d e n c e i n f o g r a m
870
Stage III
PATIENTS
2.8
.,
MEDIAN FOLLOW-UP
(years)
58 vs 39
HR = 0..47
3-yr RFS (%)
1
Pneumonia
Toxic deaths with D + T
Grades 3 to 4 pyrexia 5%, fatigue 4%, nausea < 1%, New melanoma 3%,
cutaneous carcinoma 2%
L o n g G , N E J M , 2 0 1 7
Adjuvant Dabrafenib plus Trametinib in Stage
III BRAF-Mutated Melanoma

64. 64
COMBI-AD
I n m B R A F s t a g e I I I m e l a n o m a :
D a b r a f e n i b 1 5 0 m g q 1 2 h
T r a m e t i n i b 2 m g Q D
5 years 10 years
COMBI-AD: Dabrafenib + Trametinib
COMBI-AD: Placebo
Hazard ratio for relapse, 0.47 (95% CI, 0.39–0.58)
P<0.001
Median Follow-up: 2.8 years
RFS
50%

65. 65
Long, G. V., Hauschild, A., Santinami, M., Atkinson, V., Mandalà, M., Chiarion-Sileni, V., … Kirkwood, J. M. (2017).
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF -Mutated Melanoma. New England Journal of Medicine, 377(19),
1813–1823. https://doi.org/10.1056/NEJMoa1708539

66. 66
Long, G. V., Hauschild, A., Santinami, M., Atkinson, V.,
Mandalà, M., Chiarion-Sileni, V., … Kirkwood, J. M.
(2017). Adjuvant Dabrafenib plus Trametinib in Stage III
BRAF -Mutated Melanoma. New England Journal of
Medicine, 377(19), 1813–1823. https://doi.org/
10.1056/NEJMoa1708539
COMBI-AD
Adverse Events

67. 67
Long, G. V., Hauschild, A., Santinami, M., Atkinson, V.,
Mandalà, M., Chiarion-Sileni, V., … Kirkwood, J. M.
(2017). Adjuvant Dabrafenib plus Trametinib in Stage III
BRAF -Mutated Melanoma. New England Journal of
Medicine, 377(19), 1813–1823. https://doi.org/
10.1056/NEJMoa1708539
COMBI-AD
Adverse Events

68. 68
Long, G. V., Hauschild, A., Santinami, M., Atkinson, V.,
Mandalà, M., Chiarion-Sileni, V., … Kirkwood, J. M.
(2017). Adjuvant Dabrafenib plus Trametinib in Stage III
BRAF -Mutated Melanoma. New England Journal of
Medicine, 377(19), 1813–1823. https://doi.org/
10.1056/NEJMoa1708539
COMBI-AD
Adverse Events
Treatment discontinuation: 3%

69. 69
COMBI-AD
I n m B R A F s t a g e I I I m e l a n o m a :
D a b r a f e n i b 1 5 0 m g q 1 2 h
T r a m e t i n i b 2 m g Q D

70. 70
COMBI-AD
I n m B R A F s t a g e I I I m e l a n o m a :
D a b r a f e n i b 1 5 0 m g q 1 2 h
T r a m e t i n i b 2 m g Q D
P o s s i b l e S t a n d a r d o f c a r e
Adjuvant use of combination
therapy with dabrafenib plus
trametinib resulted in a
significantly lower risk of
recurrence in patients with
stage III melanoma with
BRAF V600E or V600K
mutations
5 years 10 years
COMBI-AD: Dabrafenib + Trametinib
COMBI-AD: Placebo
Hazard ratio for relapse, 0.47 (95% CI, 0.39–0.58)
P<0.001
Median Follow-up: 2.8 years
RFS
50%

71. 71
ADJUVANT
A P E R F E C T
E F F E C T I V E
I N C R E A S E S C U R E
D E L AY S R E L A P S E
S T R A I G H T - F O R W A R D
E A S Y T O D E L I V E R
S H O R T
L OW T OXI C I T Y
R E P L I C A B L E
C L I N I CA L B E N E F I T
C O N F I R M E D B Y W E L L
C O N D U C T E D T R I A L S
I N E X P E N S I V E
F O R PAT I E N T / PAYE R /
S O C I E T Y
T H E R A P Y
10
30100
10
Dabrafenib + Trametinib

72. 72
KEY ADJUVANT TRIALS IN STAGE III
MELANOMA
5 years 10 years
COMBI-AD: D+T
COMBI-AD: Placebo
RFS
50%

73. 73
Ribas asks what should the strategy be for adjuvant therapy in
high risk BRAF mutant melanoma. This will need RCTs. #AACR18
15.04.2018

74. 74
Trial Biology STAGE IIB STAGE IIIA STAGE IIIB/C STAGE IV
E1684 - Ifn
EO18071 - Ipi *
CM238 - Nivo
COMBI-AD -
Dab + Tram
mBRAF+
EO1325 -
Pembro
*
*: Lymph-node >1 mm
Heterogeneity in melanoma adjuvant
trialsInclusion Criteria

75. 75
Trial Biology STAGE IIB STAGE IIIA STAGE IIIB/C STAGE IV Toxic deaths
E1684 - Ifn Non-significant No
EO18071 - Ipi * 1%
CM238 - Nivo No
COMBI-AD -
Dab + Tram
mBRAF+ Anecdotal
EO1325 -
Pembro
* Anecdotal
*: Lymph-node >1 mm
Heterogeneity in melanoma adjuvant
trialsRFS benefit / Toxic deaths

76. 76
Trial Veredict STAGE IIB STAGE IIIA STAGE IIIB/C STAGE IV Toxic deaths
E1684 - Ifn Non-significant No
EO18071 - Ipi * 1%
CM238 - Nivo No
COMBI-AD -
Dab + Tram
Anecdotal
EO1325 -
Pembro
* Anecdotal
*: Lymph-node >1 mm
Heterogeneity in melanoma adjuvant
trials

77. 77
I w o u l d n o t
r e c o m m e n d
a d j u v a n t t h e r a p y
i n m e l a n o m a
( p e r s o n a l t a k e )
P O S I T I O N S T A T E M E N T
Non-cutaneous melanoma
Stages I and II (including T4)
Stage N1a melanoma with only micro metastasis (≤1 mm)
Interval after LN resection > 13 weeks
ECOG PS ≥2
Autoimmune disease (if Anti PD1 therapy considered)
Cardiovascular disease (if Combi anti BRAF considered)
Expected poor compliance

78. 78
I w o u l d n o t
r e c o m m e n d
a d j u v a n t t h e r a p y
i n m e l a n o m a
( p e r s o n a l t a k e )
P O S I T I O N S T A T E M E N T
Non-cutaneous melanoma
Stages I and II (including T4)
Stage N1a melanoma with only micro metastasis (≤1 mm)
Interval after LN resection > 13 weeks
ECOG PS ≥2
Autoimmune disease (if Anti PD1 therapy considered)
Cardiovascular disease (if Combi anti BRAF considered)
Expected poor compliance

79. 79
I w o u l d n o t
r e c o m m e n d
a d j u v a n t t h e r a p y
i n m e l a n o m a
( p e r s o n a l t a k e )
P O S I T I O N S T A T E M E N T
Am I right? Quizás, quizás, quizás!
Non-cutaneous melanoma
Stages I and II (including T4)
Stage N1a melanoma with only micro metastasis (≤1 mm)
Interval after LN resection > 13 weeks
ECOG PS ≥2
Autoimmune disease (if Anti PD1 therapy considered)
Cardiovascular disease (if Combi anti BRAF considered)
Expected poor compliance

80. 80
References
M a i n
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H.
J., Arance, A. M., Cowey, C. L., … CheckMate
238 Collaborators. (2017). Adjuvant Nivolumab
versus Ipilimumab in Resected Stage III or IV
Melanoma. New England Journal of Medicine,
377(19), 1824–1835. https://doi.org/10.1056/
NEJMoa1709030
C h e c k M a t e 2 3 8
Eggermont, A. M. M., Chiarion-Sileni, V., Grob, J.-J.,
Dummer, R., Wolchok, J. D., Schmidt, H., …
Testori, A. (2015). Adjuvant ipilimumab versus
placebo after complete resection of high-risk
stage III melanoma (EORTC 18071): a
randomised, double-blind, phase 3 trial. The
Lancet. Oncology, 16(5), 522–30. https://doi.org/
10.1016/S1470-2045(15)70122-1
E O R T C 1 8 0 7 1
Eggermont, A. M. M., Blank, C. U., Mandala, M.,
Long, G. V., Atkinson, V., Dalle, S., … Robert,
C. (2018). Adjuvant Pembrolizumab versus
Placebo in Resected Stage III Melanoma. New
England Journal of Medicine, NEJMoa1802357.
https://doi.org/10.1056/NEJMoa1802357
K e y n o t e 0 5 4
Long, G. V., Hauschild, A., Santinami, M., Atkinson,
V., Mandalà, M., Chiarion-Sileni, V., …
Kirkwood, J. M. (2017). Adjuvant Dabrafenib
plus Trametinib in Stage III BRAF -Mutated
Melanoma. New England Journal of Medicine,
377(19), 1813–1823. https://doi.org/10.1056/
NEJMoa1708539
C o m b i - A D
Kirkwood, J. M., Manola, J., Ibrahim, J., Sondak, V.,
Ernstoff, M. S., Rao, U., & Eastern Cooperative
Oncology Group. (2004). A pooled analysis of
eastern cooperative oncology group and intergroup
trials of adjuvant high-dose interferon for
melanoma. Clinical Cancer Research : An Official
Journal of the American Association for Cancer
Research, 10(5), 1670–7. Retrieved from http://
www.ncbi.nlm.nih.gov/pubmed/15014018
I F N p o o l e d a n a l y s i s
Kirkwood, J. M., Strawderman, M. H., Ernstoff, M. S.,
Smith, T. J., Borden, E. C., & Blum, R. H. (1996).
Interferon alfa-2b adjuvant therapy of high-risk
resected cutaneous melanoma: the Eastern
Cooperative Oncology Group Trial EST 1684.
Journal of Clinical Oncology, 14(1), 7–17. https://
doi.org/10.1200/JCO.1996.14.1.7
E C O G 1 6 8 4