Simposios auspiciado por Novartis, en el marco del simposio de tumores de piel y tejidos blandos

3. 3
Conflicts of interest for this talk
Mauricio Lema Medina
ALL
@Onconerd

4. SEER database, 2019

7. SEER database, 2019

10. 10N 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
A J C C 8 t h
IIIA T1a/b, T2a N1a or N2a
IIIB T0
T1a/b, T2a
T2b, T3a
N1b, N1c
N1b/c, N2b
N1a/b/c, N2a/b
IIICT0
T1a/b, T2a/b, T3a
T3b, T4a
T4b
IIIDT4b N3a/b/c

11. Final Trial Report of
Sentinel-Node Biopsy
versus Nodal Observation in
Melanoma
Morton DL, NEJM, 2014
Morton, D. L., Thompson, J. F., Cochran, A. J., Mozzillo, N., Nieweg, O. E., Roses, D. F.,
… Faries, M. B. (2014). Final Trial Report of Sentinel-Node Biopsy versus Nodal
Observation in Melanoma. New England Journal of Medicine, 370(7), 599–609.
https://doi.org/10.1056/NEJMoa1310460
Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in
Melanoma- MSLT-I trial

12. HR
95% Confidence-interval
0.37-0.84
1
Favors ObservationFavors SNB
1.50.5
0.56
10-year melanoma-specific survival
of intermediate-thickness (1.2-3.5 mm) melanoma (%)
Morton DL, NEJM, 2014
Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in
Melanoma- MSLT-I trial

13. Biopsy-based management
prolongs disease-free
survival for all patients and
prolongs distant disease–free
survival and melanoma-
specific survival for patients
with nodal metastases from
intermediate-thickness
melanomas
Morton DL, NEJM, 2014
Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in
Melanoma- MSLT-I trial

14. Occult LN
metastasis (ie,
findings in the
SNB)

15. Gershenwald, J. E., CA: Cancer Journal for Clinicians, 67(6), 472–492, 2017
Melanoma Staging: Evidence-Based Changes in the American Joint Committee on Cancer Eighth
Edition Cancer Staging Manual
Melanoma-specific survival according to máximum
dimensión of metastatic focus in SNB
High risk
>1 mm

16. Completion Dissection or
Observation for Sentinel-Node
Metastasis in Melanoma
Faries MB, NEJM, 2017
Faries, M. B., Thompson, J. F., Cochran, A. J., Andtbacka, R. H., Mozzillo, N., Zager, J. S.,
… Elashoff, R. M. (2017). Completion Dissection or Observation for Sentinel-Node
Metastasis in Melanoma. New England Journal of Medicine, 376(23), 2211–2222.
https://doi.org/10.1056/NEJMoa1613210
Completion Dissection or Observation for Sentinel-Node Metastasis in
Melanoma - MSLT-II trial

17. 3-year melanoma-specific survival (%)
0
21.5
43
64.5
86
Observation Dissection
86 86
p=0.42 Faries MB, NEJM, 2017
Completion Dissection or Observation for Sentinel-Node Metastasis in
Melanoma - MSLT-II trial

21. Gershenwald, J. E., CA: Cancer Journal for Clinicians, 67(6), 472–492, 2017
Melanoma Staging: Evidence-Based Changes in the American Joint Committee on Cancer Eighth
Edition Cancer Staging Manual
Melanoma-specific survival according to N-subcategories 8th Edition

22. Gershenwald, J. E., CA: Cancer Journal for Clinicians, 67(6), 472–492, 2017
Melanoma Staging: Evidence-Based Changes in the American Joint Committee on Cancer Eighth
Edition Cancer Staging Manual
Melanoma-specific survival in sub-stages III

23. Longer Follow-Up Confirms Relapse-Free
Survival Benefit With Adjuvant Dabrafenib
Plus Trametinib in Patients With
Resected BRAF V600–Mutant Stage III
Melanoma - COMBI-AD Trial
Hauschild, A., Dummer, R., Schadendorf, D., Santinami, M., Atkinson, V., Mandalà, M., … Long, G. V. (2018). Longer Follow-Up
Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600–Mutant
Stage III Melanoma. Journal of Clinical Oncology, 36(35), 3441–3449. https://doi.org/10.1200/JCO.18.01219
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

24. Underwent complete
resection of
histologically
confirmed melanoma
IIIA (lymph node
metastasis > 1 mm),
IIIB or IIIC (AJCC 7ed)
Age ≥ 18 years
Positive for
a BRAF V600E or
V600K mutation
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial
Have undergone and
recovered from a
complete
lymphadenectomy
within 12 weeks of
random assignment
ECOG PS 0/1

25. Eligible patients (age ≥ 18 years)
underwent complete resection of
histologically confirmed stage IIIA (lymph
node metastasis > 1 mm), IIIB, or IIIC
cutaneous melanoma (per AJCC 7th
edition) that was positive for
a BRAF V600E or V600K mutation
confirmed in primary tumor or lymph node
tissue by a central reference laboratory.
Patients were required to have undergone
and recovered from a complete
lymphadenectomy without clinical or
radiographic indication of regional nodal
disease within 12 weeks of random
assignment and to have an Eastern
Cooperative Oncology Group performance
status of 0 or 1.
R
Dabrafenib + Trametinib
x1y
Two matched placebos
x1y
Primary endpoint: Relapse-Free Survival
1:1
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial
Stratification factors:BRAF mutation status
(V600E or V600K) and disease stage (IIIA, IIIB,
or IIIC according to AJCC 7th edition).

26. Dabrafenib 150 mg PO q12h
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial
Trametinib 2 mg PO q24h

27. Dabrafenib 150 mg PO q12h
MEDSCAPE
Take on empty stomach at least 1 hr before or 2 hr
after meals
A missed dose can be taken up to 6 hr prior to the
next dose
Capsules: 75 mg / 50 mg

28. Trametinib 2 mg PO q24h
MEDSCAPE
Take on empty stomach at least 1 hr before or 2 hr
after meals
A missed dose can be taken up to 12 hr prior to the
next dose
Tablets: 0.5 mg / 2 mg (keep refrigerated)

29. RFS, defined as the time from random
assignment until disease relapse (or new
primary melanoma) or death from any
cause.
DMFS was defined as the time from random
assignment to the date of first distant
metastasis or date of death
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

30. CT/MRI q3mo x24mo,
then q6mo
Dermatologic evaluation q2mo during
treatment,
then q3mo x24mo on follow-up,
then q6mo
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

31. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

32. Long G, NEJM, 2017
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
- COMBI-AD Trial

33. 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

34. 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

35. 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%

36. Long G, NEJM, 2017
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
- COMBI-AD Trial

37. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

38. Relapse-Free Survival (%)
0 15 30 45 60
Dabrafenib + trametinib
Placebo
59
40 HR: 0.49
Median follow-up: 44 months
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

39. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

40. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

41. Weibull cure rate
model
Probability alive at timet = probability cured
+ probability not cured × probability alive at timetif not
cured

42. Time
Survival
Non-cured
Cured
Cure-rate model
Treatment A

43. Time
Survival
Non-cured
Cured
Cure-rate model
Time
Survival
Non-cured
Cured
Treatment A Treatment B

45. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial
Weibull mixture cure-rate model

46. RFS HR 95% CI
IIIA 0.63 0.26-1.56
IIIB 0.48 0.34-0.67
IIIC 0.50 0.38-0.64
IIID 0.34 0.14-0.79
Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

47. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial
According to th AJCC 8th edition

48. Hauschild A, JCO, 2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in
Patients With Resected BRAF V600–Mutant Stage III Melanoma - COMBI-AD Trial

49. 49
Weber, J., NEJM,
After
complete
resection of
stage IIIB,
IIIC, or IV
melanoma
RANDOMIZED
.,1 : 1
Nivolumab
Ipilimumab

50. Trial Biology
Median follow-
up
STAGE IIIA STAGE IIIB/C/D STAGE IV
CM238 - Nivo 24 months
COMBI-AD -
Dab + Tram
mBRAF+ 44 months
*: Lymph-node >1 mm
RFS benefit
Choices for adjuvant therapy in BRAF+ resected melanoma
(in Colombia, 2019)

51. Three reasons why:
Feasible
Cures
Long follow-up
Adjuvant Dabrafenib and
Trametinib in BRAF mutatated
melanoma

52. Three reasons why:
Feasible
Cures
Long follow-up
Adjuvant Dabrafenib and
Trametinib in BRAF mutatated
melanoma

53. Three reasons why:
Feasible
Cures
Long follow-up
Adjuvant Dabrafenib and
Trametinib in BRAF mutatated
melanoma