Adyuvancia melanoma BRAF mutado
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Hotel InterContinental Medellín, 05/04/2019, patrocinado por Novartis.
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Adyuvancia melanoma BRAF mutado
- 1. Hotel Intercontinental, Medellín, 04/05/2019
- 2. 2 Conflicts of interest for this talk Mauricio Lema Medina @Onconerd
- 8. Occult LN metastasis (ie, findings in the SNB)
- 12. 12 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 IIIC T0 T1a/b, T2a/b, T3a T3b, T4a T4b N2b/c N3b/c N2c, N3a/b/c N1 N1a-N2c IIID T4b N3a/b/c Stage III melanomas are highly heterogeneous
- 13. 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
- 14. 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 greatest dimension of metastatic focus in SNB High risk >1 mm
- 16. 7651 CR3 457-714 Active site 577-622 B-RAF mutations in human cancer CR3 Active site 577-622 714457 CR2 236-283CR1 156-227 RBD 151-231 CRD 239-285 N-region V459L lung N486-P490del ovary M117R skin V600E skin V459L lung L597V lung Frequency of mutation: ≥50% <1% 1-2% P453T colon R444W skin, uterus R444T uterus T440P lung R443T uterus K439Q lung K439T skin, lung I326T breast A727V leukemia R462I colon, uterus I463S colon G464V colon, breast G464E colon, ovary G464R skin G466V lung, skin G466E skin G466R skin G469A lung, leukemia G469V colon, skin G469E colon V471F lung K475M skin L588R skin L588P skin D587E skin, colon D587A colon D587N skin G596R colon G596D uterus G596S skin L597V lung L597S skin L597R ovary L618S skin N581S colon N581I skin I582M skin L584F skin E586K skin, ovary D594G colon, skin D594K colon D594N skin A598T skin A598V skin A598-T599insV thyroid F595L skin F595S skin T599I colon, skin T599ins skin, thryroid V600E skin, colon, thyroid V600-S605>D skin K601E skin, colon, thyroid K601N skin, leukemia K601Q colon W604G skin W604S skin W604del colon S605G skin S605N skin S605F skin G606E skin G606L lung G606R colon H608R skin S614P skin Q612X thyroid S616F pancreas, ovary S616P skin G615R skin R682R uterus
- 17. RTK Ras V600 BRAF mutation MEK ERK Transcription Cell membrane Nuclear membrane DNA ↑Proliferation ↑Survival
- 18. MEK ERK Transcription Nuclear membrane DNA ↑Proliferation ↑Survival V600 BRAF mutation Approx 50% of cutaneous melanoma
- 19. MEK ERK Transcription Nuclear membrane DNA ↑Proliferation ↑Survival V600 BRAF mutation Anti BRAF RTK Ras Cell membrane
- 20. MEK ERK Transcription Nuclear membrane DNA ↓Proliferation ↓Survival V600 BRAF mutation Anti BRAF RTK Ras Cell membrane Dabrafenib Vemurafenib Encorafenib
- 21. MEK ERK Transcription Nuclear membrane DNA V600 BRAF mutation Anti BRAF ↑RTK ↑Ras Cell membrane Dabrafenib Vemurafenib Encorafenib Anti BRAF resistance Mechanisms ↑cRAF ↓Proliferation ↓Survival ↑COT
- 22. mMEK ERK Transcription Nuclear membrane DNA V600 BRAF mutation Anti BRAF ↑RTK ↑Ras Cell membrane Dabrafenib Vemurafenib Encorafenib Anti BRAF resistance Mechanisms ↑cRAF ↓Proliferation ↓Survival ↑COT
- 23. MEK ERK Transcription Nuclear membrane DNA ↓Proliferation ↓Survival V600 BRAF mutation Anti BRAF RTK Ras Cell membrane Dabrafenib Vemurafenib Encorafenib Anti MEK Trametinib Cobimetinib Binimetinib Dual, BRAF and MEK, blockade
- 24. Cutaneous melanoma (≤1 mm) Wide resection of the primary
- 25. Cutaneous melanoma (≤1 mm), cN0 Wide resection of the primary Cutaneous melanoma, cN+ Wide resection of the primary Lymph-node dissection
- 26. Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy
- 27. Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy Low-risk N1 (<1 mm tumor diameter)
- 28. Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy Low-risk N+ (≤1 mm tumor diameter) Higher risk N+ (≥1 mm tumor diameter)
- 29. Cutaneous melanoma (≤1 mm), cN0 Wide resection of the primary Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy Cutaneous melanoma, cN+ Wide resection of the primary Lymph-node dissection Low-risk N+ (≤1 mm tumor diameter) Higher risk N+ (≥1 mm tumor diameter)
- 30. Cutaneous melanoma (≤1 mm), cN0 Wide resection of the primary Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy Cutaneous melanoma, cN+ Wide resection of the primary Lymph-node dissection Low-risk N+ (≤1 mm tumor diameter) Higher risk N+ (≥1 mm tumor diameter) BRAF mutated (V600E/D)
- 31. 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
- 32. 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
- 33. 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).
- 34. 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
- 35. 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
- 36. 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)
- 37. 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
- 38. 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
- 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. Long G, NEJM, 2017 Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma - COMBI-AD Trial
- 41. 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
- 42. 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
- 43. 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: 26%
- 44. Long G, NEJM, 2017 Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma - COMBI-AD Trial
- 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
- 46. 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
- 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
- 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. Weibull cure rate model Probability alive at time t = probability cured + probability not cured × probability alive at time t if not cured
- 51. Time Survival Not-cured Cured Cure-rate model Time Survival Not-cured Cured Treatment A Treatment B
- 52. 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
- 53. 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
- 54. 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
- 55. 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
- 56. Cutaneous melanoma (≤1 mm), cN0 Wide resection of the primary Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy Cutaneous melanoma, cN+ Wide resection of the primary Lymph-node dissection Low-risk N+ (≤1 mm tumor diameter) Higher risk N+ (≥1 mm tumor diameter) BRAF mutated (V600E/D) Adjuvant: Dabrafenib / Trametinib
- 57. 57 Weber, J., NEJM, After complete resection of stage IIIB, IIIC, or IV melanoma RANDOMIZED .,1 : 1 Nivolumab Ipilimumab
- 58. Cutaneous melanoma (≤1 mm), cN0 Wide resection of the primary Cutaneous melanoma (>1 mm), cN0 Wide resection of the primary Sentinel-node biopsy Cutaneous melanoma, cN+ Wide resection of the primary Lymph-node dissection Low-risk N+ (≤1 mm tumor diameter) Higher risk N+ (≥1 mm tumor diameter) BRAF mutated (V600E/D) Adjuvant: Dabrafenib / Trametinib Adjuvant: Nivolumab
- 59. 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)
- 60. Three reasons why: Feasible Cures Long follow-up Adjuvant Dabrafenib and Trametinib in BRAF mutatated melanoma
- 61. Three reasons why: Feasible Cures Long follow-up Adjuvant Dabrafenib and Trametinib in BRAF mutatated melanoma
- 62. Three reasons why: Feasible Cures Long follow-up Adjuvant Dabrafenib and Trametinib in BRAF mutatated melanoma