Melanoma BRAF mutado y terapias dirigidas. Javier Medina Martínez Hospital Virgen de la Salud, Toledo

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1 Melanoma BRAF mutado y terapias dirigidas Javier Medina Martínez Hospital Virgen de la Salud, Toledo

2 Enfermedad avanzada: Seguimiento a largo plazo Retratamiento Metástasis cerebrales Adyuvancia

3 November-2017 Approach to Melanoma Immunotherapy Targeted BRAFmutant melanoma Checkpoint inhibitors Anti CTLA-4 (ipilimumab) Anti PD-1 (nivolumab, pembrolizumab) Anti PD-1 + anti CTLA-4 (nivolumab + ipilimumab) Monotherapy Vemurafenib Dabrafenib Trametinib Intralesional oncolytic immunotherapy T-VEC (talimogene laherparepvec) BRAF/MEK combination therapy Dabrafenib/trametinib Vemurafenib/cobimetinib

4 Genomic Classification of Cutaneous Melanoma

6 ENFERMEDAD AVANZADA

7 PFS (%) PFS (%) Single-Agent BRAF Inhibition vs Dacarbazine in Advanced Melanoma: PFS Dabrafenib [1] HR: 0.30 (95% Cl: ; P <.0001) Dabrafenib (n = 187) Vemurafenib [2] HR: 0.26 (95% Cl: ; P <.001) Vemurafenib (n = 275) Dacarbazine (n = 63) Dacarbazine (n = 274) Mos ORR: 50% vs 6% with dacarbazine Mos ORR: 48% vs 5% with dacarbazine 1. Hauschild A, et al. Lancet Oncol. 2012;380:

8 PFS (%) PFS (%) Single-Agent BRAF Inhibition vs Dacarbazine in Advanced Melanoma: PFS Dabrafenib [1] HR: 0.30 (95% Cl: ; P <.0001) Dabrafenib (n = 187) Vemurafenib [2] HR: 0.26 (95% Cl: ; P <.001) Vemurafenib (n = 275) Dacarbazine (n = 63) Dacarbazine (n = 274) Mos ORR: 50% vs 6% with dacarbazine Mos ORR: 48% vs 5% with dacarbazine 2. Chapman PB, et al. N Engl J Med. 2011;364:

10 Overall Survival BRIM3

11 OS: ECOG 0 vs 1

12 OS: LDH normal vs elevated

13 Mechanisms of resistance to BRAF inhibitor therapy 1. Wood K, Luke J, AJHO. 2017;13(1):4-10

14 Phase III Studies: BRAF + MEK Inhibition in Previously Untreated Adv Melanoma Pts with stage IIIc/IV unresectable melanoma with BRAF V600E/K, ECOG PS 0/1 (N = 704) Pts with stage IIIc/IV unresectable melanoma with BRAF V600 mutation, ECOG PS 0/1 (N = 495) Combi-V [1] Dabrafenib 150 PO BID + Trametinib 2 mg PO QD (n = 352) Vemurafenib 960 mg PO BID (n = 352) cobrim [2] Vemurafenib 960 mg PO BID + Cobimetinib 60 mg PO QD 3 wks on, 1 wk off (n = 247) Vemurafenib 960 mg PO BID + Placebo BID 3 wks on, 1 wk off (n = 248) Until disease progression or unacceptable toxicity Until disease progression or unacceptable toxicity Primary endpoint (both trials): OS 1. Robert C, et al. N Engl J Med. 2015;372: Larkin J, et al. N Engl J Med. 2014;371:

15 PFS (%) PFS (%) Combination BRAF/MEK Inhibition vs Single-Agent BRAF Inhibition: PFS HR: 0.56 (95% CI: ; P <.001) HR: 0.51 (95% CI: ; P <.001) Dabrafenib + trametinib (n = 352) Vemurafenib + cobimetinib (n = 247) Vemurafenib (n = 352) Mos Vemurafenib + placebo (n = 248) Mos Combi-V [1] cobrim [2] 1. Robert C, et al. N Engl J Med. 2015;372:

16 PFS (%) PFS (%) Combination BRAF/MEK Inhibition vs Single-Agent BRAF Inhibition: PFS HR: 0.56 (95% CI: ; P <.001) HR: 0.51 (95% CI: ; P <.001) Dabrafenib + trametinib (n = 352) Vemurafenib + cobimetinib (n = 247) Vemurafenib (n = 352) Mos Vemurafenib + placebo (n = 248) Mos Combi-V [1] cobrim [2] 2. Larkin J, et al. N Engl J Med. 2014;371:

17 OS (%) Combi-V Study of Dabrafenib + Trametinib vs Vemurafenib: OS Dabrafenib + trametinib Vemurafenib Median, mos (95% CI) Adjusted HR (95% CI) 2-sided P value (stopping boundary) D+T Vemurafenib (n = 352) (n = 352) NR 17.2 (18.3-NR) (16.4-NR) 0.69 ( ).005 (<.0214) Mos Robert C, et al. N Engl J Med. 2015;372:30-39.

18 OS (%) CoBRIM Study of Vemurafenib ± Cobimetinib: OS Vemurafenib + placebo (N = 248) HR: 0.65 (95% CI: ; P =.046) Vemurafenib + cobimetinib (N = 247) Mos Larkin J, et al. N Engl J Med. 2014;371:

20 PFS

21 PFS

22 PFS by RECIST response

23 OS

24 OS by RECIST response

25 Efficacy of Long-Term Cobimetinib + Vemurafenib in Advanced BRAF V600 -Mutated Melanoma: 3-Year Follow-up of cobrim (Phase 3) and Grant A. McArthur, 1 Brigitte Dréno, 2 Victoria Atkinson, 3 James Larkin, 4 Paolo A. Ascierto, 5 Adil Daud, 6 Anna Pavlick, 7 Rene Gonzalez, 8 Karl D. Lewis, 8 Omid Hamid, 9 Thomas Gajewski, 10 Igor Puzanov, 11 Jessie Hsu, 12 Erica Park, 12 Antoni Ribas 13 1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia and University of Melbourne, Parkville, VIC, Australia; 2 Nantes University, Nantes, France; 3 Princess Alexandra Hospital, Gallipoli Medical Research Foundation and University of Queensland, Woolloongabba, QLD, Australia; 4 The Royal Marsden NHS Foundation Trust, London, UK; 5 Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy; 6 University of California, San Francisco, San Francisco, CA, USA; 7 New York University Medical Center, New York, NY, USA; 8 University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 9 The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 10 University of Chicago, Chicago, IL, USA; 11 Roswell Park Cancer Institute, Buffalo, NY, USA; 12 Genentech, Inc., South San Francisco, CA, USA; 13 Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, CA, USA Presented as a poster at: the Society for Melanoma Research 2016 Congress; McArthur G et al. November 6-9, 2016; Boston, MA, USA.

26 cobrim: PFS Corte base de datos: 16 enero Ascierto PA, McArthur GA, Dréno B et al. Cobimetinib combined with vemurafenib in advanced BRAFV600 mutant melanoma (cobrim): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol Sep;17(9):

27 cobrim: OS benefit remained stable OS, % C + V P + V Median OS, months (95% CI) 22.5 (20.3, 28.8) 17.4 (15.0, 19.8) HR (95% CI); P-value 0.76 ( ); P = Time, Months C, cobimetinib; OS, overall survival; P, placebo; V, vemurafenib. Data cutoff: 20 June 2016

28 cobrim : landmark survival rates were higher in patients with normal LDH patients with elevated LDH in cobrim (43 46%) vs COMBIv (32 37%); these pts have poorer prognosis, and disease severity was likely greater in cobrim than in COMBI-v. C + V (LDH normal) P + V (LDH normal) C + V (LDH elevated) P + V (LDH elevated) Censored Patients at risk, n C + V (LDH normal) P + V (LDH normal) C + V (LDH elevated) P + V (LDH elevated) C, cobimetinib; LDH, lactate dehydrogenase; OS, overall survival; P, placebo; V, vemurafenib. Data cutoff: 20 June 2016

29 14th International Congress of the Society for Melanoma Research/9th World Congress of Melanoma; October 18 21, 2017.

32 Randomised, open-label phase 3 study done in 26 countries. Patients with advanced, unresectable, IIIC or stage IV NRAS-mutant melanoma who were: previously untreated had progressed on or after previous immunotherapy were randomised (2:1) to receive: binimetinib 45 mg orally twice daily dacarbazine 1000 mg/m² intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy.

33 The primary endpoint was progression-free survival assessed by blinded central review in the intention-totreat population.

34 Progression-free survival 2 8 months VS 1 5 months Overall survival 11 0 months VS 10 1 months

35 Progression-free survival in prespecified subgroups 2 8 months VS 1 5 months 5 5 months VS 1 6 months

36 Adverse events

37 ENFERMEDAD AVANZADA: RETRATAMIENTO

39 Methods Open-label, single arm, dual-centre, phase 2 academic study in Belgium BRAF V600 -mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks Treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigatorassessed overall response at any time

Between April 2014, and Feb 2016 25 patients were enrolled Partial response in 8

40 Between April 2014, and Feb patients were enrolled Partial response in 8 (32%) of 25 patients (95% CI 15 54; Stable disease in 10 patients (40%; 95% CI 21 61). Median PFS was 4.9 months 6 patients had progressed on previous treatment with dabrafenib plus trametinib and 2 patients had progressed on previous BRAF inhibitor monotherapy.

41 Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]).

42 ENFERMEDAD AVANZADA: METÁSTASIS CEREBRALES

44 Dabrafenib in patients with Val600Glu or Val600Lys BRAFmutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D McArthur GA, Maio M, Arance A, Nathan P, Blank C, Avril MF, Garbe C, Hauschild A, Schadendorf D, Hamid O, Fluck M, Thebeau M, Schachter J, Kefford R, Chamberlain M, Makrutzki M, Robson S, Gonzalez R, Margolin K Lancet Oncol Nov;13(11): Ann Oncol. 2017;28(3):634. not received previous local treatment: RR 39 2% received previous local treatment: RR 30 8% not received previous local treatment: RR INV 29% received previous local treatment: RR INV 23%

45 Multicentre, multicohort, open-label, phase 2 study evaluated dabrafenib plus trametinib in four patient cohorts with melanoma brain metastases 32 hospitals in Europe, North America, and Australia (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an ECOG performance status of 0 or 1 (B) BRAF V600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1 (C) BRAF V600D/K/R V600D/K/R -positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1 (D) BRAF V600D/E/K/R V600D/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2.

46 The primary endpoint was investigatorassessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D.

Best intracranial response 58%; 95% CI 46-69 56%;

48 Best intracranial response 58%; 95% CI %; 95% CI %; 95% CI %; 95% CI 33-82)

49 ADYUVANCIA

50 SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE. PRESENTED AT ESMO BRIM8: a randomized, double-blind, placebo-controlled COMBI-AD: ADJUVANT DABRAFENIB PLUS TRAMETINIB study of adjuvant vemurafenib FOR RESECTED in patients STAGE with completely III resected, BRAF V600+ melanoma at high risk for recurrence BRAF V600 MUTANT MELANOMA Lewis K, Maio M, Demidov L, et al. abstract LBA7

51 In a phase III trial, 498 patients were randomly assigned to vemurafenib (960 mg twice daily) or placebo for one year. All patients had completely resected stage IIC or III melanoma. Disease-free survival was significantly prolonged with vemurafenib median not reached versus 25.8 months with placebo, hazard ratio 0.65, 95% CI ). On subset evaluation, benefit appeared to be limited to patients with stages II, IIIA, and IIIB, and was not significant in those with stage IIIC disease.

52 SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE. PRESENTED AT ESMO COMBI-AD: ADJUVANT DABRAFENIB PLUS TRAMETINIB FOR RESECTED STAGE III BRAF V600 MUTANT MELANOMA Axel Hauschild, Mario Santinami, Georgina V. Long, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Jacob Schachter, Ran Ji, Pingkuan Zhang, Bijoyesh Mookerjee, Jeff Legos, Richard Kefford, Reinhard Dummer, John M. Kirkwood

53 Combi-AD: Study design Key eligibility criteria Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma BRAF V600E/K mutation Surgically free of disease 12 weeks before randomization ECOG performance status 0 or 1 No prior radiotherapy or systemic therapy Stratification BRAF mutation status (V600E, V600K) Disease stage (IIIA, IIIB, IIIC) R A N D O M I Z A T I O N N = 870 1:1 Treatment: 12 months a Dabrafenib 150 mg BID + trametinib 2 mg QD (n = 438) 2 matched placebos (n = 432) Follow-up b until end of study c Primary endpoint: RFS d Secondary endpoints: OS, DMFS, FFR, safety BID, twice daily; DMFS, distant metastasis free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; b Patients were followed for disease recurrence until the first recurrence and thereafter for survival; c The study will be considered complete and final OS analysis will occur when 70% of randomized patients have died or are lost to follow-up; d New primary melanoma considered as an event.

54 Baseline demographics and patient characteristics a Dabrafenib Plus Trametinib (n = 438) Placebo (n = 432) Total (N = 870) Median age (range), years 50 (18-89) 51 (20-85) 50 (18-89) Male, n (%) 195 (45) 193 (45) 388 (45) BRAF mutation status, n (%) V600E V600K b 397 (91) 41 (9) 395 (91) 37 (9) 792 (91) 78 (9) ECOG performance status of 0, n (%) 402 (92) 390 (90) 792 (91) Disease stage, n (%) IIIA IIIB IIIC III (unspecified) 83 (19) 169 (39) 181 (41) 5 (1) 71 (16) 187 (43) 166 (38) 8 (2) 154 (18) 356 (41) 347 (40) 13 (1) a Reported for patients with available data; b One patient had both BRAF V600E and BRAF V600K mutations and was included in the V600K subset.

55 Baseline demographics and patient characteristics a (cont) Number of positive lymph nodes, n (%) 1 2 or 3 4 Type of lymph node involvement, n (%) Microscopic Macroscopic Not reported Primary tumour ulceration, n (%) Yes No In-transit disease, n (%) Yes No Dabrafenib Plus Trametinib (n = 438) 177 (40) 158 (36) 73 (17) 152 (35) 158 (36) 128 (29) 179 (41) 253 (58) 51 (12) 387 (88) Placebo (n = 432) 183 (42) 150 (35) 72 (17) 157 (36) 161 (37) 114 (26) 177 (41) 249 (58) 36 (8) 395 (91) Total (N = 870) 360 (41) 308 (35) 145 (17) 309 (36) 319 (37) 242 (28) 356 (41) 502 (58) 87 (10) 782 (90) a Reported for patients with available data.

56 Proportion Alive and Relapse Free Relapse-free survival y, 88% y, 56% 2 y, 67% P = y, 58% Group Dabrafenib plus trametinib Events, n (%) 166 (38) Placebo 248 (57) Median (95% CI), mo NR (44.5-NR) 16.6 ( ) HR (95% CI) 0.47 ( ); P < y, 44% 3 y, 39% No. at Risk Dabrafenib plus trametinib Placebo NR, not reached Months From Randomization

57 Relapse-free survival by Subgroup V600K (n = 78) V600E (n = 792) Male (n = 482) Female (n = 388) < 65 years (n = 712) 65 years (n = 158) Disease stage IIIA (n = 154) Disease stage IIIB (n = 356) Disease stage IIIC (n = 347) Micrometastasis (n = 309) Macrometastasis (n = 319) Micrometastasis and ulceration (n = 143) Micrometastasis and no ulceration (n = 165) Macrometastasis and ulceration (n = 116) Macrometastasis and no ulceration (n = 201) 1 Nodal metastatic mass (n = 360) 2 3 Nodal metastatic masses (n = 308) 4 Nodal metastatic masses (n = 145) HR Favors Dabrafenib Plus Trametinib Favors Placebo 10.00

58 Proportion Alive and Distant Metastasis Free Distant metastasis free survival y, 91% y, 70% 2 y, 77% 2 y, 60% 3 y, 71% 3 y, 57% Group Dabrafenib plus trametinib Events, n (%) 110 (25) Placebo 152 (35) Median (95% CI), mo NR (NR-NR) NR (41.2-NR) HR (95% CI) 0.51 ( ); nominal P <.001 No. at Risk Dabrafenib plus trametinib Placebo Months From Randomization

59 Proportion Alive Overall survival (first interim analysis) y, 97% 1 y, 94% 2 y, 91% 2 y, 83% 3 y, 86% 3 y, 77% No. at Risk Dabrafenib plus trametinib Placebo Group Dabrafenib plus trametinib Events, n (%) 60 (14) Placebo 93 (22) Median (95% CI), mo NR (NR-NR) NR (NR-NR) HR (95% CI) 0.57 ( ); P =.0006 a Months From Randomization a Prespecified significance boundary (P = ).

60 Post-recurrence therapy among patients with relapse Post-recurrence Therapy Dabrafenib Plus Trametinib (n = 163 relapses) Placebo (n = 247 relapses) Any post-recurrence anticancer therapy, n (%) 148 (91) 217 (88) Surgery 78 (48) 131 (53) Radiotherapy 60 (37) 72 (29) Any systemic post-recurrence anticancer therapy, n (%) 120 (74) 183 (74) Small molecule targeted therapy Any BRAF inhibitor a Any MEK inhibitor b Immunotherapy Anti PD-1/PD-L1 Anti CTLA-4 Interferon T-VEC 63 (39) 63 (39) 47 (29) 89 (55) 71 (44) 53 (33) 6 (4) (55) 137 (55) 77 (31) 103 (42) 68 (28) 68 (28) 11 (4) 1 (< 1) Biologic therapy 1 (1) 1 (< 1) Chemotherapy 20 (12) 23 (9) Investigational treatment 6 (4) 19 (8) Other therapy 2 (1) 0 Median time from disease recurrence to start of systemic postrecurrence CTLA-4, cytotoxic therapy, T-lymphocyte associated excluding radiotherapy 4; PD-1, and programmed surgery (range), cell death 1; PD-L1 programmed cell 7.1 death (0-136) ligand 1; T-VEC, talimogene laherparepvec. 7.3 (0-78) a Included weeks dabrafenib, vemurafenib, and encorafenib; b Included trametinib, cobimetinib, and binimetinib.

61 Safety summary AE Category, n (%) Dabrafenib Plus Trametinib (n = 435) AE, adverse event; SAE, serious adverse event. a Most common AEs leading to treatment discontinuation in the dabrafenib plus trametinib arm were pyrexia (9%) and chills (4%). Placebo (n = 432) Any AE 422 (97) 380 (88) AEs related to study treatment 398 (91) 272 (63) Any grade 3/4 AE 180 (41) 61 (14) Any SAE 155 (36) 44 (10) SAEs related to study treatment 117 (27) 17 (4) Fatal AEs related to study drug 0 0 AEs leading to dose interruption 289 (66) 65 (15) AEs leading to dose reduction 167 (38) 11 (3) AEs leading to treatment discontinuation a 114 (26) 12 (3)

62 Common adverse events Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) AEs, n (%) All Grades Grade 3/4 All Grades Grade 3/4 Any AE (> 20% with dabrafenib plus trametinib) a 422 (97) 180 (41) 380 (88) 61 (14) Pyrexia 273 (63) 23 (5) 47 (11) 2 (< 1) Fatigue 204 (47) 19 (4) 122 (28) 1 (< 1) Nausea 172 (40) 4 (1) 88 (20) 0 Headache 170 (39) 6 (1) 102 (24) 0 Chills 161 (37) 6 (1) 19 (4) 0 Diarrhoea 144 (33) 4 (1) 65 (15) 1 (< 1) Vomiting 122 (28) 4 (1) 43 (10) 0 Arthralgia 120 (28) 4 (1) 61 (14) 0 Rash 106 (24) 0 47 (11) 1 (< 1) a Eleven patients (3%) in the treatment arm and 10 patients (2%) in the placebo arm had new primary melanomas; 8 (2%) and 7 (2%), respectively, had cutaneous squamous cell carcinoma/keratoacanthoma; 19 (4%) and 14 (3%), respectively, had basal cell carcinoma; and 10 (2%) and 4 (1%), respectively, had noncutaneous malignancies.

63 Conclusions This is the first randomized study of combination BRAF and MEK inhibition as melanoma adjuvant therapy Dabrafenib plus trametinib significantly reduced the risk of disease recurrence vs placebo in patients with resected high-risk, stage III, BRAF V600E/K mutant melanoma (RFS HR, 0.47 [95% CI, ]; P <.001) Estimated 1-, 2-, and 3-year RFS rates with dabrafenib plus trametinib were 88%, 67%, and 58%, respectively Similar RFS benefit was observed across patient subgroups, including all stage categories

64 Conclusions (cont) OS improvement with dabrafenib plus trametinib was demonstrated (HR, 0.57 [95% CI, ]) Similar rates of post-recurrence therapy in each arm attributes OS improvement to adjuvant dabrafenib plus trametinib treatment Manageable safety profile with combination dabrafenib and trametinib Dabrafenib plus trametinib is a novel adjuvant treatment option for BRAF V600 mutant melanoma

66 Muchas gracias Javier Medina Martínez Hospital Virgen de la Salud, Toledo

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