Adjuvant treatment in melanoma. María González Cao Servicio Oncología Médica Institut Universitari Dexeus-Quiron. Barcelona Formigal, 24th June PDF Free Download

Adjuvant treatment in melanoma María González Cao Servicio Oncología Médica Institut Universitari Dexeus-Quiron. Barcelona Formigal, 24th June 2016

Charles M. Balch et al. JCO 2009;27:6199-6206 Survival by AJCC stages

Breast Cancer Oncotype This material has been prepared by the WW medical team for internal training purposes. It may also be used externally but only after local approval has been obtained.

Melanoma-specific survival for sentinel-node tumor burden according to (A) Rotterdam criteria, (B) subcapsular location, and (C) Rotterdam-Dewar Combination criteria Submicrometastases in the subcapsular: NSN positivity rate 2% and MSS 10y of 95% Augustinus P.T. van der Ploeg et al. JCO 2011;29:2206-2214

BRAF IIIB/C 134 patients lymphadenectomy and no adjuvant treatment: 39 BRAF+ G Long 2011

NRAS and BRAF Mutational Status and MSS Higher-Risk Primary Melanoma JAMA Oncol. 2015;1(3):359-368

Figure 4 PD-L1 and NKG2D on CD8 blood cells and TILs Zitvogel 2016 Journal of Investigative Dermatology 2016 136, 994-1001DOI: (10.1016/j.jid.2015.12.042)

Adjuvant treatments Failled BCG BVZ Cellular vaccines Biochemo? FDA Approved Interferon alpha IIB/C and III 1995 Pegintron ------III 2001 Ipilimumab-----III 2015 Ongoing Anti PD-1/PD-L1 (KEYNOTE054; CheckMate238) BRAF/MEKi (COMBI-AD; BRIM-8)

Interferon Producing cells IFN alpha Plasmocitoi IFN beta d dendrtics Fibroblast Most cells IFN gamma TH1 Inhibitories CK IL10 Activating CK IL12

Interferon Acción antiproliferativa Activación de NK Sobreregulación de HLA I y II antígenos Antiangiogénico

Ivaskiv. Nature 2015.

PRRPs: pattern recognition receptors Figure 2 Three members: RIG-1 (retinoic acid inducible gene 1)(also known as DDX58) i MDA-5 (melanoma differentiation associated gene 5) LGP2: laboratory of genetics and phisiology 2 : negative regulator dsrna also recognized by TLRs (in mbrane or endosomes). Chiappinelli et al. Cell 2015

Dear, NEJM, 2016

Enhancing Tumor-Cell Visibility to the Immune System with the Use of Viral Mimicry Dear AE. N Engl J Med 2016;374:684-686.

Persistent type I interferon exposure in chronic infection induces immunosuppression Ivaskiv. Nature 2015.

IFN alpha Neoadyuvant 20 pac, RO 55%, p RC 15% Moschos, S. J. et al. J Clin Oncol; 24:3164-3171 2006

Immunohistochemical staining for CD3 (A, B) and CD11c (C, D) in melanoma-infiltrated lymph nodes from a clinical responder before (A, C) and after (B, D) treatment Moschos, S. J. et al. J Clin Oncol; 24:3164-3171 2006

Wang W, Kirwood JM. Clin Cancer Res 2007 Wang. Cancer Imm Immunotherapy 2008

IFN regimens Low doses: 3 MU per day for 3 d/w Medium doses: 5 to 10 MU per day sc for 3 to 5 d/w High dose: 20 MU/m2/d iv for 5 d/w followed by 11 months of intermediate-dose sc IFN with 10 MU/m 2 /d for 3 d/w.

Low/intermedium doses

High doses IFN

Efficacy in ECOG 1684 1 Individual Studies: Improvement in RFS but Not OS in the Adjuvant Setting High-Dose IFN- -2b (n=143) Observation (n=137) Median RFS, Years 1.72 0.98 P=0.0023 Median OS, Years 3.82 2.78 P=0.0237 Efficacy in ECOG 1690 2 High-Dose IFN- -2b Low-Dose IFN- -2b Observation 5-Year RFS, % 44 40 35 5-Year OS, % 52 53 55 Efficacy in ECOG 1694 3 GMK IFN- -2b Relapse at 16 Months 39% 25% P=0.0015 OS at 16 Months 1.52 in favor of IFN- -2b P=0.009 1. Kirkwood JM, et al. J Clin Oncol. 1996;14:7-17. 2. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 3. Kirkwood JM, et al. J Clin Oncol. 2001;19:2370-2380.

ECOG 1684

(A) E1684 at median follow-up of 12.6 years, (B) E1690 at a median follow-up of 6.6 years, (C) E1694 at a median follow-up of 2.1 years, and (D) E2696 at a median follow-up of 2.8 years John M. Kirkwood et al. Clin Cancer Res 2004;10:1670-1677

John M. Kirkwood et al. Clin Cancer Res 2004;10:1670-1677

Survival of pooled analysis of E1684 and E1690 (n = 713) John M. Kirkwood et al. Clin Cancer Res 2004;10:1670-1677

Forest plot of hazard ratios (HRs) (interferon alpha [IFN-α] vs control) for DFS Simone Mocellin et al. JNCI J Natl Cancer Inst 2010;102:493-501

Forest plot of hazard ratios (HRs) (interferon alpha [IFN-α] vs control) for OS Simone Mocellin et al. JNCI J Natl Cancer Inst 2010;102:493-501

Qué población se beneficia? 1 ganglio 1684 2-3 ganglios 1690 T4 N0 1694

Safety in ECOG 1690 (Incidence of Grade 3 and 4 AEs Occurring in 5% of Patients) 1 Toxicity Type, n (%) High-Dose IFN- -2b (n=212) Low-Dose IFN- -2b (n=214) Observation (n=207) Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Granulocytopenia 85 (40) 9 (4) 12 (6) 0 0 0 Liver toxicity 61 (29) 0 8 (4) 1 (0.05) 6 (3) 0 Fatigue 49 (23) 2 (1) 7 (3) 0 0 0 Neuroclinical 42 (20) 0 14 (6) 0 2 (1) 0 Myalgia 35 (16) 2 (1) 18 (8) 0 0 0 Leukopenia 30 (14) 0 2 (1) 0 0 0 Nausea 19 (9) 0 5 (2) 0 2 (1) 0 Neuropsychiatric 18 (8) 2 (1) 5 (2) 0 0 0 Neuromotor 12 (6) 1 (0.05) 2 (1) 0 0 0 Vomiting 11 (5) 1 (0.05) 3 (1) 0 2 (1) 0 AEs, adverse events. 1. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458.

Reducción o retraso dosis E1684 n % E1690 n % E1694 n % Inducción 53/143 37 89/202 44 109/396 28 Manteni miento 46/128 36 97/185 52 131/356 37

EORTC 18991 Pegylated IFN-a-2b, 6mg/kg/w sc for 8 w, then 3mg/kg/w for 5y EORTC 18991:Stage IIII; At 7.6 years median follow-up, 384 recurrences or deaths had occurred with pegylated IFN-a-2b vs 406 in the observation group (P=0.055) 4 There was no significant effect on OS or distant metastasis-free survival DeCOG 3 MIU por 18m vs 60m en N0 y T>1.5mm: ns DFS, JCO 08 Bottomley. J Clin Oncol 09, Eggermont, Lancet 08

This material has been prepared by the WW medical team for internal training purposes. It may also be used externally but only after local approval has been obtained. Ipilimumab Clinical Trials in Adjuvant Melanoma Trial NCT Identifier Phase Comparator Stage N Outcome EORTC 18071/CA184-029 1 NCT00636168 3 placebo III 951 ECOG 1609 2 NCT01274338 3 IFN- -2b III-IV 1545 (estimated enrollment) Moffitt pilot study 3 NCT00084656 2 NA IIIc/IV 75 RFS (P=0.0013) RFS, OS (--) OS, RFS (NR) 1. Eggermont AM, et al. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL. 2. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/nct01274338. Accessed on December 1, 2014. 3. Sarnaik AA, et al. Clin Cancer Res. 2011;17:896-906.

Study EORTC 18071/CA184-029 1 A phase 3 study of ipilimumab versus placebo to prevent recurrence after complete resection of high-risk stage III melanoma (NCT00636168) R0 Stage III skin melanoma (LN >1 mm, no in-transit mets) No prior treatment (except surgery) N=951 R a Ipi high dose N=475 Induction Phase 10 mg/kg IV Q3W 4 Placebo N=476 Induction Phase 10 mg/kg IV Q3W 4 Maintenance Phase 10 mg/kg IV Q3M 12 Maintenance Phase 10 mg/kg IV Q3M 12 Stratification factors: Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC 4 positive lymph nodes) Regions (North America, European countries, and Australia)

Ipilimumab EORTC18071 Ongoing ECOG 1609. IFN vs IPI 3 vs 10 Eggermont. Lancet Oncol 2015

EORTC 18071/CA184-029: Patient Disposition and Treatment 1 Ipilimumab (n=471) Placebo (n=474) Discontinuation, % a 91.7 83.1 Reasons for discontinuation, % Normal completion a 7.0 16.2 Disease progression 28.0 57.6 AE related to study drug 48.8 1.7 Other reasons b 7.9 7.6 Median doses, per patient 4.0 8.0 Mean doses, per patient 5.7 8.8 Receiving 1 maintenance dose, % 42.0 70.0 Receiving 7 doses (1 year of therapy), % 28.9 56.8 a 1.9% of patients in the ipilimumab group and 3.0% in the placebo group had 16 cycles reported as per protocol without a documented reason for discontinuation. b Less than 1% difference between groups; includes AE unrelated to study drug, both (related and unrelated to study drug), patient request, poor/noncompliance, death, pregnancy, patient no longer eligible, other. 1. Eggermont AM, et al. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL.

EORTC 18071/CA184-029 Safety: iraes 1 Patients, % Ipilimumab (n=471) Placebo (n=474) All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Any irae 90.4 36.5 5.5 38.6 2.3 0.2 Dermatologic 63.3 4.5 0 20.9 0 0 Rash 34.4 1.3 0 11.0 0 0 Gastrointestinal 46.3 14.9 1.1 17.7 0.6 0.2 Diarrhea 41.4 9.6 0 16.7 0.4 0 Colitis a 15.9 6.8 0.8 1.3 0.2 0 Endocrine 37.6 7.9 0.6 6.5 0 0 Hypophysitis 18.3 4.7 0.4 0.4 0 0 Hypothyroidism 8.9 0.2 0 0.8 0 0 Hepatic 25.1 7.9 2.8 4.4 0.2 0 LFT increase 19.7 3.8 1.5 4.0 0 0 Neurologic 4.5 1.1 0.8 1.9 0 0 Other 23.6 7.4 0.4 4.4 1.7 0 a Gastrointestinal perforations: ipilimumab, 6 related (1.3%); placebo, 3 unrelated (0.6%). 1. Eggermont AM, et al. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL.

Proportion With Event Proportion With Event Proportion With Event Proportion With Event EORTC 18071/CA184-029: Time to Onset of Grade 2-5 iraes 1 0.35 Skin 0.35 Gastrointestinal Ipilimumab 10 mg/kg (n=471) Placebo (n=474) 0.30 0.30 0.25 0.25 0.20 0.15 Median time to onset (ipilimumab): 4.3 weeks (range: 0.3-144.1) 0.20 0.15 Median time to onset (ipilimumab): 6.3 weeks (range: 0.3-145.0) 0.10 0.10 0.05 0.05 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Number of Doses 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Number of Doses 0.35 Hepatic 0.35 Endocrine 0.30 0.30 0.25 0.20 Median time to onset (ipilimumab): 8.7 weeks (range: 1.9-48.0) 0.25 0.20 Median time to onset (ipilimumab): 10.8 weeks (range: 0.3-90.1) 0.15 0.15 0.10 0.10 0.05 0.05 0.00 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Number of Doses Number of Doses 1. Eggermont AM, et al. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL.

EORTC 18071/CA184-029: Resolution of Grade 2-4 iraes 1 Ipilimumab (n=471) Placebo (n=474) Skin irae N with event 129 14 Resolved, n (%) 115 (89.1) 13 (92.9) Median, weeks (95% CI) 5.5 (4.1-8.1) 2.6 (0.1-39.7) Gastrointestinal irae N with event 144 18 Resolved, n (%) 135 (93.8) 17 (94.4) Median, weeks (95% CI) 4.0 (2.7-5.1) 0.9 (0.4-1.9) Hepatic irae N with event 77 5 Resolved, n (%) 73 (94.8) 4 (80.0) Median, weeks (95% CI) 5.0 (3.7-8.4) 12.0 (1.1-NR) Endocrine irae N with event 134 5 Resolved, n (%) 75 (56.0) 4 (80.0) Median, weeks (95% CI) 31.0 (13.9-186.0) 12.6 (3.4-NR) NR, not reached. 1. Eggermont AM, et al. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL.

EORTC 18071/CA184-029: Deaths 1 Five patients (1.1%) died due to drug-related AEs in the ipilimumab group 3 patients with colitis (2 with gastrointestinal perforations) 1 patient each with myocarditis 1 patient with Guillain-Barré syndrome had multi-organ failure 1. Eggermont AM, et al. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL.

Phase 3 Study ECOG 1609 1 Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery (NCT01274338) Arm A: Ipi High Dose n=500 Induction Phase 10 mg/kg IV Q3W 4 Maintenance Phase 10 mg/kg IV Q3M 4 R0 Stage IIIB- IV (M1a/b) (no IIIA) N=1500 R a Arm B: : Ipi High Dose n=500 Induction Phase 20 MU/m 2 IV 5 /wk 4 wk Maintenance Phase 10 MU/m 2 SC TIW Arm C: Ipi Low Dose n=500 Induction Phase 3 mg/kg IV Q3W 4 Maintenance Phase 3 mg/kg IV Q3M 4 1. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/nct01274338. Accessed on December 1, 2014.

Phase 3 Study ECOG 1609 1 (cont d) Coprimary endpoints: RFS and OS Secondary endpoints: Safety and quality of life Current estimated enrollment: 1545 (1-Dec-14) Study Start Date: May 2011 Estimated Primary Completion Date: May 2018 1. Clinicaaltrials.gov. https://clinicaltrials.gov/ct2/show/nct01274338. Accessed on December 1, 2014.

Randomization 1:1 Design: CA209-238 Screening Double-Blind Treatment Follow -Up Stage IIIb/c or stage IV Previously untreated Tumor tissue available for PD-L1 testing Pathology report (Stage III and IV) Arm A ipilimumab 10 mg/kg (IV Q3W for 4 doses and then every 12 weeks starting at WK 24) + nivolumab placebo IV Q2 weeks Arm B nivolumab 3 mg/kg IV Q2 weeks + ipilimumab placebo IV Q3W for 4 doses and then every 12 weeks starting at WK 24 Post treatment follow-up for safety, recurrence events, and overall survival 2 visits: 1 & 2 Survival Follow-up visit Primary Endpoint: Recurrence Free Survival Treat until disease recurrence or unacceptable toxicity with maximum one year Secondary Endpoint: Overall Survival

Randomization 1:1 Keynote-054 Screening Double-Blind Treatment Follow -Up Stage III Previously untreated Tumor tissue available for PD-L1 testing Arm A placebo Post treatment follow-up for safety, recurrence events, and overall survival Arm B Pembrolizumab 200mg iv 3w for 12m Treat until disease recurrence or unacceptable toxicity with maximum one year Survival Follow-up visit Primary Endpoint: Recurrence Free Survival in PD-L1 + Secondary Endpoint: Overall Survival

Unsupervised hierarchical clustering of 83 primary melanoma Véronique Winnepenninckx et al. JNCI J Natl Cancer Inst 2006;98:472-482

Pedram Gerami et al. Clin Cancer Res 2015;21:175-183 prognostic 28-gene signature

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mucosal Chemo

Adjuvant treatment in melanoma. María González Cao Servicio Oncología Médica Institut Universitari Dexeus-Quiron. Barcelona Formigal, 24th June 2016