Melanoma maligno. Aggiornamenti in oncologia tra ricerca e clinica
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1 Aggiornamenti in oncologia tra ricerca e clinica Melanoma maligno M. Del Vecchio Responsabile Gruppo Melanoma Dipartimento di Oncologia Medica Fondazione IRCCS Istituto Nazionale dei Tumori Milano
2 Metastatic melanoma. Limited survival outcomes associated with historical treatment options Historical data indicate median overall survival for patients with metastatic melanoma of 6 to 9 months In a meta-analysis of 42 phase 2 trials in 2,100 patients with metastatic melanoma treated in North America (Korn, JCO 2008): Median overall survival was 6.2 months (range: months) 1-year survival rate was 25.5% (range: %) Months
3 Signalling Pathways Sullivan RJ et al. Clin Cancer Res 2013;19:
4 Genomic Classification of Cutaneous Melanoma
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6 Treatment Options for BRAF V600- Mutant Metastatic Melanoma BRAF/MEK Inhibitors Dabrafenib + trametinib Vemurafenib + cobimetinib Immunotherapy Ipilimumab Nivolumab Nivolumab + ipilimumab Pembrolizumab
7 Combinatorial approaches to overcome BRAFi/MEKi resistance Manzano JL et al. Ann Transl Med 2016
8 RAFI Resistance Mechanisms Lito P et al. Nat Med 2013;19:
9 Rationale for Combination of Dabrafenib and Trametinib in BRAF-mutant Tumours BRAF inhibitor (dabrafenib) OS: 20.1 months 1 PFS: 6.9 months 2 ORR: 59% 2 Hyperproliferative skin AEs 1,2 MEK inhibitor (trametinib) OS: 15.6 months 3 PFS: 4.8 months 4 RR: 22% 4 Rash AE 3,4 Preclinical BRAFi + MEKi 5 Delays BRAFi resistance Reduces hyperproliferative skin AEs AE=adverse event; BRAFi=BRAF inhibitor; HR=hazard ratio; MAPK=mitogen-activated protein kinase; MEK=MAPK kinase; MEKi=MEK inhibitor; ORR=objective response rate; OS=overall survival; perk=phosphorylated extracellular signal-regulated kinase; PFS=progression-free survival; RR=response rate. RAS Mutant BRAF MEK perk Proliferation Survival Invasion Metastasis Goals of combination are to: Suppress MAPK-dependent resistance mechanism Improve PFS, RR and OS Prolong duration of response Reduce the incidence of BRAFi-induced proliferative skin lesions 1. Grob JJ, et al. Poster presented at SMR 2014; 2. Hauschild A, et al. Poster presented at ASCO 2013; 3. Schadendorf D, et al. Poster presented at SMR 2013; 4. Flaherty KT, et al. N Eng J Med 2012;367:107 14; 5. King AJ, et al. PLoS ONE 2013;8(7):e For Internal Use Only. Not for Distribution outside Novartis.
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11 COMBI-v PFS COMBI-d: Progression-free Survival Presented By Georgina Long at 2015 ASCO Annual Meeting
12 COMBI-v: Duration of Response Dabrafenib + Trametinib Vemurafenib Patients Patients Complete response Partial response Survival, months Complete response Partial response Survival, months Median DOR (95% CI), months Dabrafenib + Trametinib Vemurafenib All responders (CR + PR) 13.8 ( ) 7.9 ( ) Complete responders 39.6 (26.5-NR) 29.9 (16.7-NR) Partial responders 10.8 ( ) 7.3 ( ) 36 of 68 patients (53%) with a CR on dabrafenib + trametinib are still in CR 21 of 41 patients (51%) with a CR on vemurafenib are still in CR SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE. PRESENTED AT ESMO
13 COMBI-v and COMBI-d: Overall Survival Curves D + T in COMBI-v D + T in COMBI-d 1 2-year OS 53% (95% CI, 48-58) 52% (95% CI, 45-59) 3-year OS 45% (95% CI, 39-50) 44% (95% CI, 37-51) OS Probability Patients at risk, n COMBI-d: D + Pbo COMBI-d: D + T COMBI-v: D + T COMBI-v: Vem Vem in COMBI-v D + Pbo in COMBI-d 1 2-year OS 39% (95% CI, 34-45) 43% (95% CI, 36-50) 3-year OS 31% (95% CI, 26-36) 32% (95% CI, 25-38) Months From Randomization Pbo, placebo. 1. Flaherty KT, et al. J Clin Oncol. 2016;34 (suppl) [abstract 9502]. SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE. PRESENTED AT ESMO
14 CoBRIM: OS benefit remained stable during long-term follow-up of extended treatment 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 = OS, % Time, Months C, cobimetinib; OS, overall survival; P, placebo; V, vemurafenib. Data cutoff: 20 June
15 Five Baseline Factors Influenced OS a LDH Normal N = 398 1Y = 85% 2Y = 67% 3Y = 57% Disease Sites < 3 Disease Sites 3 N = 237 1Y = 90% 2Y = 75% 3Y = 70% N = 161 1Y = 76% 2Y = 55% 3Y = 38% N = 617 ECOG = 0 ECOG 1 N = 93 1Y = 71% 2Y = 43% 3Y = NE LDH >1-2 ULN N = 149 1Y = 60% 2Y = 33% 3Y = 9% LDH ULN N = 219 1Y = 54% 2Y = 25% 3Y = 7% LDH 2 ULN N = 56 1Y = 42% 2Y = 19% 3Y = 16% N = 70 1Y = 40% 2Y = 7% 3Y = 7% a Regression tree analysis. NE, not estimable. PRESENTED BY GV LONG AT SMR 2015
16 COMBI-d: Normal LDH a and < 3 Disease Sites b PFS OS 1.0 Dabrafenib + Trametinib (n = 76) 1.0 Dabrafenib + Trametinib (n = 76) y OS, 68 % 3-y OS, 62% PFS Probability y PFS, 38% OS Probability y OS, 61% 3-y OS, 45% Dabrafenib + Placebo (n = 96) 3-y PFS, 15% 0.0 Dabrafenib + Placebo (n = 96) Number at risk D+T D+Pbo Months From Randomization Number at risk D+T D+Pbo Months From Randomization a Baseline LDH ULN; b Any organ at baseline with 1 metastasis could be counted as a single disease site; +, censored. Presented by: Keith T. Flaherty, MD
17 COMBI-v: Normal LDH and < 3 Organ Sites With Metastasis OS PFS 1.00 Dabrafenib + trametinib (n = 141) Median OS, NR (95% CI, NR-NR) 1.00 Dabrafenib + trametinib (n = 141) Median PFS, 23.0 (95% CI, ) OS Probability Patients at risk, n 14 D + T 1 Vem 16 1 Vemurafenib (n = 161) Median OS, 26.4 (95% CI, ) HR, 0.47 (95% CI, ) 2-y OS, 79% 2-y OS, 52% 3-y OS, 70% 3-y OS, 46% Months From Randomization PFS Probability Patients at risk, n 14 D + T 1 Vem 16 1 Vemurafenib (n = 161) 2-y PFS, 27% Median PFS, 10.7 (95% CI, ) HR, 0.52 (95% CI, ) 2-y PFS, 46% 3-y PFS, 39% 3-y PFS, 16% Months From Randomization SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE. PRESENTED AT ESMO
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19 COMBI-d: Treatment-Related Adverse Events ( 20% of Patients) Presented By Georgina Long at 2015 ASCO Annual Meeting
20 Discontinuations V + P (n = 246) 30 Sept 2015 P + V (n = 245) 20 June 2016 C + V (n = 247) 30 Sep 2015 C + V (n = 248) 20 June 2016 Discontinued both V and C/P 216 (88) 225 (92) 193 (78) 209 (84) Disease Progression 180 (73) 185 (76) 127 (51) 135 (54) Adverse Events 21 (8.5) 21 (8.6) 36 (14.6) 38 (15.3) Deaths 2 (0.8) 3 (1.2) 3 (1.2) 4 (1.6) Other a 13 (5.3) 16 (6.5) 27 (10.9) 32 (12.9) 20
21 Conclusion TT BRAFI/MEKI: Standard of Care in BRAF mut metastatic melanoma patients Open Issues: Strategies for overcoming the resistance Intermittent dosing of double MAPKi (S1320 Trial) Treatment Beyond Progression BeyPro2 Trial
22 Treatment Beyond Progression: BeyPro2 «local» PD Combo + local treatment BRAFI + MEKI PD Second line treatment «systemic» PD Second line treatment Study Design: multicenter phase II randomized study Sites: 16 Number of Patients: 120 Primary endpoint : OS, Secondary PFS, ORR, Toxicity
23 Treatment Options for BRAF V600 Mutant Metastatic Melanoma BRAF/MEK Inhibitors Dabrafenib + trametinib Vemurafenib + cobimetinib Immunotherapy Ipilimumab Nivolumab Nivolumab + ipilimumab Pembrolizumab
24 Topics Background and Rationale Immunotherapy with immune checkpoint inhibitors (anti-ctla4 and anti-pd1) New combinations (e.g. anti-pd1 + anti-ido) Combination of immune checkpoint inhibitors and vaccinations Combination of targeted therapy and immune checkpoint inhibitors Search for Biomarkers
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27 Kaplan-Meier: analysis of survival MDX Proportion alive year 2 years Survival Rate Ipilimumab + gp100 (n=403) Ipilimumab + placebo (n=137) gp100 + placebo (n=136) 1 year 44% 46% 25% 2 year 22% 24% 14% median OS (mts) (95% CI) Years lpilimumab + gp100 lpilimumab + placebo gp100 + placebo (A) (B) (C) Comparison HR p- value Arms A vs. C Arms B vs. C 0.66 median f/u (mts) No. At Risk Ipi plus gp Ipi gp Hodi FS, et al. N Engl J Med 2010;363:
28 Rapid and Durable Changes in Target Lesions Change in target lesions from baseline (%) 1 mg/kg nivolumab + 3 mg/kg ipilimumab Weeks since treatment initiation First occurrence of new lesion A 52-year-old patient presented with extensive nodal and visceral disease Baseline LDH was elevated (2.3 x ULN); symptoms included nausea and vomiting Within 4 wk, LDH normalized and symptoms resolved At 12 wk, there was marked reduction in all areas of disease as shown Pretreatment 12 weeks Presented by: Jedd D. Wolchok, MD, PhD
29 Topics Background and Rationale Immunotherapy with immune checkpoint inhibitors (anti-ctla4 and anti-pd1) New combinations (e.g. anti-pd1 + anti-ido) Combination of immune checkpoint inhibitors and vaccinations Combination of targeted therapy and immune checkpoint inhibitors Search for Biomarkers
30 Primary Analysis of Pooled OS Data:<br />1861 Patients
31 OS: Randomized Patients Alive (%) Number of patients at risk 0 IPI 10 mg/kg IPI 3 mg/kg 54% 48% OS IPI 10 mg/kg n = 365 IPI 3 mg/kg n = 362 Events (%) 262 (72) 279 (77) Median (95% CI), mo 15.7 (11.6, 17.8) 11.5 (9.9, 13.3) HR (95% CI) 0.84 (0.70, 0.99) Log-rank P value Time (Months) IPI 10 mg/kg IPI 3 mg/kg Minimum OS follow-up: ~43 mo 38% 31% 31% 23% 31
32 Safety Summary: Treated Patients IPI 10 mg/kg n = 364 IPI 3 mg/kg n = 362 AEs during initial treatment phase Any grade Grades 3-5 Any grade Grades 3-5 AEs, % Treatment-related AEs, % Serious AEs, % AEs leading to discontinuation, % Immune-related AEs, % During the entire study period, study-drug toxicity led to death in 4 patients (1%) in the 10 mg/kg arm Diarrhea leading to general deterioration, fulminant colitis, multi-organ failure, bowel perforation 2 patients (<1%) in the 3 mg/kg arm Multifocal colon perforation, myocardial infarction from complications of diarrhea and colitis 32
33 Response to NIVO Monotherapy Dose, mg/kg ORR, %, (n/n) *3 mg/kg IV Q2W dose selected for phase III studies of NIVO monotherapy Median Duration of Response, months (range) All doses 32 (34/107) 23 (4 32) (6/17) 10 (6 27+) (5/18) 32 (4 32) 1 34 (12/35) 24 (8 31+) 3* 41 (7/17) 22 (9 27+) (4/20) 26 (17 27+) Database lock Oct 2015 Database lock Sep
34 Time to Response and Durability of Response Follow-up (range): months Patients On treatment Off treatment First response Ongoing response 44% (15/34) of responding patients showed a response at first tumor assessment (8 weeks) Responses ongoing in 13/34 (38%) responders Time (Month) Database lock Oct
35 Overall Survival at 5 Years of Follow-up Probability of Survival All Patients (events: 69/107), median and 95% CI: 17.3 ( ) NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2 NR) Number of Patients at Risk All Patients NIVO 3 mg/kg Months Database lock Oct
36 Summary of Overall Survival Landmark timepoint OS Rate, % (95% CI)* All Patients (N = 107) NIVO 3 mg/kg (n = 17) 12-month 63 (53 71) 65 (38 82) 24-month 48 (38 57) 47 (23 68) 36-month 42 (32 51) 41 (19 63) 48-month 35 (26 44) 35 (15 57) 60-month 34 (25 43) 35 (15 57) Median OS, months (95% CI) 17.3 ( ) 20.3 (7.2-NR) *Based on Kaplan-Meier estimates NR, not reached Database lock Oct
37 Long term outcomes from Pembrolizumab<br />Keynote 001: 3 year survival Presented By Marc Ernstoff at 2016 ASCO Annual Meeting
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41 CA : Study Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone N = 314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Stratify by: Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Tumor PD-L1 expression a BRAF mutation status AJCC M stage N = 316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression b or unacceptable toxicity N = 315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo a Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses b Patients could have been treated beyond progression under protocol-defined circumstances ASCO 2016
42 Progression-Free Survival (Intent-to-Treat Population) NIVO + IPI (N = 314) NIVO (N = 316) IPI (N = 315) Median PFS, months (95% CI) 11.5 (8.9, 16.7) 6.9 (4.3, 9.5) 2.9 (2.8, 3.4) Progression-free Percentage Survival of PFS (%) Number of patients at risk: Nivolumab + Ipilimumab Nivolumab Ipilimumab 0 49% 42% 18% NIVO+IPI NIVO IPI HR (99.5% CI) vs. IPI 0.42 (0.31, 0.57) a 0.55 (0.43, 0.76) a -- HR (95% CI) vs. NIVO 0.76 (0.60, 0.92) b PFS per Investigator (months) % 39% 14% a Stratified log-rank P< vs. IPI b Exploratory endpoint Database lock Nov 2015 ASCO 2016
43 Response to Treatment NIVO + IPI (N = 314) NIVO (N = 316) IPI (N = 315) ORR, % (95% CI) a 57.6 (52.0, 63.2) 43.7 (38.1, 49.3) 19.0 (14.9, 23.8) Two-sided P value vs IPI <0.001 < Best overall response, % Complete response Partial response Stable disease Progressive disease Unknown Median duration of response, months (95% CI) NR (20.5, NR) 22.3 (20.7, NR) 14.4 (8.3, NR) Ongoing response among responders, % a By RECIST v1.1 NR = not reached Database lock Nov 2015 ASCO 2016
44 Progression-free Survival by Tumor PD-L1 Expression Tumor PD-L1 Expression Level <5% Tumor PD-L1 Expression Level 5% Percentage of PFS Number of patients at risk: NIVO + IPI 210 NIVO 208 IPI 202 Database lock Nov 2015 NIVO + IPI NIVO IPI Median PFS, months (95% CI) HR (95% CI) vs NIVO PFS (months) NIVO + IPI (N = 210) 11.1 (8.0, 22.2) NIVO (N = 208) 5.3 (2.8, 7.1) IPI (N = 202) 2.8 (2.8, 3.1) 0.74 (0.58, 0.96) a *Exploratory endpoint Percentage of PFS Number of patients at risk: NIVO + IPI 68 NIVO 80 IPI Median PFS, months (95% CI) HR (95% CI) vs. NIVO NIVO + IPI (N = 68) NR (9.7, NR) NIVO (N = 80) 22.0 (8.9, NR) IPI (N = 75) 3.9 (2.8, 4.2) 0.87 (0.54, 1.41) a a Exploratory endpoint NIVO + IPI 10 NIVO IPI PFS (months) For the original PD-L1 PFS analysis, the descriptive hazard ratio comparing NIVO+IPI vs NIVO was 0.96, with a similar median PFS in both groups (14 months) ASCO 2016
45 Types of tumor microenvironment and cancer immunotherapeutic modules Teng MWL et al. Cancer Res 2015; 75:2139
46 Safety Summary Updated safety information with 9 additional months of follow-up were consistent with the initial report NIVO+IPI (N = 313) NIVO (N = 313) IPI (N = 311) Patients reporting event, % Any grade Grade 3-4 Any grade Grade 3-4 Any grade Grade 3-4 Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation Treatment-related death a % of patients who discontinued NIVO+IPI due to treatment-related AEs achieved a response a One reported in the NIVO group (neutropenia) and one in the IPI group (colon perforation) Database lock Nov 2015 ASCO 2016
47 Topics Background and Rationale Immunotherapy with immune checkpoint inhibitors (anti-ctla4 and anti-pd1) New combinations (e.g. anti-pd1 + anti-ido) Combination of immune checkpoint inhibitors and vaccinations Combination of targeted therapy and immune checkpoint inhibitors Search for Biomarkers
48 T-Cell Checkpoint Regulation: other immune checkpoints Activating receptors CD28 OX40 CD137 Agonistic antibodies T-cell stimulation Inhibitory receptors CTLA-4 PD-1 TIM-3 LAG-3 Antagonistic (blocking) antibodies T-cell responses are regulated though a complex balance of inhibitory ( checkpoint ) and activating signals Tumors can dysregulate checkpoint and activating pathways, and consequently the immune response Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response Adapted from Mellman I, et al. Nature. 2011:480; ; Pardoll DM. Nat Rev Cancer. 2012;12: ONCHQ13NP09700 SMR 2014
49 Co-inhibitory Receptor Pathways Anderson AC et al. Immunity 2016; 44:989
50 Hierarchy of Co-inhibitory Receptors Anderson AC et al. Immunity 2016; 44:989
51 Specification of Checkpoint-Receptor Pathways Anderson AC et al. Immunity 2016; 44:989
52 Clinical Trials Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors ClinicalTrials.gov Identifier: NCT Sponsor: Bristol-Myers Squibb A Phase 1 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS ) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS ) in Advanced Solid Tumors
53 Clinical Trials Safety and Efficacy of LAG525 Single Agent and in combination with PDR001 in Patients with Advanced Malignancies ClinicalTrials.gov Identifier: NCT Sponsor: Novartis Pharm. A Phase I/II, Open Label, Multicenter Study of the Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 Administered to Patients With Advanced Malignancies
54 IDO
55 A phase III Randomized, Double Blind, Placebo-Controlled Study of Pembrolizumab (MK-3475) in Combination with Epacadostat or Placebo in subjects with unresectable or metastatic melanoma Keynote-252
56 Clinical Trials Pembrolizumab plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-Small Cell Lung Cancer ClinicalTrials.gov Identifier: NCT Sponsor: Yale University Phase II Trial 53 pts: 33 with NSCLC
57 Future Perspectives Combination of immunotherapy and targeted therapy Search for Biomarkers helping to determine Frontline Treatment for unresectable metastatic BRAF-mutant melanoma New Combinations Combination of immune checkpoint inhibitors and vaccinations Combination of immune checkpoint inhibitors and RT
58 TVEC: summary of genetic modifications Modification Use of new HSV-1 strain (JS1) Deletion of ICP34.5 Deletion of ICP47 Earlier insertion of US11 Insertion of human GM-CSF gene Result Improved tumor cell killing ability compared with other strains Prevents HSV infection of non-tumor cells, providing tumor-selective replication Enables antigen presentation Increases replication and oncolysis of tumor cells Enhances anti-tumor immune response by recruiting and stimulating dendritic cells to tumor site
59 T-VEC + PEMBROLIZUMAB MASTERKEY-265 trial Phase 1b T-VEC (HCV-1 oncolytic immunotherapy)+ pembrolizumab in stage IIIB-IV melanoma Pembrolizumab starting at day36 Injectable lesions, no prior therapy 21 pts enrolled 19% BRAF mut Safety: 33% G3-4 Adverse Events Fatigue, pyrexia, chills Confirmed RR=48% CR=14% Time to response= 17 weeks Increased of CD8+ during T-VEC, reduced after pembrolizumab start T-VEC+ Pembrolizumab associated with clinical benefit, trials ongoing! Long et al, Abst # 9568
60 Future Perspectives Combination of immunotherapy and targeted therapy Search for Biomarkers helping to determine Frontline Treatment for unresectable metastatic BRAF-mutant melanoma New Combinations Combination of immune checkpoint inhibitors and vaccinations Combination of immune checkpoint inhibitors and RT
61 Abscopal Effect Herrera FG, et al. CA Cancer J Clin 2016
62 Abscopal Effect Herrera FG, et al. CA Cancer J Clin 2016
63 Abscopal Effect of local RT Trial of SBRT With Concurrent Ipilimumab in Metastatic Melanoma (Phase I) NCT pts Sponsor: Radiotherapie, University Hospital, Ghent Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma (PERM) NCT pts Sponsor: Royal Marsden NHS Foundation Trust Study RADVAX: A Stratified Phase I Trial of Pembrolizumab With Hypofractionated Radiotherapy in Patients With Advanced and Metastatic Cancers (Phase I) NCT pts
64 Topics Background and Rationale Immunotherapy with immune checkpoint inhibitors (anti-ctla4 and anti-pd1) New combinations (e.g. anti-pd1 + anti-ido) Combination of immune checkpoint inhibitors and vaccinations Combination of targeted therapy and immune checkpoint inhibitors Search for Biomarkers
65 Effects of BRAFIs on Melanoma and Immune cells Hu-Lieskovan S, et al. J Clin Oncol 32:2248, 2014
66 Antitumor Activity (RECIST v1.1, Investigator Review) Manageable toxicity, phase II ongoing!
67 IDO
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72 Response to anti-pd1 therapy in metastatic melanoma: genomic and transcriptomic features Hugo W et al. Cell 2016; 165:35
73 EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo<br />PIs: Michael Atkins (ECOG), Bartosz Chmielowski (SWOG) Presented By Antoni Ribas at 2016 ASCO Annual Meeting
74 (SECOMBIT) Study Prospective randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivoluma b) followed by combo target therapy (dabrafenib/ trametinib) and viceversa ARM A Combo T LGX 450 mg MEK mg ARM B Combo I Ipilimumab 3 mg/kg Nivolumab 1mg /Kg PD PD Combo I until PD Combo T until PD Patients affected by metastatic melanoma BRAF V600 mutated Sample size 230 pts ARM C Sandwich LGX 450 mg MEK mg for 8 weeks Combo I until PD Combo T until PD This study is designed as a phase II randomized trial with no formal comparative test. Endpoints: Primary OS Secondary PFS, Total PFS (TPFS): the time to the second progression, % patients alive at 2-3 years, BORR; Duration of Response, Toxicity, Biomarkers study
75 Topics Background and Rationale Immunotherapy with immune checkpoint inhibitors (anti-ctla4 and anti-pd1) New combinations Combination of immune checkpoint inhibitors and vaccinations Combination of targeted therapy and immune checkpoint inhibitors Search for Biomarkers
76 Immune parameters in peripheral blood as predictive factors of response to anti-ctla-4 Subset/immune parameter Type of association with clinical outcome Author/year Lymphocyte count >1000/mm 3 Improved OS when observed at the start of second course Deylon / Baseline Neutrophil to Lymphocyte Ratio (NLR) Baseline ANC and dnlr Monocyte counts, eosinophil counts NLR<5 associated with improved OS Ferrucci /2015 ANC>7500 and dnlr>3 associated with increased risk of death Baseline low absolute monocyte count and high absolute eosinophil count associated with better survival 1. Eomes + CD8+ and 1. increase at 6 months associated with relapse. 2. Ki67 + Eomes + CD Low baseline level associated with relapse Ferrucci 2016 Martens / 2016 Wang / 2012 ICOS + CD4 + and ICOS + CD8 + increase at wk7 associated with improved survival Di Giacomo / 2013 PD-1 + CD4 + Low pre-treatment level associated with better OS Kwek / 2015 CD14 + CD11b + HLA-DR - MDSCs Higher baseline or post-infusion levels in non responders Gebhardt / 2015 Lin - CD14 + HLA-DR - MDSCs Lower frequency in responders Meyer / FOXP3 + Treg at wk 12 Decrease associated with improved survival Simeone / 2014 Lin-CD14+HLA-DR -/low MDSC and CD4+FoxP3+ Tregs Low baseline MDSCs and high Treg frequencies associated with better survival Martens / 2016 scd25 High baseline level associated with resistance to therapy Hannani / 2015 IL-17, TGF-β1, IL-10 Baseline IL-17 levels associated with subsequent colitis. Combined IL-10 and TGF-β1 associated with PFS Tarhini / 2015
77 Case Report: T cell activation and maturation at tumor site associated with objective response to Ipi in metastatic melanoma M. Del Vecchio, R. Mortarini, G. Tragni, L. Di Guardo, I. Bersani, G. Di Tolla, F. Agustoni, V. Colonna, J.S. Weber, A. Anichini. J Clin Oncol, 2011;29(32):e Epub 2011 Oct 11
78 Infiltration of activated T cells in the lesion responding to anti-ctla4 Pre-therapy lesion Regressing lesion Progressing lesion
79 Reduced frequency of regulatory T cells in the lesion responding to Ipilimumab Post-therapy, regressing lesion: FOXP3 + lymphocytes Post-therapy, progressing lesion: FOXP3 + lymphocytes
80 Why is the progressing lesion not responding? Is immune escape involved in the progressing lesion? Regressing lesion Progressing lesion MART-1 gp100
81 Why is the progressing lesion not responding? Pre-therapy lesion PRE Post-therapy lesion 1 (regressing lesion) POST1a Post-therapy lesion 2 (progressing lesion) POST2a Adrenal Tissue Post-2 Tumor only POST1 POST1 POST1 POST2 POST2 POST2 PRE PRE PRE ADR. TISSUE ADR. TISSUE ADR. TISSUE TUMOR only TUMOR only TUMOR only HLA-DOB HLA-G HLA-DQA2 HLA-DPB2 HLA-DPB1 HLA-A29.1 HLA-DRB5 HLA-C HLA-F HLA-A HLA-E HLA-DMB HLA-DMA B2M HLA-DRA HLA-DRB3 HLA-B B2M HLA-DRB1 HLA-DRB4 HLA-F HLA-DPA1 HLA-DRA HLA-DRB6 HLA-DPB2 HLA-DQB1
82 HLA Class I Post-therapy lesion 1- responding lesion HLA Class I Post-therapy lesion 2- non responding lesion
83 HLA Class II expression Post-therapy lesion 1- responding lesion Post-therapy lesion 2- non responding lesion
84 Why only some tumors have infiltrating T cells
85 Lack of T cell infiltrate in β-catenin - areas of a metastatic lesion CD3 CD4 CD8 PD-L1 β catenin
86 (At least) three different immune profiles associated with lack of response to anti-ctla4 therapy Immune profile 1: No T cell infiltration; Immune profile 2: No T cell infiltration and loss of HLA (I/II) molecules; Immune profile 3: Presence of infiltrating T cells but loss of HLA molecules; CD8+ T cell MHC Class I Melanoma CD4+ T cell MHC Class II Acknowledgements Human Tumors Immunobiology Unit Medical Oncology Dept. of Pathology Grant support Andrea Anichini Roberta Mortarini Elena Tassi Valentina Perotti Ilaria Penna Giulia Grazia Ilaria Bersani Alessandra Molla Claudia Vegetti Gabriella Nicolini Paola Baldassari Lorenza Di Guardo Carolina Cimminiello Lorenzo Pilla* Filippo De Braud Melanoma and Sarcoma Unit Andrea Maurichi Mario Santinami Gabrina Tragni* Barbara Valeri Functional Genomic Core Facility Loris de Cecco Edo Marchesi Silvana Canevari
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