New treatments in melanoma
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1 New treatments in melanoma Paolo A. Ascierto, MD Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy
2 Meta-analysis of Phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future Phase II trials This metanalysis summarises the outcome of advanced melanoma patients before 2011 Median survival time 6.2 months Alive at 1 year 25.5% Median PFS 1.7 months Progression free at 6 months 14.5% Korn E, et al. J Clin Oncol 2008;26: Reprinted with permission 2008, American Society of Clinical Oncology. All rights reserved
3 Treatment for advanced melanoma approved by EMA after ipilimumab 2012 vemurafenib 2013 dabrafenib 2014 trametinib 2015 nivolumab pembrolizumab combo dabrafenib-trametinib combo vemurafenib-cobimetinib talimogene laherparepvec pending combo ipilimumabnivolumab Agent Company Indication Nivolumab BMS Unresectable or metastatic melanoma Ipilimumab BMS Unresectable or metastatic melanoma Vemurafenib Roche/Genentech Unresectable or metastatic melanoma with BRAF V600E mutation Dabrafenib Novartis Unresectable or metastatic melanoma with BRAF V600E mutation Trametinib Novartis Unresectable or metastatic melanoma with BRAF V600E/K mutation Talimogene laherparepvec Amgen Unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease. Hodi FS, et al. N Engl J Med 2010;363:711 23; Chapman PB, et al. J Clin Oncol 2012;30(suppl; abstr 8502). Hauschild A, et al. Lancet 2012;380:358 65; Flaherty KT, et al. N Engl J Med 2012;367:107 14; Flaherty KT, et al. N Engl J Med 2012;367: ; Robert C, et al. N Engl J Med 2015;372:320 30; Andtbacka R, et al. J Clin Oncol Sep 1;33(25):
4 Two different drugs... Two different concepts Ipilimumab (immunotherapy) Slow action, but it is able to make the disease chronic BRAF inhibitors (target therapy) Quick action, rapid metabolic shutdown, unfortunately resistance after a median of 6-8 months Oct-2010 Jun-2011 Day 0 Day 15 Courtesy of Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy
5 Advanced melanoma: Different approaches according to mutational status BRAF V600E/K Q61 NRAS c-kit NRAS wt BRAF wt Ascierto PA, et al. J Transl Med. 2012;10:83
6 TARGET THERAPY
7 BRAF inhibitors VEMURAFENIB DABRAFENIB
8 Growth factors RAS RAF pathway MAPK pathway and BRAF inhibitors mechanism of action Oncogenic BRAF signaling Oncogenic BRAF signaling arrested with BRAF inhibitors RTK RAS GTP (activated RAS) Constitutive activation is independent of extracellular factors and does not respond to biochemical signals that would normally regulate activity Normal activation of RAS via extracellular factors at the inner cell membrane via RTK PP PP BRAF MEK ERK BRAF V600 PP MEK PP ERK BRAF V600 MEK ERK BRAF inhibitors Selective binding of oncogenic BRAF kinase by vemurafenib, blocks the constitutively activated pathway and downstream activity Normal cell proliferation and survival cell proliferation and survival cell proliferation and survival Ascierto PA, et al. J Trans Med 2012;10:85. This work is licensed under a Creative Commons Attribution 4.0 International License
9 Vemurafenib and dabrafenib: Data from the BRIM-3 and BREAK-3 studies BRIM-3 Randomised Phase III open label vemurafenib vs. dacarbazine Primary endpoint: OS Cross-over: no Patients enrolled: 675 (337 vemurafenib; 338 dacarbazine) Median follow-up: 12.5 mo Median OS: 13.6 mo vemurafenib vs. 9.7 mo dacarbazine HR = 0.70 (95% CI ); p= ORR: 57% vemurafenib vs. 9% dacarbazine PFS: median PFS was 5.9 months for vemurafenib and 1.7 mo for dacarbazine (HR 0.30, 95% CI ; p<0.0001) BREAK-3 Randomised Phase III open label dabrafenib vs. dacarbazine Primary endpoint: PFS Cross-over: Yes Patients enrolled: 250 (187 dabrafenib; 63 dacarbazine) Median follow-up time: 16.9 mo Median OS: 20 mo dabrafenib vs.15.6 mo dacarbazine HR = 0.77 (95% CI ); p=not significant ORR: 50% dabrafenib vs. 6% dacarbazine PFS: median PFS was 6.9 mo for dabrafenib versus 2.7 mo for dacarbazine (HR = 0.37, 95% CI ; p<0.0001) 9,7 13,6 McArthur G, et al. Lancet Oncol 2014;15: Reprinted from The Lancet 2014, with permission from Elsevier Hauschild A, et al. Lancet 2012;380:358 65; Hauschild A, et al. J Clin Oncol 2013 ASCO Annual Meeting Abstracts;31 suppl May:9013; By permission of Hauschild A, et al. ESMO Poster 1092
10 AE (%) BRAF inhibitors*: AEs (grade 2 in 5% patients) Vemurafenib (n=336) Dabrafenib (n=187) Grade 2 Grade 3 Grade 2 Grade 3 Arthralgia <1 Rash 10 8 NR NR Fatigue cuscc/keratoacanthoma Nausea 7 1 NR NR Alopecia 8 NR NR Pruritus 6 1 NR NR Hyperkeratosis a Diarrhoea 5 <1 NR NR Headache 4 <1 5 Pyrexia NR NR 8 3 PPE/palmar-plantar hyperkeratosis NR NR 6 2 *Data from BRIM-3 and BREAK-3 trials a Includes 1 (<1%) patient with grade 4 event AEs = adverse events; cuscc = cutaneous squamous-cell carcinoma; NR = not reported; PPE = palmar-plantar Chapman erythrodysaesthesia PB, et al. N Engl J Med 2011;364: ; Hauschild A, et al. Lancet 2012;380: Adapted from Ascierto PA, et al. Am J Ther. 2015; 22:44-53
11 The paradoxical effect of BRAF inhibitors Hatzivassiliou et al., Heidorn et al. and Poulikakos et al. described how RAF inhibitors can drive downstream ERK signaling in the absence of BRAF mutations, contributing to resistance in tumours treated with these drugs BRAF inhibitors reduce ERK activation with subsequent tumour regression. In case of lacking BRAF mutation but in presence of a mutant form of a RAS protein, activated RAS binds and stimulates BRAF-CRAF or CRAF-CRAF dimers to switch on the ERK pathway This promotes tumour growth in NRAS-mutant melanoma or can induce a premalignant lesion in other tissues. On treatment with BRAF inhibitors, binding of the drug to one RAF subunit transactivates the other, in cooperation with RAS interaction, resulting in paradoxical ERK activation and tumour progression Hatzivassiliou G, et al. Nature 2010;464:431 5; Heidorn SJ, et al. Cell 2010;140:209 1; Poulikakos PI, et al. Nature 2010; 464:427 30; Reprinted by permission from Macmillan Publishers Ltd: Downward J, et al. Nature Med 2011;17:286 8, 2011
12 Factors significantly associated with longer median PFS and OS: LDH level PFS Median PFS 7,6 months [95% CI ] OS Median OS 21,6 months [95% CI 17 5 not reached] Reprinted from Larkin J, et al. Lancet Oncol 2014;15: , with permission from Elsevier
13 Proportion alive Factors significantly associated with longer median PFS and OS: LDH level (cont d) OS extended follow-up in V600E-mutant positive patients enrolled 1.0 in BREAK-2 study V600E: 0.7 Median OS 13.1 months 0.6 (95% CI: ) Time since first dose, months Number 76 at risk Median follow-up of 13 months In the BRAF V600E group, 21 patients (28%) were alive beyond 30 months All these patients had a baseline normal LDH As of 9 December 2013, 8 (9%) patients continued on dabrafenib without disease progression (median exposure of 37 months) Data cut off: December 2013 Ascierto PA, et al. J Clin Oncol 2014;32:5s(suppl; abstr 9034). Poster presented at ASCO 2014
14 Factors significantly associated with longer median PFS and OS: Tumour burden Prolonged responses to vemurafenib in patients with BRAFV600-mutant melanoma with low tumour burden at baseline: data from the phase I study (BRIM-1) Long-term survival with vemurafenib can be achieved in patients with low baseline tumour burden Baseline targets, PFS & OS TARGETS <11.5 cm TARGETS 11.5 cm Median PFS Median OS BREAK-3 Long-term responders on dabrafenib were observed to have smaller lesions at baseline vs. patients that experienced disease progression. Indeed, 10% of patients continued to receive dabrafenib without disease progression at data cut-off. The 72% of them had a low tumour burden With permission from Amaravadi R, SMR-P3, presented at SMR Congress Tampa, Florida November 2011 Hauschild A, et al. Poster presented at ESMO 2014, Poster 1092PD, Abstract 5785.
15 Effect of BRAF inhibitors on the immune system BRAF inhibition is associated with increased melanoma antigen expression in tumours of patients with metastatic melanoma CD4+ and CD8+ increase in responder lesion and decrease in lesions which progressed Antitumour activity of combined BRAFi+MEKi plus anti-pd-1 3 MHC and melanoma antigen expression 3 BRAF inhibition is associated with increased CD8+ T-cell infiltrate in tumours of patients with metastatic melanoma Wilmott JS, et al. Clin Cancer Res 2011;18: , Reprinted from Clinical Cancer Research 2012, with permission from AACR Frederick DT, et al. Clin Cancer Res 2013;19: , Reprinted from Clinical Cancer Research 2013, with permission from AACR From Hu-Lieskovan S, et al. Sci Transl Med 2015;7:279ra41., Reprinted with permission from AAAS
16 Resistance BRAF-mutant melanomas acquire BRAF inhibitor resistance via upregulation of both MAPK and PI3K AKT pathways. However, MAPK reactivation is the major pathway of acquired BRAF inhibitor resistance in melanoma. Among MAPK-reactivating mechanisms associated with acquired BRAF inhibitor resistance the most frequents are NRAS mutations, mutant BRAF amplification and alternative splice variants, MAP2K1 and CDKN2A mutations Shi H, et al. Cancer Discovery 2014; 4:80-93 Courtesy of Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy Day 0 Day 7 Day 15 Day 30
17 BRAF plus MEK inhibitors DABRAFENIB + TRAMETINIB VEMURAFENIB + COBIMETINIB ENCORAFENIB + BINIMETINIB
18 Rationale for the combination of BRAF and MEK inhibitors Rationale Most common mechanism of acquired resistance to vemurafenib is MAPK reactivation through MEK 1,2 MEK + BRAF inhibition prevents the development of acquired resistance in preclinical models 3 MEK + BRAF inhibition (dabrafenib + trametinib 4 phase 3 and vemurafenib + cobimetinib phase 1/2) 5 improved response rates and PFS in BRAF inhibitor naive melanoma patients Reduced incidence of hyperproliferative lesions by blocking paradoxical activation of the MAPK pathway from RAF inhibition 6 BRAF inhibitors vemurafenib dabrafenib encorafenib MEK inhibitors trametinib cobimetinib binimetinib 1. Shi H, et al. Cancer Discov Trunzer K, et al. J Clin Oncol Paraiso K, et al. Br J Cancer Long GV, et al. J Clin Oncol Ribas A, et al. Lancet Oncol Su F, et al. New Engl J Med Gowrishankar et al.; licensee InTech. ISBN: , DOI: / Available from: Open access article distributed under the terms of the Creative Commons Attribution License 3.0
19 Estimated Survival Function Results from the fase I/II dabrafenib/ trametinib Cohort 150/2 Median: 25 mo 12-mo OS rate: 80% 24-mo OS rate: 51% 36-mo OS rate: 38% Cohort Dabrafenib 150 mg BID Dabrafenib 150 mg BID/trametinib 1 mg QD Dabrafenib 150 mg BID/trametinib 2 mg QD 0.0 Patients at Risk Data as of 15 January 2015 Time Since Randomization, months Longer follow-up reveals median OS of 25 months for patients in the 150/2 cohort. Landmark OS results for the 150/2 cohort: 1 year, 80%; 2 year, 51%; 3 year, 38%. Normal LDH and fewer disease sites were associated with prolonged survival. Prior immunotherapy had no effect on OS. No new safety signal observed and no increase in cuscc cases or treatment-emergent malignancies Daud A, et al. ASCO 2015, J Clin Oncol 2015;33 (suppl; abstr 9036) Poster 279 (with permission of Daud A.)
20 Combi-D study: Phase III study which compared dabrafenib/trametinib to dabrafenib monotherapy The combination dabrafenib/trametinib improved PFS and OS: PFS HR was 0,67, and OS HR was 0,71 with 1-year OS rate of 74% and 2-years OS rate of 51%. The median OS was 25,1 months. The treatment was well tolerated and the toxicity was manageable Long G, et al. N Engl J Med 2014; 371: Reprinted from Long G, et al. Lancet 2015;386: , with permission from Elsevier
21 Combi-V study: Phase III study which compared dabrafenib/trametinib to vemurafenib monotherapy PFS OS Median Follow-up: D + T = 11 months and Vem = 10 months Robert C, et al. N Engl J Med 2015; 372:30-9. Copyright 2015 Massachusetts Medical Society.Reprinted with permission from Massachusetts Medical Society,
22 CoBrim study: Phase III study which compared vemurafenib/cobimetinib to vemurafenib monotherapy PFS OS With permission from Larkin J, et al. J Clin Oncol 2015;33(suppl. Abstr 9006). Larkin J, et al. N Engl J Med 2015;373: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
23 Comparison between vemurafenib and dabrafenib/trametinib or vemurafenib/cobimetinib: PFS D+T V+C dabra/trame PFS = 11,4 months vs HR = 0,56 vemu = 7,3 months ORR = 64 % vs. 51% vemu/cobi PFS = 12,3 months vs HR = 0,58 vemu = 7,2 months ORR = 70% vs. 50% Robert C, et al. N Engl J Med 2015; 372:30-9. Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society With permission from Larkin J, et al. J Clin Oncol 2015;33(suppl. Abstr 9006).
24 Comparison between vemurafenib and dabrafenib/trametinib or vemurafenib/cobimetinib: OS D + T HR = 0.69 (95% CI ) P = V + C HR = 0.65 (95% CI ) P = Robert C, el al. N Engl J Med 2015; 372:30-9. Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society Larkin J, et al. N Engl J Med 2015;373: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
25 Overall safety summary for Combi-V and CoBrim studies Combi-V D + T (n=350) CoBrim V + C (n=254) Patients with at least 1 AE, n (%) 343 (98) 250 (98) Grade 3 AE, n (%) 184(54) 165 (65) AEs leading to permanent discontinuation, n (%) 44 (13) 32 (13) Any SAE, n (%) 131 (37) 75 (30) Fatal SAEs, n (%) 3 (< 1) 6 (2) Robert C, et al. N Engl J Med 2015;372:30-9. Larkin J, et al. N Engl J Med 2015;373:23-34.
26 Overall safety summary for Combi-V and CoBrim studies: AEs in > 20% patients D + T (n=350) V + C (n=254) AE (%) All grades Grade 3/4 All grades Grade 3/4 Pyrexia Nausea 35 <1 39 <1 Diarrhoea Fatigue Vomiting Hypertension Arthralgia 24 < Rash Pruritus 9 0 NR NR Hyperkeratosis Photosensitivity Increased LFTs NR NR 16 <1 NR = not reported Robert C, et al. N Engl J Med 2015; 372:30-9. Larkin J, et al. N Engl J Med 2015;373:23-34.
27 Overall safety summary for Combi-V and CoBrim studies: Selected adverse events D + T (n=350) V + C (n=254) AE (%) All grades Grade 3/4 All grades Grade 3/4 Cutaneous small-cell carcinoma and keratoacanthoma 1 0 <1 3 Increased CPK NR NR Retinal detachment NR NR 8 2 Chorioretinopathy <1 NR 12 <1 QT prolongation NR NR 3 <1 Decreased ejection fraction 8 NR 7 1 NR = not reported In the majority of cases asymptomatic and resolved without treatment Robert C, et al. N Engl J Med 2015; 372:30-9. Larkin J, et al. N Engl J Med 2015;373:23-34.
28 Encorafenib plus binimetinib: A new combination Combination of encorafenib and binimetinib is well tolerated and shows promising activity for BRAFinhibitor naïve, BRAF-mutant melanoma. Response rate (74,5%) and PFS (11.3 months) are consistent with other BRAFi/MEKi combinations. Lower rates of pyrexia and photosensitivity distinguishes this combination from dabrafenib/trametinib and vemurafenib/cobimetinib. Further evaluation of this combination is underway: COLUMBUS (ENCO/BINI vs. ENCO vs. vemurafenib). Sullivan RJ, et al. ASCO 2015, abstract 9007, With permission from Sullivan RJ
29 IMMUNOTHERAPY
30 Anti-CTLA-4 IPILIMUMAB
31 Mechanism of action T-Lymphocyte activation requires two signals Simeone E and Ascierto PA. J Immunotoxicol 2012:9: Reprinted by permission of Taylor & Francis Ltd.
32 The MDX study: Randomised Phase III, double blinded, three arms study which compared ipilimumab + gp100 vs. ipilimumab + placebo vs. gp100 + placebo N=676 pretreated advanced melanoma patients were enrolled. Randomisation was 3:1:1 and the primary endpoint was OS No separation in curves for the first 3 months Separation and survival impact occurs after 3 months (~ 4 months improvement in median OS Near doubling of 1 and 2 years when we start to see durable long-term survivors Median OS ipi + gp100 = 10,0 mos Ipi + placebo = 10,1 mos gp100 + placebo = 6,4 mos Hodi SF, et al. New Engl J Med 2010;363:711-23, Copyright 2010 Massachussetts Medical Society. Reprinted with permission from Massachussetts Medical Society
33 Proportion alive CTLA-4 immune checkpoint pathway inhibition using ipilimumab: Pooled OS data from melanoma patients In a pooled analysis of 12 studies, an OS plateau starts at approximately 3 years with follow-up of up to 10 years in some patients N=1861 Median OS, months (95% CI): 11.4 ( ) a 3-year OS rate, % (95% CI): 22 (20 24) a Ipilimumab CENSORED Months Patients at risk Ipilimumab Schadendorf D, et al. J Clin Oncol 2015;33: Reprinted with permission American Society of Clinical Oncology. All rights reserved
34 Ipilimumab activity is independent by the mutational status Ascierto PA, et al. J Trans Med 2014:12:116. Open Access article distributed under the terms of the Creative Commons Attribution License 4.0
35 No effect in surrogate endpoints Best Overall Response Rate (BORR) ipi + gp100 = 5.7% Ipi + placebo = 10,9% gp100 + placebo = 1.5% Hodi FS, et al. New Engl J Med 2010;363: Copyright 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
36 The concept of pseudo-progression Reprinted from Ribas A, et al. Clin Cancer Res 2009;15: With permission from AACR
37 Immuno-related response criteria (irrc): Patterns of response to ipilimumab The four response patterns observed in advanced melanoma patients treated with ipilimumab in clinical studies. The new patterns of responses consider response after initial increase in total tumour burden, and response in index and new lesions after the appearance of new lesions Reprinted from Wolchok JD, et al. Clin Cancer Res 2009; 15: , With permission from AACR
38 Evolution of the antitumoural effect One of the characteristics of ipilimumab is the possibility to achieve SD, PR, or CR after a «pseudo» progression of the disease (see immuno-related Response Criteria). In order to catch these responses, it is recommended to perform the first assessment at week 16 (instead of week 12), and, in case of progression, this should be confirmed with another CT scan after 4 weeks Total volume of tumour * 25% 50% 100% Basal SD PR CR * Tumoural volume can include infiltrating lymphocytes and tumoural cells PD SD PR CR Models of response Adapted from Wolchok JD, et al. Clin Cancer Res 2009;15:
39 Safety profile: Most common immunorelated adverse events (grades 3 4) experienced in the MDX study The most common immuno-related adverse events occur in the skin, gastrointestinal apparatus (colitis, diarrhea), liver, and endocrinopathies (thyroiditis and hypophisitis). Ocular, neurological, and renal are less frequent irae (%) Ipi + gp100 (N=380) Patients (%) Ipi + placebo (N=131) Grade 3 Grade 4 Grade 3 Grade 4 Any Dermatologic Gastro-intestinal (colitis, diarrhoea) Endocrinopathies Hepatic Death due to irae Hodi FS, et al. New Engl J Med 2010;363:711-23
40 Safety profile: Real world experience the Italian Expanded Access Programme The safety profile of ipilimumab found in a real world experience (Italian expanded access programme of ipilimumab) was consistent with those found in clinical studies 12:116 12:116 12:116 12:116 Ascierto PA, et al. J Trans Med 2014:12:116
41 Treatment guidelines: Managing iraes early enables completion of 12-week induction cycle Most ipilimumab iraes managed with product-specific treatment guidelines iraes, including grade ¾, generally managed with 3-step approach Ascierto PA, et al. Am J Ther 2015;22:44-53
42 Anti-PD-1 NIVOLUMAB PEMBROLIZUMAB
43 Mechanisms of action of PD1, PDL1 and PDL2 The roles of programmed cell death protein 1 (PD1), programmed cell death protein 1 ligand 1 (PDL1) and PDL2 in various cell types that can affect anti-tumour immunity Anti-PD-1 antibodies prevent the link PD-1/PD-L1 removing the negative signal generated by this interaction Reprinted by permission from Macmillan Publishers Ltd: Nguyen LT, et al. Nat Rev Immunol 2015;15: Copyright 2015 Reprinted from Zang X, et al. Clin Cancer Res 2007;13:5271 9, with permission from AACR
44 Nivolumab: Data from the Phase I study (CA ) The dosage selected for the Phase 3 studies was 3 mg/kg every two weeks on the basis of the higher response rate (41%) reached by this schedule. With this dosage the median PFS and OS was 10 months and 20 months respectively, while the duration of response was 22 months. In all cohorts patients the 1-, 2-, 3-, 4-years OS rate was 63%, 48%, 42%, 32% respectively Topalian S, et al. NEJM 2012; 366: ; Topalian S, et al. J Clin Oncol. 2014;32 (10): Reprinted with permission American Society of Clinical Oncology. All rights reserved Hodi FS, et al. SMR 2014 Congress. Pigment Cell Melanoma Res 2014;27:1199
45 Nivolumab: Data from the randomised Phase III study in ipilimumab pre-treated patients (CA ): Nivolumab vs. investigator chemotherapy choiche (ICC) Nivolumab ICC In patients with advanced melanoma who have progressed despite anti-ctla-4 therapy, and BRAF inhibitors if BRAF mutated, nivolumab monotherapy demonstrated superior efficacy to ICC: Objective response rate of 32% with nivolumab compared to 11% with ICC. Majority (95%) of responses were ongoing in patients who received nivolumab; median DOR not reached. Responses were observed regardless of pre-treatment PD-L1 expression status, BRAF mutation status, and prior anti-ctla-4 benefit Reprinted from Weber J, et al. Lancet Oncol 2015;16:375-84, 2015 with permsssion from Elsevier
46 Nivolumab: Data from the randomised Phase III study in first line in BRAF wt advanced melanoma patients (CA ): Nivolumab vs. dacarbazine In treatment-naïve, BRAF wild-type patients with metastatic melanoma, nivolumab led to significant improvements over dacarbazine in OS (mos NR vs. 10,8 mos; HR 0,42), PFS (mpfs 5,1 mos vs. 2,2 mos; HR 0,43), ORR (40% vs. 13,9%). The survival benefit of nivolumab vs. dacarbazine was observed irrespective of tumour PD-L1 status, and across all pre-defined subgroups From Robert C, et al. N Engl J Med 2015;372:320-30, Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
47 Unconventional responses in patients treated with nivolumab CA CA In both the two randomised phase III studies (CA and CA ) there was a 8% of patients who progressed according with RECIST v1.1 criteria, but achieved or maintained a 30% reduction in the target lesion tumour burden ( immune-related, unconventional response pattern ) For this reason, together the classical RECIST criteria, we must consider immunorelated criteria even for nivolumab treatment By permission of Weber J, Weber J, et al. ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA3. Weber J, et al. Lancet Oncol 2015; 16:375-84, Reprinted from The Lancet, Copyright 2015, with permission from Elsevier. From Robert C, et al. N Engl J Med 20145;372: Supplementary material. Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
48 Nivolumab safety profile: Selected immuno-related adverse events experienced in the Phase I-III trials Select AE organ category patients, n (%) Nivolumab CA n. 107 pts Any Grade Grade 3 4 Nivolumab CA n. 268 pts Any Grade Grade 3 4 Nivolumab CA n. 206 pts Any Grade Grade 3 4 Skin 36 (38) 2 (2) 78 (29) 1 (<1) 77 (37) 3 (2) Gastrointestinal 18 (19) 2 (2) 31 (12) 3 (1) 35 (17) 3 (2) Endocrine 13 (14) 2 (2) 21 (8) 0 (0) 15 (7) 2 (1) Hepatic 7 (7) 1 (1) 12 (5) 2 (1) 15 (7) 2 (1) Pulmonary 4 (4) 0 6 (2) 0 (0) 3 (2) 0 Infusion reaction 6 (6) 0 5 (2) 1 (<1) 9 (4.4) 0 Renal 2 (2) 1 (1) 4 (2) 1 (<1) 4 (2) 1 (1) 1. Topalian S, et al. N Engl J Med 2012; 366: Sznol M, et al. ASCO Weber J, et al. Lancet Oncol 2015; 16: Robert C, et al. N Engl J Med 20145; 372:320-30
49 Pembrolizumab: Data from the Phase I study (Keynote-001) (cont d) PFS In the keynote-001 study the PFS and OS data showed no differences between the two different treatment's schedules used in the study: 2 mg/kg Q3W and 10 mg/kg Q3W OS This data supported the use of the lower dosage of pembrolizumab (2 mg/kg Q3W) for the following studies Hamid O, et al. N Engl J Med Jul 11;369: Reprinted from Robert C, et al. Lancet 2014;384: Copyright 2014, with permission from Elsevier
50 Pembrolizumab: Data from the Phase I study (Keynote-001) All population (n. 655 patients) Long-term follow-up of 655 patients enrolled in the Keynote 001 showed that pembrolizumab is associated with an important antitumour activity: 33% of ORR with 8% of complete response; median duration of response was 28.2 months Only naive patients (n. 152 patients) In the cohort of treatment-naïve patients (n. 152), pembrolizumab showed 45% of ORR with 14% of complete response; ORR in BRAF wt and BRAF mutated patients was 45% and 50% respectively; median duration of response was not reached Daud A, et al. ASCO 2015 J Clin Oncol 2015;33 suppl May 20:abstract 9005 (Permission of Daud A.)
51 Pembrolizumab: Data from the randomised Phase II study in ipilimumab refractory advanced melanoma patients (Keynote-002): Pembrolizumab (2 mg/kg Q3W and 10 mg/kg Q3W) vs. investigator chemotherapy choiche (ICC) Both pembrolizumab doses substantially improved PFS compared with chemotherapy (P < ). Mean PFS up to 12 months of follow-up was approximately 2-fold longer with pembrolizumab. ORR was 21% for pembro 2 mg/kg Q3W, 25% for pembro 10 mg/kg Q3W, and 4% for ICC. Reprinted from Ribas A, et al. Lancet Oncol 2015;16: Copyright 2015, with permission from Elsevier
52 Pembrolizumab: Data from the randomised Phase II study in ipilimumab refractory advanced melanoma patients (Keynote-002): Pembrolizumab (2 mg/kg Q3W and 10 mg/kg Q3W) vs. investigator chemotherapy choiche (ICC) (Cont d) Median duration of response not reached for pembrolizumab, 37 weeks for chemotherapy There was no significant differences in PFS, ORR, or duration of response between pembrolizumab doses Reprinted from Ribas A, et al. Lancet Oncol 2015;16: Copyright 2015, with permission from Elsevier
53 Pembrolizumab: Data from the randomised Phase III study in advanced melanoma patients (Keynote-006): Pembrolizumab (10 mg/kg Q2W and 10 mg/kg Q3W) vs. ipilimumab Both pembrolizumab arms showed a better ORR, PFS, and OS compared to ipilimumab. ORR was 33,7% for pembro 10 mg/kg Q2W, 32,9% for pembro 10 mg/kg Q3W, and 11,9% for ipilimumab Robert C, et al. N Engl J Med 2015;372: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
54 Pembrolizumab: Data from the randomised Phase III study in advanced melanoma patients (Keynote-006): Pembrolizumab (10 mg/kg Q2W and 10 mg/kg Q3W) vs. ipilimumab. (Cont d) Median OS was not reached in all the three arms. 1-year OS rate was 74,1% for pembro 10 mg/kg Q2W, 68,4% for pembro 10 mg/kg Q3W, and 58,2% for ipilimumab. OS HR was 0,63 for pembro 10 mg/kg Q2W vs. ipilimumab, and 0,68 for pembro 10 mg/kg Q3W vs. ipilimumab Robert C, et al. N Engl J Med 2015;372: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
55 Unconventional responses in patients treated with pembrolizumab Immune-related, unconventional response pattern was observed in 6% of the 327 patients treated with pembrolizumab in the Keynoye-001 study For this reason, together the classical RECIST criteria, we must consider immunorelated criteria even for pembrolizumab treatment By permission from Wolchok JD; Wolchok JD, et al. ASCO J Clin Oncol 2015;33(suppl; abstr 3000)
56 Select AE Organ Category Patients, n (%) Pembrolizumab safety profile: Selected immuno-related adverse events experienced in the Phase I-III trials Pembrolizumab Keynote All cohorts n. 655 pts Any Grade Grade 3 4 Pembrolizumab Keynote mg/kg Q3W n. 178 pts N (%) Any Grade Grade 3 4 Pembrolizumab Keynote mg/kg Q3W n. 179 pts N (%) Any Grade Grade 3 4 Skin* NR NR 68 (39) 0 69 (38) 0 Pembrolizumab Keynote mg/kg Q2W n. 278 pts N (%) Any Grade 106 (38,1) Grade Pembrolizumab Keynote mg/kg Q3W n. 277 pts N (%) Any Grade 107 (38,7) Grade 3 4 Gastrointestinal** 11 (1,7) 7 (1.1) 17 (9) 0 20 (11) 4 (2) 52 (18,7) 11 (3,9) 50 (18) 10 (3,6) Endocrine 64 (9,8) 3 (0,5) 19 (11) 1 (<1) 18 (10) 0 47 (17) 2 (0,8) 35 (12,6) 1 (0,4) Hepatic 4 (0,6) 2 (0,3) 2 (1) 1 (<1) 2 (1) 2 (1) 3 (1.1) 3 (1.1) 5 (1.8) 5 (1.8) Pulmonary 18 (2,7) 2 (0,3) 3 (2) 0 3 (2) 2 (1) 1 (0.4) 0 5 (1.8) 1 (0.4) Infusion reaction NR NR (<1) 0 NR NR NR NR Renal 3 (0,5) 2 (0,3) 1 (<1) 0 1 (<1) (0.4) 0 Uveitis 6 (0,9) (1) 1 (<1) 1 (0.4) 0 3 (1.1) 0 * Pruritus, rash, vitiligo **Colitis, diarrhea NR = not reported diarrhea was not reported hypophysitis was not reported 0 1. Daud A, et al. ASCO Ribas A, et al.lancet Oncol 2015 Jun 23. pii: S (15) Robert C, et al. N Engl J Med 2015;372:
57 Proportion of patients Tumour PD-L1 expression as candidate predictive biomarker: First evidence in the nivolumab Phase I trial 42 pts include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC 1 17/17 Melanoma /25 16*/25 PD-L1(+) 0/17 PD-L1(-) PD-L1(+) PD-L1(-) analysis not pre-planned and based on subset of subjects'. *2 pts still under evaluation * RCC Association between pretreatment tumour PD-L1 expression and clinical response Response status PD-L1 Positive no. (%) PD-L1 Negative no. (%) Total no. (%) CR/PR 9 (36) 0 9 (21) Nonresponder 16* (64) 17 (100) 33 (79) All patients NSCLC From Topalian S, et al. NEJM 2012;366: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
58 Tumour PD-L1 expression as candidate predictive biomarker: Response according to PD-L1 expression in NSCLC and melanoma Subsequent experiences showed that there is a 15-20% of patients PD-L1 negative who respond. Moreover, in the phase I study with the combination ipilimumab/nivolumab, the ORR was similar in both the groups (PD-L1 positive and negative). (Simeone et al. Melanoma Manag. 2015; 2:41 50) Tumour PDL1+ Positive ORR n/n (%) PDL1-Negative ORR n/n (%) MPDL3280A (Hamid ASCO 2013) Melanoma 4/15 (27) 3/15 (20) Nivolumab (Weber ASCO 2013) Melanoma 8/12 (67) 6/32 (19) Nivolumab (Grosso ASCO 2013) Melanoma 7/16 (44) 3/18 (17) Nivolumab (Topalian, N Engl J Med, 2012) NSCLC 9/25 (36) 0/17 (0) Nivolumab (Antonia, WCLC 2013) NSCLC 5/31 (16) 4/32 (13) Pembrolizumab (Garon, WCLC 2013) NSCLC 4/7 (57) 2/22 (9) MPDL3280A3 (Horn, WCLC 2013) NSCLC 8/26 (31) 4/20 (20) Nivolumab/ Ipilimumab (Callahan ASCO 2013) NSCLC 4/10 (40) 8/17 (47) Key questions Variability in tissue collection timing, cell sampling, types of assay, IHC criteria 1. Antonia SJ, et al. Poster presentation at WCLC J Thorac Oncol 2013;8(Suppl 2):abstract: P ; 2. Garon EB, et al. Oral presentation at WCLC J Thorac Oncol 2013;8(Suppl 2):abstract: MO18.02; 3. Horn L, et al. Mini-Oral presentation at WCLC J Thorac Oncol. 2013;8(Suppl 2):abstract: MO Bottom table Presented by: Walter J. Urba, MD, PhD
59 Tumour PD-L1 expression as candidate predictive biomarker: Experience from the randomised Phase III studies with nivolumab (CA ) In the CA study, the patients enrolled were stratified according the PD-L1 expression The ORR according the PD-L1 expression was of 44% in the PD-L1 positive group and 20% in the PD-L1 negative group, confirming that patients PD-L1 negative can respond to anti- PD-1 treatment OS data are not still mature D Angelo S, et al. SMR 2014 Weber J, et al. Lancet Oncol 2015;16:375-84, Reprinted from The Lancet, Copyright 2015, with permission from Elsevier. By permission of Weber J, Weber J et al. ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA3.
60 ORR (%, 95% CI) Tumour PD-L1 expression as candidate predictive biomarker: Experience from the randomised Phase III studies with nivolumab - (CA ) Even in the CA study, the patients enrolled were stratified according the PD-L1 expression The ORR according the PD-L1 expression was, in the group of patients treated with nivolumab, 53% in the PD-L1 positive and 33% in the PD-L1 negative % (41 64%) 11% (5 20%) 33% (25 42%) 16% (10 23%) Nivolimumab (n=210) Dacarbazine (n=208) The survival benefit of nivolumab vs. dacarbazine was observed irrespective of tumour PD-L1 status. The 1-year OS rate of the patients treated with nivolumab was 82,1% in the PD-L1 positive group and 67,8% in the PD-L1 negative group 10 0 PD-L1+ PD-L1- From Robert C, et al. N Engl J Med 20145;372: Supplementary material. Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; Redrawn from Long Y, et al. J Translat Med 2015, 13(Suppl 1):O6
61 Tumour PD-L1 Expression as candidate predictive biomarker: Experience from the randomised Phase III studies with pembrolizumab Ribas A, et al. AACR 2015 From Robert C, et al. N Engl J Med 2015;372: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
62 Tumour PD-L1 expression as candidate predictive biomarker: % of pts PD-L1 positive in the different clinical trials Study NIVOLUMAB: Pts PDL1+ Positive (%) CA (Weber J et al. LO 2015) 49 CA (Robert C et al. NEJM 2014) 35 Ca (Larkin J et al. NEJM 2015) ipi/nivo arm 21.7 Ca (Larkin J et al. NEJM 2015) nivo arm 25.3 PEMBROLIZUMAB: Keynote 006 (Robert C et al. NEJM 2015) pembro every 2 wks 80.6 Keynote 006 (Robert C et al. NEJM 2015) pembro every 3 wks 79.8 Keynote 002 (Puzanov I et al. ASCO 2015) 69 Keynote 001 (Daud A et al. SMR 2014)) 77 Ascierto PA, et al. J Trans Med 2015; 13:213
63 Differences between anti-ctla-4 and anti-pd-1 mechanism of action Rationale for the combination While anti-ctla-4 acts primarily during the early activation of T cells (priming phase) in lymphoid tissue, anti-pd-1 is mostly active during the T-cell effector phase, since its major role is in the tumour microenviroment where the interaction PD-1/PD-L1 represents one of the most important mechanism for the immuno escape From Ribas A, et al. N Engl J Med 2012;366: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
64 Ipilimumab plus nivolumab: Results from the phase I study (CA ) The combination nivolumab and ipilimumab showed an interesting OS rates of 79% at 2 years. Moreover, in the nivolumab 1 mg/kg + ipilimumab 3 mg/kg cohort (cohort 2), this combo showed 94% and 88% 1- and 2-year OS rate, respectively. The responses were early and durable and the activity was observed regardless of tumour BRAF mutation or PD-L1 expression status. Relatively lower response rate and worse survival with nivolumab 0.3 mg/kg dose, indicating an efficacy threshold between 0.3 and 1 mg/kg By permission from Dr Mario Sznol; Mario Sznol et al. ASCO 2014, Abstract LBA9003^
65 Ipilimumab plus nivolumab: Results Results from the randomised phase II study ipilimumab/nivolumab vs. ipilimumab alone (CA ) From Postow M, et al. N Engl J Med 2015; 372: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
66 Ipilimumab plus nivolumab - Results Results from the three arms randomised phase III study in untreated advanced melanoma patients with ipilimumab/nivolumab or nivolumab alone vs. ipilimumab alone (CA ): NIVO + IPI resulted in a longer PFS From Larkin J et al. N Engl J Med 2015;373: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
67 Baseline reduction from baseline in target lesions (%) Baseline reduction from baseline in target lesions (%) Baseline reduction from baseline in target lesions (%) Ipilimumab plus nivolumab - Results Results from the three arms randomised Phase III study in untreated advanced melanoma patients with ipilimumab/nivolumab or nivolumab alone vs. ipilimumab alone (CA ): NIVO + IPI resulted in a higher ORR NIVO + IPI Median change: -51.9% IPI Median change: +5.9% NIVO Median change: -34.5% From Larkin J et al. N Engl J Med 2015;373: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
68 Ipilimumab plus nivolumab (CA ): PFS and ORR by PD-L1 expression level (cut-off 5%) In patients whose tumours have 5% PD-L1 expression, both NIVO alone and NIVO + IPI resulted in a similar prolongation in PFS, although ORR was numerically higher with NIVO + IPI. However we should be cautious when interpreting this data because we should wait the OS data before making any conclusion. From Larkin J, et al. N Engl J Med 2015;373: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
69 Ipilimumab/nivolumab safety profile: selected immuno-related adverse events experienced in the Phase I, II, and III trials Select AE organ category patients, n (%) Ipi/Nivo CA n. 53 pts (all cohorts) Any Grade Grade 3 4 Ipi/Nivo CA n. 94 pts Any Grade Grade 3 4 Ipi/Nivo CA n. 313 pts Any Grade Grade 3 4 Skin 37 (70) 2 (4) 67 (71) 9 (10) 185 (59,1) 18 (5,8) Gastrointestinal 20 (38) 5 (9) 48 (51) 20 (21) 145 (46,3) 46 (14,7) Endocrine 7 (13) 1 (2) 32 (34) 5 (5) 94 (30,0) 15 (4,8) Hepatic 12 (23) 8 (15) 26 (28) 14 (15) 94 (30,0) 59 (18,8) Pulmonary 3 (6) 1 (2) 11 (12) 3 (2) 22 (7,0) 3 (1,0) Infusion reaction 1 (2) 0 NR NR NR NR Renal 3 (6) 3 (6) 3 (3) 1 (1) 17 (5,4) 6 (2,0) 1. Wolchok J, et al. N Engl J Med 2013; 369: Postow M, et al. N Engl J Med 2015; 372: Larkin J, et al. N Engl J Med 2015;373:23-34 NR = Not reported
70 Conclusions After more than 40 years we got the approval of several compounds effective in the treatment of melanoma (ipilimumab, vemurafenib, dabrafenib, trametenib, cobimetinib, nivolumab, pembrolizumab) These drugs can be split into two important categories with different characteristics and kinetics of action: immunotherapy and target therapy Anti-PD-1s (nivolumab and pembrolizumab) showed to be superior to ipilimumab The combination BRAF + MEK inhibitors is superior to the BRAF inhibitors monotherapy Considering the data coming from the recent phase III trials, anti-pd-1s (nivolumab and pembrolizumab) should be used in first line. However, in case of patients with symptoms and a fast progression of the disease, the combination BRAF plus MEK inhibitors represents a valid opportunity for the treatment in first line At the moment, the combination ipilimumab/nivolumab should be used only in clinical trials
71 Thank you!
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