IMMUNOTHERAPY OF MELANOMA Anti PD1 Takes Center Stage. Dr Peter Hersey Professor of Melanoma Biology University of Sydney

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1 IMMUNOTHERAPY OF MELANOMA Anti PD1 Takes Center Stage Dr Peter Hersey Professor of Melanoma Biology University of Sydney

2 What we have learnt about immunotherapy over the past 3 years Inhibition of Physiologic Checkpoints is a more effective form of therapy than stimulation of the immune system

3 The Ig Super Family of Co-stimulators and Checkpoint inhibitors

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5 Differences between blocking CTLA4/B7 and blocking PD-1/PD-L1 Receptor T cell expression Ligand expression Knock out mouse phenotype Prediction upon blockade CTLA4 ~48 h after antigen exposure CD80 (B7.1)/CD80 (B7.2) by APCs Early death from autoimmunity Less specific for antitumor T cells PD-1 Upon chronic antigen exposure PD-L1 (B7-H1) by tumors and inflamed tissues PD-L2 (B7-DC) by APCs Late onset autoimmunity More specific for antitumor T cells PRESENTED BY: ANTONI RIBAS, MD

6 Ipilimumab (anti CTLA-4): First in a New Class of Immunopotentiating Agents 1. Co-stimulation via CD28 ligation transduces T-cell activating signals T-cell activation 2. CTLA-4 ligation on activated T cells down-regulates T-cell responses T-cell inactivation 3. Blocking CTLA-4 ligation enhances T-cell responses T-cell activation T cell CTLA-4 T cell T cell TCR MHC CD28 B7 TCR MHC CD28 CTLA-4 B7 TCR MHC CD28 B7 CTLA-4 Ipilimumab APC APC APC Ipilimumab stimulates the immune system to destroy melanoma cells APC, antigen-presenting cell; CTLA, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.

7 Kaplan-Meier Analysis of Survival Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) Comparison HR p-value Arms A vs. C Arms B vs. C Years

8 Pr opor t i on A l i ve Ipilimumab Study 024: Overall Survival Ipilimumab + DTIC Placebo + DTIC Ipilimumab + DTIC versus Placebo + DTIC HR (95% CI) 0.72 ( ) Median OS 11.2 vs 9.1 months P value Years 8

9 APC Role of PD-1 in Suppressing Antitumor Immunity B7.1 CD28 T cell Activation (cytokines, lysis, prolif., migration) MHC-Ag TCR Signal 1 PD-1 (-) (-) (-) Tumor PD-L1 Inhibition (anergy, exhaustion, death) Tumor Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

10 APC Role of PD-1 in Suppressing Antitumor Immunity B7.1 CD28 T cell Activation (cytokines, lysis, prolif., migration) MHC-Ag TCR Signal 1 PD-1 (-) (-) (-) Anti- PD-1 Tumor PD-L1 Inhibition (anergy, exhaustion, death) Tumor Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

11 Clinical Activity of BMS NIVOLUMAB in Melanoma Patients (ASCO 2012) Pop Dose (mg/kg) Pts n ORR n (%) Duration of Response (mo) SD 24 wk n (%) PFSR at 24 wk (%) All MEL (28) 1.9+ to (6) (29) 5.6 to (7) 40 MEL (19) 1.9+ to (6) (30) 5.3+ to (11) (41) 9.2+ to (6) (20) 17.0 to ORR was assessed using modified RECIST v melanoma patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation.

12 Changes in Target Lesions Over Time in Melanoma Patients

13 Possible Effect of BMS Nivolumab on survival Phase 1 study only at different doses so effect on survival is a guess only 13 of 18 patients (72%) who had a response and were followed for 1 year or more, had ongoing responses at 1 year Compares with about 70% 1 year survival of responders to Ipilimumab and 40% 1 year survival of patients responding to DTIC ASCO 2013 Sznol. Overall Median 16.8 mths. Responders 24mths 1Year 61%, 2 years 44%

14 Lambrolizumab (MK3475) A new player on the block sponsored by Merck

15 Phase I Trial Design (NCT ) Apr Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Cohort A: Dose Escalation IPI-N 10Q2W (n = 41) IPI-T 10Q2W (n = 16) IPI-T 10Q3W (n = 32) IPI-N 10Q3W (n = 24) IPI-N 2Q3W (n = 22) Cohort B: Metastatic or locally advanced, unresectable MEL IPI-N, ipilimumab-naive; IPI-T, ipilimumab-pretreated; MEL, melanoma; NSCLC, non-small cell lung cancer. Cohorts C-F: Additional MEL and NSCLC cohorts Presented by: Antoni Ribas

16 Cohort B: Confirmed Objective Response Rate by Dosing Regimen and Prior IPI Treatment Lambrolizumab Dose Prior IPI Treatment N RECIST 1.1, Independent Central Review ORR, % (95% CI) Response Duration Range, mo irrc, Investigator Assessment* N ORR, % (95% CI) Total (25 44) (29 45) 10 mg/kg Q2W Naive (32 65) (40 72) Treated (32 86) (30 80) Total (38 66) (42 69) 10 mg/kg Q3W Naive (9 51) (16 55) Treated (12 48) (9 40) Total (15 42) (16 40) 2 mg/kg Q3W Naive (9 49) (3 35) + indicates censored observation. ORR, objective response rate. *Response rate per irrc (immune-related Response Criteria) was the primary study endpoint. Including unconfirmed responses, ORR was 44% (95% CI, 35% 54%). Presented by: Antoni Ribas

17 Percent Change from Baseline in Longest Diameter of Target Lesion Cohort B: Maximum Change From Baseline in Tumor Size (Independent Central Review) Individual Patients Treated with Lambrolizumab IPI-Pretreated IPI-Naive Presented by: Antoni Ribas

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19 Individual Patients Treated With Lambrolizumab Cohort B: Time to Response and Time on Study Treatment by Central Review IPI-Pretreated IPI-Naive Complete Response Partial Response On Study Weeks The median duration of response had not been reached at the time of analysis, with median follow-up time of 11 months. Presented by: Antoni Ribas

20 Clinical Activity, Patient Baseline: April 13, 2012 July 27, year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab Images courtesy of A. Ribas, UCLA. Presented by: Antoni Ribas

21 Clinical Activity, Patient year-old male with desmoplastic melanoma who progressed after ipilimumab Baseline After 1 cycle Images courtesy of W.J. Hwu, MD Anderson Cancer Center. Patient provided written, informed consent to have his images included in congress presentations. After 3 cycles

22 Clinical Activity, Patient Baseline: February 29, 2012 August 20, 2012 CD8+ IHC CD8+ IHC 61-year-old with a previously untreated metastatic melanoma to the lung Images courtesy of A. Ribas and P. Tumeh, UCLA. Presented by: Antoni Ribas

23 Cohort B: Safety Profile by Dose 10 mg/kg Q2W n = mg/kg Q3W n = 56 2 mg/kg Q3W n = 22 Total N = 135 Any grade treatment-related adverse events, n (%) 52 (91.2) 41 (73.2) 14 (63.6) 107 (79.3) Grade 3-4 treatment-related adverse events, n (%) 13 (22.8) 2 (3.6) 2 (9.1) 17 (12.6) Grade 3-4 adverse events of any causality, n (%) 25 (43.9) 17 (30.4) 7 (31.8) 49 (36.3) Time on therapy, median (range), wk 40.1 ( ) 20.6 ( ) 18.1 ( ) 23.1 ( ) Number of doses, median (range) 12 (1 26+) 6.5 (1 18+) 7 (1 14+) 8 (1 26+) Presented by: Antoni Ribas

24 Presented by: Antoni Ribas Cohort B: Drug-Related Adverse Events Observed in >5% of Patients (N = 135) Adverse Event All Grades, n (%) Grade 3-4, n (%) Any 107 (79.3) 17 (12.6) Fatigue 41 (30.4) 2 (1.5) Rash 28 (20.7) 3 (2.2) Pruritus 28 (20.7) 1 (0.7) Diarrhea 27 (20.0) 1 (0.7) Myalgia 16 (11.9) 0 Headache 14 (10.4) 0 AST increased 13 (9.6) 2 (1.5) Asthenia 13 (9.6) 0 Nausea 13 (9.6) 0 Vitiligo 12 (8.9) 0 Hypothyroidism 11 (8.1) 1 (0.7) ALT increased 11 (8.1) 0 Cough 11 (8.1) 0 Pyrexia 10 (7.4) 0 Chills 9 (6.7) 0 Abdominal pain 7 (5.2) 1 (0.7)

25 Summary of Lambrolizumab Efficacy and Safety in Previously Treated, Advanced Melanoma Confirmed response rate per RECIST 1.1 of 38% across all dose levels Complete response in 5% of patients Highest ORR with 10 mg/kg Q2W dosing (52%) Most responding patients (80%) were still on study at the time of analysis Acceptable, manageable toxicity profile Highest rate of drug-related AEs observed with 10 mg/kg Q2W dosing Efficacy and safety appear similar in ipilimumab-naive and ipilimumab-treated patients Findings support on-going clinical development of lambrolizumab in melanoma and other cancers Currently, studies are ongoing in patients with melanoma, NSCLC, breast cancer, head and neck cancer, and bladder cancer Presented by: Antoni Ribas

26 What Happens When Ipi and Nivolumab are Combined?

27 Clinical Activity: Concurrent Regimen Nivolumab Dose (mg/kg) Ipilimumab Response Evaluable Patients n CR n PR n Objective Response Rate % [95% CI] Aggregate Clinical Activity Rate % [95% CI] 80% Tumor Reduction at 12 wk n (%) [5-51] 50 [23-77] 4 (29) [28-77] 65 [38-86] 7 (41) [16-68] 73 [45-92] 5 (33) [12-88] 83 [36-100] 0 Concurrent [27-55] 65 [51-78] 16 (31) With concurrent treatment of nivolumab + ipilimumab, 40% (range 21-53%) of patients had confirmed objective responses About one third of patients (31%) had rapid and deep tumor regressions Presented by: Jedd D. Wolchok, MD, PhD

28 Clinical Activity: Concurrent Regimen Nivolumab Dose (mg/kg) Ipilimumab Response Evaluable Patients n CR n PR n Objective Response Rate % [95% CI] Aggregate Clinical Activity Rate % [95% CI] 80% Tumor Reduction at 12 wk n (%) [5-51] 50 [23-77] 4 (29) [28-77] 65 [38-86] 7 (41) [16-68] 73 [45-92] 5 (33) [12-88] 83 [36-100] 0 Concurrent [27-55] 65 [51-78] 16 (31) With 1 mg/kg nivolumab + 3 mg/kb ipilimumab, 53% of patients had confirmed objective responses (3 CRs and 6 PRs) All 9 of these had 80% tumor reduction, 7 at 12 weeks and 2 at their first assessment, which was after week 12 80% tumor reductions appear infrequently (<10%) in the nivolumab and ipilimumab monotherapy experiences Presented by: Jedd D. Wolchok, MD, PhD

29 Change in target lesions from baseline (%) Best Responses in All Evaluable Patients in Concurrent Cohorts After ~13 months of follow-up, for all concurrent cohorts, 90% of all responding patients continue to respond as of Feb Patients Presented by: Jedd D. Wolchok, MD, PhD

30 Change in target lesions from baseline (%) Rapid and Durable Changes in Target Lesions 1 mg/kg nivolumab + 3 mg/kg ipilimumab First occurrence of new lesion Pretreatment 12 weeks Weeks since treatment initiation 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 Presented by: Jedd D. Wolchok, MD, PhD

31 Preliminary Survival of Patients Treated with the Concurrent Regimen n=17 1-year Survival 82% n=53 95%CI (69.0%;94.4%) Censored 1 mg/kg nivolumab + 3 mg/kg ipilimumab All concurrent regimen Died/Treated 2 / 17 9 / 53 Patients at Risk Months 1 mg + 3 mg All concurrent Presented by: Jedd D. Wolchok, MD, PhD

32 Treatment-Related Select Adverse Events Occurring in 1 Patient Select Adverse Event Concurrent Regimen All Cohorts (n=53) Sequenced Regimen All Cohorts (n=33) Number of Patients (%) All Gr Gr 3-4 All Gr Gr 3-4 Pulmonary 3 (6) 1 (2) 1 (3 ) 0 Renal 3 (6) 3 (6) 0 0 Endocrinopathies 7 (13) 1 (2) 3 (9) 2 (6) Uveitis 3 (6) 2 (4) 0 0 Skin 37 (70) 2 (4) 8 (24) 0 Gastrointestinal 20 (38) 5 (9) 3 (9) 0 Hepatic 12 (23) 8 (15) 1 (3) 0 Infusion reaction 1 (2) Lipase 10 (19) 7 (13) 4 (12) 2 (6) Amylase 8 (15) 3 (6) 1 (3) 1 (3) Presented by: Jedd D. Wolchok, MD, PhD

33 Demographics Variable Concurrent Regimen (n=53))) Sequenced Regimen (n=33) Median age, yr (range) 58 (22-79) 64 (23-89) Male, no. (%) 32 (60) 18 (55) ECOG performance status, no. (%) 0 44 (83) 22 (67) 1 8 (15) 11 (33) Unknown 1 (2) 0 M-stage at study entry, no. (%) M1a 8 (15) 5 (15) M1b 11 (21) 5 (15) M1c 30 (57) 18 (55) Unknown 4 (8) 5 (15) Lactate dehydrogenase level, no. (%) Upper limit of the normal range 33 (62) 21 (64) >Upper limit of the normal range 20 (38) 12 (36) Systemic cancer therapy, no. (%) 20 (38) 33 (100) Immunotherapy 9 (17) 33 (100) Prior ipilimumab therapy 0 33 (100) B-RAF inhibitor 3 (6) 2 (6) Number of prior systemic cancer therapies, no. (%) 0 33 (62) (26) 18 (55) 2 6 (11) 15 (45) Presented by: Jedd D. Wolchok, MD, PhD

34 Conclusions The concurrent combination of nivolumab and ipilimumab induced objective response rates appearing higher than published monotherapy values The nature of the responses appeared to be distinctly different from those of the nivolumab and ipilimumab monotherapies Responses were rapid and deep At the combined doses chosen for phase 3 study, all responding patients achieved deep or complete responses Treatment-related adverse events managed using standard protocols No treatment-related deaths Clinical activity in patients who previously progressed on ipilimumab and then received nivolumab Based on these results, a phase 3 trial is open to investigate the efficacy of the concurrent nivolumab/ipilimumab combination vs. nivolumab vs. ipilimumab in patients with advanced melanoma (NCT ) This combination is also being investigated in non-small-cell lung cancer and renal cell carcinoma Presented by: Jedd D. Wolchok, MD, PhD

35 THE NEW TREATMENT ALGORITHMS BMS 3 arm study. Ipi v Nivo v Ipi plus Nivo Merck 3 arm study Lambrolizumab 2mg v 10mg v Ipi NRAS failures Novartis MEK 162 Nemo study BRAFV600 melanoma Roche GO28141 Combi study-20% accrued. Novartis LGX818 +-MEK162

36 WHAT ABOUT SELECTIVE BRAF INHIBITORS? BRAF mutation rates Side effects including new malignancies Resistance to BRAFi and BRAF plus MEK combinations LGX 818

37 BRAF mutations NRAS BRAF MEK ERK 50% cutaneous melanomas 20% continuous sunexposure 50-80% intermittent sun-exposure >80% mutations = V600E MITF Curtin, JA et al J Clin Oncol 24, Platz A et al Mol Oncol 1, Long GV et al J Clin Oncol 29,

38 BRAF Mutation Rate by Decade >90% V600E >25% V600K/D/R Menzies AM et al, ASCO 2011, Melanoma Oral Session, Abs# 8507 Jakob JA et al J Clin Oncol 29:526s, 2011 (suppl 15s; abstr 8500) Cheng S et al J Clin Oncol 29:549s, 2011 (suppl 15s; abstr 8597) Rubinstein JC et al J Transl Med 8:67, 2010 Slide courtesy Alex Menzies

39 Potent BRAF inhibitors NRAS BRAF MEK vemurafenib (PLX4032) dabrafenib (GSK ) LGX818 ERK MITF

40 FDG-PET response to vemurafenib (PLX4032) V600E+ melanoma Flaherty KT, et al N Engl J Med 363:809, 2010 Day 1 Day 15 Image courtesy of Grant McArthur, Peter MacCallum Cancer Institute, Melbourne

41 Confirmed objective response rates across vem/dab clinical trial programmes V600E Phase I Phase 2 Phase 3 Vemurafenib 56.0% 53.0% 48.4% Dabrafenib 50.0% 59% 53.0% V600K: Dabrafenib ORR 25% (BREAK 2) Vemurafenib ORR 45% (BRIM 3) (McArthur G SMR Nov 2012 ).

42 What have we learnt? AROUND 50% OF BRAFi-TREATED V600 MUT MELANOMA PATIENTS PROGRESS AT ABOUT 6 MTHS OS 1.5X DTIC; 1/3 rd alive > 2yrs V600E SIMILAR TO V600K

43 Toxicity of BRAFi Vemurafenib SKIN PHOTOSENSITIVITY KERATOPATHY SCC (19%) New primary melanoma 2% CONSTITUTIONAL FEVER RARE ARTHRALGIA FATIGUE LIVER LFTs COMMON 26% 10% G3 Dabrafenib SKIN NO PHOTOSENSITIVITY KERATOPATHY SCC (5%) New primary melanoma 2% CONSTITUTIONAL FEVER COMMON 30% ARTHRALGIA FATIGUE LIVER LFTs RARE

44 Photosensitivity - Off target effect of Vemurafenib

45 Keratotic Lesions Dabrafenib Wks 5-7, 100mg BID Kefford R ASCO 2012 Falchook/Long Lancet

46 Squamous Cell Carcinoma (Skin) Thigh: Week 6 Low-grade squamous cell carcinoma Paradoxical oncogenesis via MAPK stimulation 1,2,3 Kefford R ASCO 2012 Falchook/Long Lancet , Heidom SJ, Marais R, et al, Cell, 2010: 140, Poulikakos PI, Rosen R, et al, Nature, 2010, e 23 Feb. 3. Hatzivassiliou G, et al Nature, 2010, e 3 Feb.

47 NRAS-mutant Chronic Myelo-monocytic Leukemia exacerbated by vemurafenib Callahan M et al NEJM Nov

48 Targeting BRAFi Refractory and Resistant Tumours PDGFR, IGF1R RTKs RTKs P P SOS Grb2 P P SHC P P NRAS NRAS B-RAF V600 B-RAF C-RAF PI3K/AKT/mTOR pathway COT p90rsk MEK ERK1/2 MSK1 MEKi : selumetinib trametinib pimasertib MEK162 GDC0973 Proliferation, Survival R Kefford 2012 not to be reproduced without written permission of the author

49 MEKi: What have we learnt? MEKi: - SINGLE AGENT ACTIVITY AGAINST MUT BRAF MELANOMA PFS 4.8 mths OS superior to chemo WON T SALVAGE BRAFi RESISTANCE

50 Combined MAPK inhibition NRAS BRAF Dabrafenib LGX818 Vemurafenib MEK Trametinib MEK162 GDC0973 ERK MITF Synergy in V600 BRAF xenografts Abrogation of keratopathy

51 Best Confirmed Response Rate Dab (N=54) Dab + Tra 150/1 (N=54)* Dab + Tra 150/2 (N=54) CR 2 (4) 3 (6) 5 (9) PR 27 (50) 24 (44) 36 (67) SD 22 (41) 24 (44) 13 (24) PD 3 (6) 2 (4) 0 Response Rate P-value 29 (54%) 27 (50%) (76%) Duration of Response Months (95% CI) 5.6 (4.5, 7.4) 9.5 (7.4, NA) 10.5 (7.4, 14.9) *1 patient in 150/1 group was not evaluable Long G et al ESMO Sept 2012 Flaherty K et al NEJM 29Sept 2012

52 Estimated survival function Combined dabrafenib + trametinib Randomized Phase II m Dabrafenib + trametinib (full dose) N=54 RR 76% 9.4 m Dabrafenib N=54 RR 54% Patients at risk Time since randomization (months) Adapted from: Long G et al ESMO Sept 2012 Flaherty K et al NEJM 29Sept 2012

53 What have we learnt? BRAFi + MEKi DELAYS RESISTANCE Med PFS 9.4 months vs 5.8 months; HR 0.39; p< months PFS 41% vs 9% ORR 76% vs 54%; p=0.026 Duration of response 10.5 vs 5.6 months SALVAGES SOME BRAFi-RESISTANT PATIENTS REDUCTION IN SKIN ONCOGENICITY PROBLEM OF FEVER

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56 Can We Combine Immunotherapy plus BRAFi?

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58 E1612: Ipi to Vem vs Vem to Ipi PD ECOG PS Stage 1. St IIIc or M1a/b 2. M1c Prior therapy 1. No prior Rx 2. Prior Rx R A N D O M I Z E Arm 1: Ipi 3 mg/kg q3 wks x 4 Arm 2: Vemurafenib 960mg BID PD Vemurafenib 960mg BID Ipi 3 mg/kg q3 wks x 4 ECOG and SWOG protocol Atkins, Chmielowski Tumor measurements q12 wks PRESENTED BY: Michael B. Atkins

59 CONCLUSIONS-MUCH TO BE EXCITED ABOUT Emphasis in treatment now on immunotherapy Need to understand why patients fail anti PD1 What combinations should be investigated How do we select patients?

60 MEKi and BRAFi Associated Adverse Events Dab (n=53) Dab + Tra 150/1 (n=54) *Skin toxicities include multiple terms No cases of RVO Dab + Tra 150/2 (n=55) Rash/Skin toxicities* 36 (68) 31 (57) 36 (65) Acneiform rash 2 (4) 6 (11) 9 (16) Skin papilloma 8 (15) 4 (7) 2 (4) Actinic keratosis 5 (9) 4 (7) 8 (15) Hyperkeratosis 16 (30) 3 (6) 5 (9) Squamous cell carcinoma/ keratoacanthoma P-value 10 (19) 1 (2) (7) 0.09 Ejection Fraction 0 2 (4) 5 (9) Chorioretinopathy (2)

61 Part 2 Partial Response in Brain 61 yo V600E Multiple Metastases Baseline Week 4 Week 10 Long GV et al ESMO, Milan 2010

62 Maximum percent change from baseline intracranial measurement BREAK-MB Trial Brain Metastases BRAF V600E melanoma No prior brain treatment OIRR: 39% ORR: 38% Intracranial disease control rate: 81% Overall disease control rate: 80% Kirkwood ASCO 2012 Long, G et al Lancet Oncology Oct 2012

63 Combined dabrafenib + trametinib Randomized Phase II Study Design BRAF V600 E/K metastatic melanoma No prior BRAFi or MEKi Up to 1 prior treatment Stable and treated brain mets Objectives N=162 R A N D O M I Z E Combination (d-t) - 150/1 N= 54 Combination (d-t) 150/2 N= 54 *cross over to Dab + Tra 150/2 after progression allowed PFS, ORR, duration of response and incidence rate of cuscc OS and safety Monotherapy*(d) -150mg BID N= 54 Long G et al ESMO Sept 2012 Flaherty K et al NEJM 29Sept 2012

64 M82 V600K Metastatic melanoma dabrafenib 150 mg bid Baseline Week 6 Kefford et al ASCO Chicago 2010; Melanoma2010 Sydney 2010 Falchook G,/Long G. et al Lancet May 2012