The changing landscape of medical management of stage III and IV melanoma Current treatments and what s on the horizon

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1 The changing landscape of medical management of stage III and IV melanoma Current treatments and what s on the horizon Samantha Bowyer Medical Oncologist Rockingham General Hospital

2 Historical perspective for treatment of melanoma Historical Perspective Median OS 7.3 months (95% CI, 6.01 to 8.84) in the fotemustine arm versus 5.6 months (95% CI, 5.03 to 6.54) in the DTIC arm Avril et al. JCO 2004: 22(6); 1118

3 New Treatment Paradigms Immunotherapy Target host Targeted Therapy Target tumour Ipilimumab Pembrolizumab Nivolumab Vemurafenib, dabrafenib Trametinib

4 TARGETED THERAPIES THE ERA OF PERSONALISED ONCOLOGY

5 What drives melanoma?

b 2517 Updated Overall Survival for BRF113220:A Phase 1-2 Study of Dabrafenib Alone vs Combined Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Metastatic Melanoma 1 Adil Daud,

7 b 2517 Updated Overall Survival for BRF113220:A Phase 1-2 Study of Dabrafenib Alone vs Combined Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Metastatic Melanoma 1 Adil Daud, 2 Jeffrey Weber, 3 Jeffrey Sosman, 4 Kevin Kim, 5 Rene Gonzalez, 6 Omid Hamid, 7 Jeffrey Infante, 8 Jonathan Cebon, 9 Lynn Schuchter, 10 Georgina Long, 1 Alain Algazi, 11 Ragini Kudchadkar, 3 Igor Puzanov, 12 Donald Lawrence, 13 Richard Kefford, 14 Amy Kline, 15 Heather Del Buono, 14 Peng Sun, 14 Diane Opatt McDowell, 12 Keith Flaherty 1 University of California San Francisco, San Francisco, CA, USA; 2 Moffitt Cancer Center, Tampa, FL, USA; 3 Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA; 4 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5 University of Colorado Cancer Center, Aurora, CO, USA; 6 Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 7 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 8 Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, VIC, Australia; 9 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 10 Melanoma Institute Australia and The University of Sydney, Sydney, Australia; 11 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 12 Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, MA, USA; 13 Melanoma Institute Australia, Westmead Institute for Cancer Research and Westmead Hospital, The University of Sydney, NSW, Australia; 14 Novartis Research and Development, East Hanover, NJ, USA; 15 Janssen Pharmaceutical Research and Development, Titusville, NJ, USA BACKGROUND BRF An open-label, dose-escalation, phase 1/2 study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the BRAF inhibitor, dabrafenib in combination with the MEK inhibitor, trametinib in patients with BRAF mutation positive metastatic melanoma Rationale for Combination Dose A statistically significant and clinically meaningful improvement in several key efficacy endpoints was observed in patients treated in the combination (D+T) dabrafenib 150 mg twice daily (BID)/trametinib 2 mg once daily (QD) group compared with the patients in the dabrafenib monotherapy group There was evidence of a dose response, as the 150/1 combination dose demonstrated a smaller treatment effect on progression-free survival (PFS) and a lower overall response rate (ORR)compared with the 150/2 dose Dabrafenib at 150 mg BID in combination with trametinib at 2 mg QD provided meaningful clinical benefit with favorable benefit/risk ratio for patients with BRAF V600 mutation positive unresectable or metastatic melanoma METHODS Overall Study Design Part A Part B Treated/stable Z 150 mg BID/ of chemotherapy or O 1 mg QD interleukin-2 M N = 54 allowed I Combination brain metastases E PK study 2 mg QD Objectives: Part D Dabrafenib (HPMC) + N = 162 N = PFS, ORR, 54 Duration of response (DOR), safety (including rateof cutaneous squamous cell carcinoma) Overall survival (OS), pharmacokinetics Trametinib a (PK) Crossover to combination D+T 150/2 after progression. PART C: Data Cutoffs Overall Study Design Part C Randomized Phase 2 Dabrafenib + Trametinib BRAF V600E/K Monotherapy Drug-drug interaction D metastatic R 150 mg BID a Dabrafenib + Trametinib melanoma A N = 54 Dose escalation No prior Combination D or T N BRAF-mutant melanoma BID/ Expansion cohorts Part C Randomized phase 2 Data Cutoffs March May March January January Start of study Data analyzed PFS, OS, safety OS PFS, OS OS, safety Flaherty KT, et al. N Engl J Med Daud A, et al. Flaherty KT, Long GV, et al. ESMO SMR et al. ASCO Flaherty KT, et al. N Engl J Med. 2012;367: ; 2. Long GV, et al. Abstract and presentation at ESMO [abstract LBA27]; 3. Daud A, et al. Abstract and presentation at SMR 2013, abstract 9013; 4. Flaherty KT, et al. Abstract and presentation at ASCO 2014, 2014 [abstract 9010]. D+T D+T One prior regimen D 150 mg RESULTS Part C: Patient Characteristics Age, median (range), years 49.5 (18-82) 49 (23-85) Died, n (%) (27-79) Male, n (%) 29 (54) 30 (56) (95) (47) Overall survival at 12 months (95% 68 (45-88 (70-34 (63) ECOG PS, n (%) 0 34 (63) 38 (70) CI), % 83) 95) Overall survival at 24 months (95% 18 (6-75 (56-35 (65) CI), % 36) 86) 1 20 (37) 16 (30) 19 Overall survival at 36 months (95% 5 (0.3-19) 62 (42- (35) CI), % 76) BRAF mutation status Number of Disease Sites 3 < 3 V600E, n (%) 45 (83) 45 (83) 47 (87) V600K, n (%) 9 (17) 9 (17) Number of patients (13) Died, n (%) Stage IV M1c, n (%) 37 (69) 33 (61) (82) (50) 38 (70) Overall survival at 12 months (95% 68 (47-92 (73-98) CI), % 82) LDH > ULN, n (%) 27 (50) 25 (46) Overall survival at 24 months (95% 30 (15-73 (52-22 (41) CI), % 48) 86) Overall survival at 36 months (95% 19 (7-58 (37- Long G, et al. ESMO 2012; Flaherty K, et al. N Engl J History of brain mets, n (%) 4 (7) 7 (13) CI), % 36) 74) Med. ECOG, European Cooperative Oncology Group; PS, performance status; LDH, lactate dehydrogenase; ULN, 2 (4) upper limit of normal. There was no difference in OS in the following subgroups: prior immunotherapy, age, target lesion sum of diameters, Part C: OverallSurvival by baseline ECOG, or sex Prior immunotherapy, n (%) 8 (15) 16 (30) Study 13 (24) Arm Part C 150/2 Arm: CoxProportional Hazards Regression Model for Prior chemotherapy, n (%) 12 (22) 15 (28) Overall CovariateSurvival Effect Tested Hazard Ratio a 95% 2-Sided P Value 7 (13) 1.0 CI Cohort 150/2 Baseline LDH ULN vs > ULN <.0001 Median: 25 mo Number of disease sites < 3 vs mo OS rate: 80% a A hazard ratio < 1 indicate a lower risk of death for the first subgroup. 24-mo OS rate: 51% 36-mo OS rate: 38% 0.6 Non-significant covariates: Estimated SurvivalFunction Overall Survival by Treatment Arm D monotherapy a (n = 54) 150/2 (n = 54) Patients at Risk Cohort Dabrafenib 150 mg BID Death s, n (%) a OS for D monotherapy is confounded by crossover to 150/ Dabrafenib 150 mg BID/trametinib 1 mg QD Part C 150/2 Arm: OverallSurvival in Subgroups Median OS (95% CI), mo (76) (14.5, 27.1) 36 (67) 25.0 (17.5, 36.5) Baseline Disease Stage M1c M1a/M1b Number of patients Died, n (%) 30 (79) Overall survival at 12 months (95% 76 (59- CI), % 87) Overall survival at 24 months (95% 42 (26- CI), % 57) Overall survival at 36 months (95% 26 (14- CI), % 41) Monotherapy D Combination D+T 150/1 Combination D+T 150/2 (n = 54) (n = 54) (n = 54) Time Since Randomization, months Dabrafenib 150 mg BID/trametinib 2 mg QD 6 (38) 88 (59-97) 74 (45-90) 68 (39-85) Data as of 15 January 2015 Hazard Ratio 12-Mo 24-Mo 36-Mo (95% CI) OS OS OS Rate Rate Rate Part (%) (%) (%) C NA (0.49, 1.21) Baseline LDH LDH > LDH ULN ULN Number of patients Age as continuous variable, sex, baseline target lesion sum of diameters as continuous covariate, BRAF mutation, prior immunotherapy, baseline ECOG PS (0 or 1), and baseline disease stage (M1cvs other) Part C 150/2 Arm Overall Survival: Investigator-Assessed Best Response Stable Disease Partial Response Complete Response Number of patients Died, n (%) 8 (62) 25 (76) OS at 12 months (95% CI), % 69 (37-79 (61-87) 89) OS at 24 months (95% CI), % 35 (11-48 (31-60) 64) OS at 36 months (95% CI), % 35 (11-33 (18-60) 49) Part C: Adverse Events > 20% (all grades D+T 150/2 arm) Monotherapy D (n = 53 a ) n (%) Pyrexi a (26) (72) (69) Chills 9 (17) (52) (60) Fatigue (42) (65) (58) Diarrhea (28) (33) (49) Nausea (21) (56) (47) Vomiting 8 (15) (43) (47) Arthralgia (32) (52) (35) Cough (21) (19) (35) Headache (32) (46) (31) Rash (36) (24) (31) Decreased appetite (21) (33) (29) Constipation 6 (11) (24) (27) Night sweats 3 (6) (20) (27) Edema peripheral 9 (17) (24) (25) Myalgia (23) (30) (24) Abdominal pain 7 (13) (19) (22) Actinic keratosis 7 (13) 6 (11) 12 (22) Anemia 4 (8) (19) (22) Back pain 6 (11) 7 (13) 12 (22) Dry skin 2 (4) 6 (11) 12 Pain in extremity 11 (21) a Monotherapy D (n = 53): 1 patient in this arm received combination D+T 150/2 (n = 55) due to dispensing error. b Pyrexia = temperature 38.5 C. Combination D+T 150/1 (n = 54) n (%) 11 (20) 3 (38) (39-98) 63 (23-86) Combination D+T 150/2 (n = 55 a ) n (%) (22) 12 (22) Part C: Adverse Events of Interest KA, keratoacanthomas; PPES, palmar-plantar erythrodysesthesia, EF, Diarrhea 15 (28) 18 (33) 27 (49) 9 CONCLUSIONS (16) PPES 9 (17) 4 (7) 4 (7) Longer follow-up reveals median OS of 25 months for patients in the 150/2 cohort Landmark OS results for the 150/2 cohort Landmark OS rates: 1 year, 80%; 2 year, 51%; 3 year, 38% Normal LDH and fewer disease siteswere associated with prolonged survival Prior immunotherapyhad no effect on OS No new safety signal observed and no increase in cuscc cases or treatment-emergent malignancies DISCLOSURES A. Daud Consultant to GlaxoSmithKline and Genentech, received researchfunding from GlaxoSmithKline, Pfizer,Genentech, and OncoSec J. Weber Consultant for and received honorariafrom GlaxoSmithKline J. Sosman Consultantfor GlaxoSmithKline, received researchfunding (forthe clinical study only)from GlaxoSmithKline K. Kim Consultant for GlaxoSmithKline, received researchfunding (forthe clinical study only)from GlaxoSmithKline R. Gonzalez Received researchfunding from GlaxoSmithKline O. Hamid Consultant to GlaxoSmithKline J. Infante Uncompensated consultant/advisor to GlaxoSmithKline J. Cebon Participated in advisory boards for, has received honoraria and researchfunding from GlaxoSmithKline L. Schuchter Participated in advisory boards for Merck, has received researchfunding from Merck, GlaxoSmithKline, and Genentech G. Long Consultant advisor for GSK A. Algazi Oncosec, Astra Zeneca,Merck, Medimmune, Bristol-Meyers Squibb, Amgen, Novartis, GlaxoSmithKline R. Kudchadkar No disclosure I. Puzanov Compensated consultant/advisor to GlaxoSmithKline D. Lawrence No disclosure R. Kefford Compensatedconsultant/advisor to GlaxoSmithKline A. Kline Employee of Novartis; Stock ownership-glaxosmithkline H. Del Buono Employee of Johnson & Johnson; Stock ownership-glaxosmithkline P. Sun Employee of Novartis; Stock ownership-glaxosmithkline D. McDowell Employee of Novartis; Stock ownership-glaxosmithkline K. Flaherty Compensated consultant/advisor to GlaxoSmithKline Study BRF113220: (NCT# )was sponsored by GlaxoSmithKline Mobile Friendly e-prints Scan this QR code Visit the web at: 6 Monotherapy D Combination D+T 150/1 Combination D+T 150/2 (n = 53) (n = 54) n (%) n (%) n (%) (n = 55) Pyrexia 14 (26) 39 (72) 38 (61) cuscc, including KA 9 (17) 1 (2) 5 (9) Hyperkeratosis 16 (30) 4 (7) 8 (15) Skin papilloma 8 (15) 4 (7) 2 (4) Noncutaneous malignancy (5) New primary melanoma 1 (2) 0 Decreased EF 0 5 (9) 7 (13) 0 Hypertension 2 (4) 4 (7) 3 ways to instantly download an electronic copy of this poster to your mobile device or a copy to your computer or tablet Text: Qe8536 Text Message (SMS) to: 8NOVA (86682) US Only North, Central and South Americas; Caribbean; China UK, Europe & Russia Sweden, Europe Standard data or message rates may apply. Copies of this poster obtained through Quick Response Code are for personal use only and may not be reproduced without permission from ASCO and the author of this poster. Poster Presentation at the 51st ASCO Annual Meeting; May 29-June 2, 2015;Chicago Illinois. This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015.

8 Baseline 6 weeks 6 months

10 SCC: Paradoxical activation BRAF BRAF inhibitors

11 Combination therapy: breaking the paradox BRAF BRAF inhibitors Trametinib Cobimetinib

12 Toxicity

13 IMMUNOTHERAPY BEYOND TARGETS

memory Disadvantages Many controls are inhibitory,

14 The Immune Systems Role Advantages Responds to tumour specific antigens Adapts to new mutations Provides memory Disadvantages Many controls are inhibitory, allowing tolerance Inhibitory controls subverted by cancer

15 Immune Checkpoint Inhibitors Currently PBS reimbursed in melanoma only Ipilimumab: CTLA-4 inhibitor Pembrolizumab: PD-1 inhibitor Ribas NEJM 2012

16 Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma Proportion Alive Ipilimumab CENSORED N = 1861 Median OS (95% CI): 11.4 mo ( ) 3-year OS Rate (95% CI): 22% (20% to 24%) Months Patients at Risk Ipilimumab Hodi S, et al European Cancer Congress. Abstract LBA 24.

17 Kinetics of Appearance of iraes with Ipilumumab Rash, pruritis Liver toxicity Diarrhea, colitis Hypophysitis Toxicity Grade Weeks Weber JS, et al. J Clin Oncol. 2012;30:

18 Immune Mediated Toxicity Common (>20%) Occasional (5-20%) Rare Ipilimumab Rash, itch, lethargy, diarrhoea/colitis Hepatitis, endocrinopathies Uveitis, nephritis, pancreatitis, neuropathies, thrombocytopenia, Stevens-Johnson syndrome PD-1 inhibitors Fatigue, headache, arthralgia, itch, hepatitis, diarrhoea/colitis, infusion reactions, endocrinopathies Pneumonits, anaemia Weber, JCO, 2015

20 Summary Statistics Response rates Complete responses Median PFS Median OS DTIC BRAFi BRAF/ MEK Ipilimumab PD-1 inhibitor Ipi + PD % 50% 70% 10-15% 44% 58% 1% 4% 10% 1-2% 9% 11% 6 weeks 6 months 10 months 3 months 6 months 11 months 6 months 20 months 25 months 11 months NR NR 3 year OS 7% 31% 38% 22% NR NR

21 ADJUVANT THERAPY

22 5 year melanoma specific survival: IIIA 78% IIIB 59% IIIC 40% Bad prognostic features: Ulcerated primaries Greater Breslow thickness Multiple nodes involved Macrometastases within lymph nodes Older age High mitotic rate

23 High dose INF-α: PBS reimbursed Meta-analysis of 14 RCTs of adjuvant HDI Who benefits most: Younger age <70 years Ulcerated primaries Low volume disease

deaths OS data immature Placebo comparator Duration: induction 3 months

24 Limitations to implementing in clinical practice: 10mg/kg dosing 40% of patients discontinued induction therapy due to AEs 1% treatment related deaths OS data immature Placebo comparator Duration: induction 3 months and maintenance for 3 years Eggermont et al. Lancet Oncology. 2015: 16(5)

25 Local Adjuvant Clinical Trials Stage III Melanoma Combi AD Dabrafenib/trametinib vs. placebo Brim 8: Vemurafenib vs. placebo Checkmate 238: Nivolumab versus ipilimumab KEYNOTE 054: Pembrolizumab vs. placebo clinicaltrials.gov

26 THE FUTURE

27 Just the beginning Combination immunotherapy Combination immunotherapy and targeted therapy Neoadjuvant therapy New approaches with improved understanding of biology

28 Questions?

J Clin Oncol 34: by American Society of Clinical Oncology INTRODUCTION

J Clin Oncol 34: by American Society of Clinical Oncology INTRODUCTION VOLUME 34 NUMBER 8 MARCH 10, 2016 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Overall Survival and Durable Responses in Patients With BRAF V600 Mutant Metastatic Melanoma Receiving Dabrafenib