The changing landscape of medicalmanagement of stage III and IV melanoma –

Current treatments and what’s on the horizon

Samantha BowyerMedical Oncologist

Rockingham General Hospital

Median OS 7.3 months (95% CI, 6.01 to8.84) in the fotemustine armversus 5.6 months (95% CI, 5.03 to 6.54)in the DTIC arm

Avril et al. JCO 2004: 22(6); 1118

Historical PerspectiveHistorical perspective for treatment of melanoma

New Treatment Paradigms

Target host

Targettumour

Immunotherapy TargetedTherapy

• Vemurafenib, dabrafenib• Trametinib

• Ipilimumab• Pembrolizumab

• Nivolumab

TARGETED THERAPIESTHE ERA OF PERSONALISED ONCOLOGY

What drives melanoma?

2517

Updated Overall Survival for BRF113220:A Phase 1-2 Study of Dabrafenib Alone vs Combined Dabrafenib andTrametinib in Patients With BRAF V600 Mutation–Positive Metastatic Melanoma

1Adil Daud, 2Jeffrey Weber, 3Jeffrey Sosman, 4Kevin Kim, 5Rene Gonzalez, 6Omid Hamid, 7Jeffrey Infante, 8Jonathan Cebon, 9Lynn Schuchter, 10Georgina Long, 1Alain Algazi, 11Ragini Kudchadkar, 3Igor Puzanov,12Donald Lawrence, 13Richard Kefford,14Amy Kline, 15Heather Del Buono, 14Peng Sun, 14Diane Opatt McDowell, 12Keith Flaherty

1University of California San Francisco, San Francisco, CA, USA; 2Moffitt Cancer Center, Tampa, FL, USA; 3Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA; 4Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5University of Colorado Cancer Center, Aurora, CO, USA;6Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 7Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 8Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, VIC, Australia; 9Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA;

10Melanoma Institute Australia and The University of Sydney, Sydney, Australia; 11Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 12Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, MA, USA; 13Melanoma Institute Australia, Westmead Institute for Cancer Research and Westmead Hospital,The University of Sydney, NSW, Australia; 14Novartis Research and Development, East Hanover, NJ, USA; 15Janssen Pharmaceutical Research and Development, Titusville, NJ, USA

BRF113220• 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 BRAFmutation–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) groupcompared with the patients in the dabrafenib monotherapy groupThere was evidence of a dose response, as the 150/1 combination dose demonstrated a smaller treatment effect onprogression-free survival (PFS) and a lower overall response rate (ORR) compared with the 150/2 doseDabrafenib at 150 mg BID in combination with trametinib at 2 mg QD provided meaningful clinical benefit with favorablebenefit/risk ratio for patients with BRAF V600 mutation–positive unresectable or metastatic melanoma

•

•

Long G, et al. ESMO 2012; Flaherty K, et al. N Engl JMed. 2012.ECOG, European Cooperative Oncology Group; PS, performance status; LDH, lactate dehydrogenase;ULN, upper limit of normal. • There was no difference in OS in the following subgroups: prior immunotherapy, age, target lesion sum of diameters,

baseline ECOG,or sexOverall StudyDesign

KA, keratoacanthomas; PPES, palmar-plantar erythrodysesthesia, EF,ejection fraction.Part C: OverallSurvival by

Study Arm Part C 150/2 Arm: Cox Proportional Hazards Regression Model forOverall Survival CONCLUSIONS

Drug-drug interaction

– Landmark OS rates: 1 year, 80%; 2 year, 51%; 3 year, 38%• Non-significant covariates:

– 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 (M1c vs other)

Part C 150/2 Arm Overall Survival: Investigator-AssessedBest Response

• Treated/stable Z 150 mg BID/

A. Daud—Consultant to GlaxoSmithKline and Genentech, received researchfunding from GlaxoSmithKline, Pfizer,Genentech, and OncoSecJ. Weber—Consultant for and received honoraria from GlaxoSmithKlineJ. Sosman—Consultantfor GlaxoSmithKline, received researchfunding (for the clinical study only) from GlaxoSmithKlineK. Kim—Consultant for GlaxoSmithKline, received researchfunding (for the clinical study only) from GlaxoSmithKlineR. Gonzalez—Received researchfunding from GlaxoSmithKlineO. Hamid—Consultant to GlaxoSmithKlineJ. Infante—Uncompensated consultant/advisor to GlaxoSmithKlineJ. Cebon—Participated in advisory boards for, has received honorariaand researchfunding from GlaxoSmithKlineL. Schuchter—Participated in advisory boards for Merck, has received researchfunding from Merck, GlaxoSmithKline, and GenentechG. Long—Consultant advisor for GSKA. Algazi—Oncosec, Astra Zeneca,Merck, Medimmune, Bristol-Meyers Squibb, Amgen, Novartis, GlaxoSmithKlineR. Kudchadkar—No disclosureI. Puzanov—Compensated consultant/advisor to GlaxoSmithKlineD. Lawrence—NodisclosureR. Kefford—Compensatedconsultant/advisor to GlaxoSmithKlineA. Kline—Employee of Novartis; Stock ownership-GlaxoSmithKlineH. Del Buono—Employee of Johnson & Johnson; Stock ownership-GlaxoSmithKlineP. Sun—Employee of Novartis; Stock ownership-GlaxoSmithKlineD. McDowell—Employeeof Novartis; Stock ownership-GlaxoSmithKlineK. Flaherty—Compensated consultant/advisor to GlaxoSmithKlineStudy BRF113220: (NCT#01726738) was sponsored by GlaxoSmithKline

Objectives:• PFS, ORR,Duration of response (DOR), safety (including rate of cutaneous squamous cell carcinoma)• Overall survival (OS), pharmacokinetics (PK)

Part C: Adverse Events > 20% (all grades D+T150/2 arm)

PyrexiaPART C: Data

CutoffsData as of 15 January2015

Overall Survival byTreatment Arm

a OS for D monotherapy is confounded by crossoverto 150/2.

Part C 150/2 Arm: Overall Survival inSubgroups

http://novartis.medicalcongressposters.com/Default.aspx?doc=e8536

1. Flaherty KT, et al. N Engl J Med. 2012;367:1694-1703; 2. Long GV, et al. Abstract and presentation at ESMO 2012. 2012 [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].

a Monotherapy D (n = 53): 1 patient in this arm received combination D+T 150/2 (n = 55) due todispensing error.b Pyrexia = temperature ≥ 38.5°C.

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.

Estim

ated

Surv

ival

Func

tion

Baseline Disease Stage M1c M1a/M1bNumber of patients 38 16

Died, n (%) 30(79)

6 (38)

Overall survival at 12 months (95%CI), %

76 (59-87)

88 (59-97)

Overall survival at 24 months (95%CI), %

42 (26-57)

74 (45-90)

Overall survival at 36 months (95%CI), %

26 (14-41)

68 (39-85)

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Treatment Deaths, n(%)

Median OS (95%CI), mo

Hazard Ratio(95% CI)

12-MoOS

Rate(%)

24-MoOS

Rate(%)

36-MoOS

Rate(%)Part

CD monotherapya

(n = 54)41

(76)20.2

(14.5,27.1)

NA 70 44 31

150/2(n = 54)

36 (67) 25.0(17.5,36.5)

0.77(0.49,1.21)

80 51 38

Data Cutoffs

March May March January January2010 2012 2013 2014 2015

Start of study

Data analyzed PFS, OS, safety OS PFS, OS OS, safety

Flaherty KT, et al. N Engl J Med. 20121 Daud A, et al. FlahertyKT, Long GV, et al. ESMO 20122 SMR 20133 etal.

ASCO 20144

MonotherapyD (n = 53a)

n (%)

Combination D+T150/1 (n = 54)

n (%)

Combination D+T150/2 (n = 55a)

n (%)b 14

(26)39

(72)38

(69)Chills 9 (17) 28(52)

33(60)Fatigue 22

(42)35

(65)32

(58)Diarrhea 15(28)

18(33)

27(49)Nausea 11

(21)30

(56)26

(47)Vomiting 8 (15) 23(43)

26(47)Arthralgia 17

(32)28

(52)19

(35)Cough 11(21)

10(19)

19(35)Headache 17

(32)25

(46)17

(31)Rash 19(36)

13(24)

17(31)Decreased appetite 11

(21)18

(33)16

(29)Constipation 6 (11) 13(24)

15(27)Night sweats 3 (6) 11

(20)15

(27)Edema peripheral 9 (17) 13(24)

14(25)Myalgia 12

(23)16

(30)13

(24)Abdominal pain 7 (13) 10(19)

12(22)Actinic keratosis 7 (13) 6 (11) 12(22)Anemia 4 (8) 10

(19)12

(22)Back pain 6 (11) 7 (13) 12(22)Dry skin 2 (4) 6 (11) 12(22)Pain in extremity 11

(21)11

(20)12

(22)

DISCLOSURESBest Response Stable Disease Partial Response Complete Response

Number of patients 13 33 8

Died, n (%) 8 (62) 25(76)

3 (38)OS at 12 months (95% CI), % 69 (37-

87)79 (61-

89)100

OS at 24 months (95% CI), % 35 (11-60)

48 (31-64)

88 (39-98)OS at 36 months (95% CI), % 35 (11-

60)33 (18-

49)63 (23-

86)

• Longer follow-up reveals median OS of 25 months for patients in the 150/2 cohort• Landmark OS results for the 150/2 cohort

– Normal LDH and fewer disease siteswere associated with prolonged survival– Prior immunotherapyhad no effect on OS

• No new safety signal observedand no increase in cuSCC cases or treatment-emergent malignancies

Covariate Effect Tested Hazard Ratioa 95%CI

2-Sided P Value

Baseline LDH ≤ ULN vs > ULN 0.21 0.10-0.44 < .0001

Number of disease sites < 3 vs ≥ 3 0.34 0.17-0.70 .0036a A hazard ratio < 1 indicate a lower risk of death for the first subgroup.

1.0Cohort150/2Median: 25 mo

0.8 12-mo OS rate: 80%24-mo OS rate: 51%

0.6 36-mo OS rate: 38%

0.4

0.2

0.0Patients at Risk

54 50 38 30 24 20 1410

54 47 35 25 21 15 1313

54 52 43 33 27 23 2016

0 6 12 18 24 30 36 42 48

Time Since Randomization, months

CohortDabrafenib 150 mg BID Dabrafenib150 mg BID/trametinib 2 mg QDDabrafenib 150mg BID/trametinib 1 mg QD

Overall Study Design Part C Randomized Phase 2Part A Dabrafenib + Trametinib • BRAF V600E/K Monotherapy

Dmetastatic R 150 mg BIDa

Dabrafenib + Trametinib melanoma A N = 54

Part BDose escalation • No prior D or T N Combination

D+TBRAF-mutant melanoma • One prior regimen D 150 mg

BID/

Expansion cohorts of chemotherapy or O 1 mg QDinterleukin-2 M N = 54allowed

Part C Randomized phase 2 I Combination

D+T

PK studybrain metastases E 2 mg

QD

Part D Dabrafenib (HPMC) + N = 162 N =

54Trametinib a Crossover to combination

D+T 150/2 after progression.

METHODS

n (%) n (%) n (%)

Decreased EF 0 5 (9) 7 (13)

RESULTSPart C: Patient Characteristics

Monotherapy D Combination D+T 150/1Combination D+T 150/2 (n = 54) (n = 54)(n = 54)

Age, median (range), years 49.5 (18-82) 49 (23-85)57.5 (27-79) Male, n (%) 29 (54) 30 (56)34 (63) ECOG PS, n (%) 0 34 (63) 38 (70)35 (65)

1 20 (37) 16 (30) 19(35)

BRAF mutation statusV600E, n (%) 45 (83) 45 (83)47 (87) V600K, n (%) 9 (17) 9 (17)7 (13)

Stage IV M1c, n (%) 37 (69) 33 (61)38 (70)

LDH > ULN, n (%) 27 (50) 25 (46)22 (41)

History of brain mets, n (%) 4 (7) 7 (13)2 (4)

Prior immunotherapy, n (%) 8 (15) 16 (30)13 (24)

Prior chemotherapy, n (%) 12 (22) 15 (28)7 (13)

Part C: Adverse Events of InterestMonotherapy D Combination D+T 150/1

Combination D+T 150/2 (n = 53) (n = 54)(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 0 03 (5)

New primary melanoma 1 (2) 00

Diarrhea 15 (28) 18 (33)27 (49)

Hypertension 2 (4) 4 (7)9 (16)

PPES 9 (17) 4 (7)4 (7)

Baseline LDH LDH >ULN

LDH ≤ULN

Number of patients 22 32

Died, n (%) 21(95)

15(47)

Overall survival at 12 months (95%CI), %

68 (45-83)

88 (70-95)

Overall survival at 24 months (95%CI), %

18 (6-36)

75 (56-86)

Overall survival at 36 months (95%CI), %

5 (0.3-19) 62 (42-76)

Number of Disease Sites ≥ 3 < 3

Number of patients 28 26

Died, n (%) 23(82)

13(50)

Overall survival at 12 months (95%CI), %

68 (47-82)

92 (73-98)

Overall survival at 24 months (95%CI), %

30 (15-48)

73 (52-86)

Overall survival at 36 months (95%CI), %

19 (7-36)

58 (37-74)

BACKGROUND

Baseline 6 weeks

6 months

SCC: Paradoxical activation

BRAFinhibitors

BRAF

Combination therapy: breaking theparadox

BRAFinhibitors

BRAF• Trametinib• Cobimetinib

Toxicity

IMMUNOTHERAPYBEYOND TARGETS

The Immune Systems Role

Advantages● Responds to tumour

specific antigens● Adapts to new

mutations● Provides memory

Disadvantages● Many controls are

inhibitory, allowingtolerance

● Inhibitory controlssubverted by cancer

Ribas NEJM 2012

Immune Checkpoint Inhibitors

Currently PBS reimbursedin melanoma only• Ipilimumab:

– CTLA-4 inhibitor• Pembrolizumab:

– PD-1 inhibitor

Patients at RiskIpilimumab 1861 839 370 254 192 170 120 26 15 5 0

Prop

ortio

nAl

ive

0.00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.91.0

Months0 12 24 36 48 60 72 84 96 108 120

N = 1861Median OS (95% CI): 11.4 mo (10.7-12.1)3-year OS Rate (95% CI): 22% (20% to 24%)

IpilimumabCENSORED

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.

Ipilimumab: Pooled Survival Analysisfrom Phase II/III Trials in Advanced

Melanoma

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Kinetics of Appearance of irAEs withIpilumumab

Rash, pruritisLiver toxicityDiarrhea, colitisHypophysitis

Toxi

city

Grad

e

Weeks14

0 2 4 6 8 10

12

Immune Mediated ToxicityIpilimumab PD-1 inhibitors

Common (>20%) Rash, itch, lethargy,diarrhoea/colitis

Occasional (5-20%) Hepatitis,endocrinopathies

Fatigue, headache,arthralgia, itch, hepatitis,diarrhoea/colitis, infusionreactions,endocrinopathies

Rare Uveitis, nephritis,pancreatitis, neuropathies,thrombocytopenia,Stevens-Johnson syndrome

Pneumonits, anaemia

Weber, JCO, 2015

Summary StatisticsDTIC BRAFi BRAF/

MEKIpilimumab PD-1

inhibitorIpi + PD-1

Responserates

7-10% 50% 70% 10-15% 44% 58%

Completeresponses

1% 4% 10% 1-2% 9% 11%

MedianPFS

6 weeks 6 months 10 months 3 months 6 months 11 months

MedianOS

6 months 20 months 25 months 11 months NR NR

3 year OS 7% 31% 38% 22% NR NR

ADJUVANT THERAPY

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

http://melanomaprognosis.org/

High dose INF-α: PBS reimbursed

Who benefits most:• Younger age <70 years• Ulcerated primaries• Low volume disease

Meta-analysis of 14 RCTs of adjuvant HDI

Eggermont et al. Lancet Oncology. 2015: 16(5)

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

Local Adjuvant Clinical TrialsStage 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

THE FUTURE

Just the beginning

• Combination immunotherapy• Combination immunotherapy and targeted

therapy• Neoadjuvant therapy• New approaches with improved

understanding of biology

Questions?