Roma 22 Settembre 2012La terapia medica del melanoma

metastatico

Paola QueiroloDept. Medical Oncology A

National Institute for Cancer Research -Genova

Metastatic Melanoma: medical treatments

Chemotherapy Single agent or poly-Chemotherapy

monochemotherapy best option of care Immunotherapy : alpha IFNs, IL-2

Vaccinations Bio-chemotherapy Targeted therapies

Overall Survival for Metastatic Melanoma

Survival data from 42 Phase II trials with over 2‘100 stage IV patients1:

12 month OS: 25.5 %, median OS: 6.2 months(stage IV melanoma including patients with brain metastases)

1Korn EL et al. J Clin Oncol 2008;26(4):527-34.2Dummer R, Hauschild A, Jost L. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008;19 Suppl 2:ii86-8.

Time (months)

Prop

ortio

n al

ive

Due to the lack of efficacious therapy, the preferred treatment for metastatic melanoma remains the inclusion in a clinical trial

Adapted from Korn 2008

0

5

10

15

20

25

RR 20 24 18 13 15 14,5 13 17 17

DTIC FTM BCNU CCNU CDDP TAX Alc.V IFNa2 IL-2

Metastatic Melanoma : Single Agent Options

Overall responses with monotherapy

Khayat, Educational Book, ASCO 2000

CT/BioCT AND RRPhase II trials

Authors Regimen N. Pts

RR Survival(month)

LeghaCancer J Sci Am ‘97

CVD+IL-2+IFN 115 60% 12

ComellaEur J Cancer ‘97

FTM+DTIC+IFN 43 40% 5.7

LeghaJCO ‘98

CVD+IL-2+IFN 53 64% 11.8

AtkinsClin Cancer Res ‘02

CV+TMZ+IL-2+IFN 48 47% 7.5

CT/BioCT AND RR

Authors Regimens N. Pts

RR Survival(month)

RosenbergJCO ‘99

CDDP+DTIC+TamCD+IL-2+IFN+Tam

5250

27%44%

1510

EtonJCO ‘02

CVDCVD+IL-2+IFN

9291

25%48% s

911

AvrilJCO ‘04

DTICFotemustine

112117

6.8%15.2% s

5.67.3

KaufmannJCO ‘05

TmzTmz+IFN

134137

13%24% s

89

BedikianJCO ‘06

DTICDTIC+Oblimersen

385386

7.5%13.5% s

7.89

Keilholz CVDI-Il-2 23 9(JCO ‘05) vs. 363

CVDI 21 9

Atkins CVD-bio 17 9(JCO ‘08) vs. 416

CVD 12 9

Author Regimen No. of pts

RR OS

Metastatic Melanoma: Phase III Biochemo vs Chemo

NEW DRUGS. FDA and EMA approval in 2011

• Targeted immunotherapy: anti-CTLA-4 mAbs

• Molecular targeted therapies: anti B raf V600 mut

Melanoma is an immunogenic cancer

• Spontaneous remissions• TILs associated with regression• Ab and CTL responses to melanoma Antigens

IMMUNOTHERAPY OF MELANOMA

BRMs: rIFN alfa, rIL-2, GM-CSF, IL-12,IL-18, IL-21

Adoptive immunotherapy: TIL,NK,DC

Vaccines: autologous, allogeneic, peptides, anti idiotypes Abs, gene modified ca cells, dendritic pulsed

DNA based therapy: allovectin 7

Targeted therapies acting on immunological cells : antCTLA4

Safety: Immune Breakthrough Events

IBEs: Immune-mediated adverse events based on the action of Anti CTLA-4 mAbs

• Correlation with clinical response

• Usually linked to drug-exposure and reversible

• Manageable with established therapies (e.g. corticosteroids)

Novel targets for immunotherapy

Potential Treatment Strategies

- Antagonize receptors that suppress the immune response (e.g. CTLA-4 and PD-1)

- Activate receptors that amplify the immune response (e.g. CD40 on APC; 4-1 BB and OX40 on T cells)

- Inhibit or deplete immunosuppressive mechanisms (e.g. Tregs, IL-10, TGF-beta…)

- Combinations of the above

Anti-CTLA-4 mAbs:SAFETY

• GI toxicity: Diarrhea: watery to frank bloodBx: inflammatory colitis

• Skin toxicity: Rash, pruritus and vitiligo

• Endocrine Toxicity:Hypophysitis; Thyroiditis

• Presumed Autoimmune Hypophysitis

- Confusion, fatigue, impotence- Headache

• Low ACTH/cortisol• ↓ T4, testosterone and/or prolactin• Increased pituitary size on MRI• Asymptomatic with replacement therapy

- Slow return of some endocrine

function

Pituitary Insufficiency in a patient with metastatic melanoma

Endocrinopathies

Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005;28(6):593-8.

Anti-CTLA-4 mAbs

• Tumor responses are sufficient but not necessary for prolonged survival

• Rationale for proceed with therapy after early progression

• Increased volume of lesions may be due to lymphocytic infiltrate

Bulanhagui et al. ASCO 2006

“Conventional” response

• Response in baseline lesions

-9 -3 3 9 15 21 27 33 39 45 51

Relative week from first dose date

Chan

ge fr

om b

asel

ine

SPD

(%)

SPD (m

m2)

2,8942,5562,2181,8811,5431,206868530193-145-482

50

25

0

-25

-50

-75

-100

-125

Response in baseline lesions

PD

PR

CR

5.2 months

'Stable disease' with slow, steady decline in total tumor volume

-9 -3 3 9 15 21 27 33 39 45 51

• Stable disease

Chan

ge fr

om b

asel

ine

SPD

(%)

2,8102,4822,1541,8261,4981,171843515187-140-468

50

25

0

-25

-50

-75

-100

-125

9 months

150125100

755025

0-25-50-75

-100-125

19,373

17,242

15,111

12,980

10,849

8,718

6,587

4,456

2,325

194

-1,937

SPD (m

m2)

Relative week from first dose date

50

25

0

–25

–50

–75

–100

–125

Chan

ge fr

om b

asel

ine

SPD

(%) 1,272

1,124

975

827

678

530

382

233

85

-64

-212

SPD (m

m2)

Chan

ge fr

om b

asel

ine

SPD

(%)

-9 -3 3 9 15 21 27 33 39 45 51

-9 -3 3 9 15 21 27 33 39 45 51

Response after initial increase in total tumor volume

6 months

9.4 months

Response in index and new lesions At or after the appearance of new lesions

“Non conventional” response

• Response in index lesions and new lesions after the appearance of new

• Response after initial increase in total tumour volume

Example of conventional pattern of response: response in baseline lesions

Baseline Week 12

Anti CTLA4 . Esempio di risposta

Screening

Week 12Initial increase in total tumour burden (mWHO PD)

Week 16Responding

Week 72Durable & ongoing response without signs of IRAEs

Courtesy of K. Harmankaya

1 2 3 4

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n al

ive

Years

lpi + Gp100 (A)lpi Alone (B)Gp100 Alone (C)

Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136

1 year 44% 46% 25%

2 year 22% 24% 14%

Kaplan-Meier Analysis of Survival

Comparison HR p-value  Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026

Hodi S et al. NEJM 2010;363(8):711-23

Baseline Tumor Assessment

First Scheduled Tumor Assessment

Screening

Ipilimumab 10 mg/kgQ12W

Ipilimumab 10 mg/kgQ3W X4

Week 12 Week 24Week 1

INDUCTION MAINTENANCE *

* in absence of progression or dose-limiting toxicity

Dacarbazine 850 mg/m2

Q3W x8

PreviouslyUntreatedMetastaticMelanoma

(N=502)

PlaceboQ3W X4

PlaceboQ12W

R

R = blindedrandomization(1:1)

Dacarbazine 850 mg/m2

Q3W x8

Study 024: Design

Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.

Estimated Survival Rate 1 Year 2 Year 3 Year*

Ipilimumab + DTICn=250

47.3 28.5 20.8

Placebo + DTICn=252 36.3 17.9 12.2

*3-year survival was a post-hoc analysis

Pro

po

rtio

nA

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.

1.0

Years0 1 3 4

Study 024:Ipi in 1st line Overall Survival

Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.

Ipilimumab. FDA Approval March 2011. EMA Approval August 2011

In USA in prima e seconda linea alla dose di 3 mg /kgIn Europa in seconda linea

14 Gennaio 2012 si è interrotto l’expanded access in attesa dell’approvazione AIFA…………

MOLECULAR TARGETSMELANOMA PATHWAY

Membrane RTK

Y-PY-P Ras GTP

Other Effectors

Growth Factors

RAF

MEK

ERK

P

P

Nuclear TranslocationGene Expression

Normal signaling

Oncogenic signaling

BRAFV600E

MEK

P

ERK

P

Abnormal CellularProliferationARRESTED

RG7204 selectively

inhibits oncogenic BRAF

BRAF KinaseAn important mediator of cellular proliferation

BRAF mutations are exclusive to tumors

> 50% malignant melanomas

~10% of CRC

~8% all solid tumors

The first-in-human trial of RO5185426 was a Phase I dose escalation study (PLX06-02) in patients with solid tumors.

- A total of 26 of the 32 patients had a response (81%), with a completeresponse in 2 patients and a partial response in 24 patients.- The estimated median progression-free survival among all patients was more than 7 months.

Flaherty KT et al NEJM 2010: 363 (9):

RG 7204 Efficacy data in BRAF V600E-mutated

melanoma

RG 7204 Rapid and dramatic tumor shrinkage

Pre-treatment

Week 8Cycle 2

Pre-treatment

P Chapman , et al, ESMO 2009, Abstract 6BA

Pre-treatment

Week 8

Summary of adverse events in ≥ 10% of patients (n=55) includes 1120 mg cohort, not ongoing 960 mg cohort

Adverse event

All related adverse events

Related Grade ≥ 3

Rash 29 % 2 %

Fatigue 24 % 2 %

Pruritus 20 % 2 %

Photosensitivity reaction 14 % 0 %

Nausea 14 % 0 %

Anemia 13 % 0 %

Cutaneous squamous cell carcinoma

11 % 11 %

Alopecia 11 % 0 %

P Chapman , et al, ESMO 2009, Abstract 6BA

Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso

RANDOM

Fattori di stratificazione

• M1 e livelli di LDH• Trattamenti

precedenti• Sesso

DTIC 1000mg/mq g1 q21

RO5185426 bid 960mg

100

90

80

70

60

50

40

30

20

10

0

Ove

rall

surv

ival

(%)

No. of patients in follow upDacarbazineVemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

Vemurafenib (N=336)Est 6 mo survival 84%

Months

336336

283320

192266

137210

98162

64111

3980

2035

16

11

Dacarbazine (N=336)Est 6 mo survival 64%

914

Hazard ratio 0.37 (95% CI; 0.26 - 0.55)Log-rank P<0.0001

Overall survival (Dec 30, 2010 cutoff)

Chapman et al. ASCO 2011

100

90

80

70

60

50

40

30

20

10

0

Prog

ress

ion-

free

sur

viva

l (%

)

No. of patients in follow upDacarbazineVemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

Hazard Ratio 0.26 (95% CI; 0.20 - 0.33)Log-rank P<0.0001

Months

274275

213268

85211

48122

28105

1650

1035

616

34

03

Dacarbazine (N=274)

Vemurafenib (N=275)

Progression-free survival (Dec 30, 2010 cutoff)

Median 1.6 mos Median 5.3 mos

Chapman et al. NEJM 2011

Number of patients receiving anti-cancer therapies after initial treatment on BRIM-3

Subsequent anti-cancer therapy

Dacarbazine (n=338)

Vemurafenib (n=337)

Any 149 (44%) 122 (36%)

Ipilimumab 73 (22%) 60 (18%)

Dabrafenib 5 (1.5%) 0

Crossover to vemurafenib 83 (25%) –

Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

Summary of overall survival dataASCO 2011 ASCO 2012

(post-hoc)

DTIC Vemurafenib DTICa Vemurafenib

Median follow-up, months 2.3 3.8 9.5 12.5

Median OS, months Not reliably estimated 9.7 13.6

6-month survival, % 64 84 66 84

12-month survival, % – – 44 56

Hazard ratio, OS 0.37 0.70

% reduction in risk of death

63 30

aCensored at crossover Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

Patterns of disease progression and role for continuous dosing in a Phase 1 study of

vemurafenib (PLX4032, RG7204) in patients with metastatic melanoma

K Kim, K Flaherty, P. Chapman, J Sosman, A Ribas, G. McArthur, R Amaravadi, R Lee, K Nolop, I. Puzanov

M. D. Anderson Cancer Center; Massachusetts General Hospital Cancer Center; Memorial Sloan-Kettering Cancer Center; Vanderbilt University; University of California, Los Angeles; Peter MacCallum Cancer Centre; Abramson Cancer

Center; Roche Pharmaceuticals; Plexxikon Inc.

Clinical outcomeOutcome Duration of treatment post-

progressionAll patients

N=48)

>30 days(N=20)

<30 days (N=24)

P-value

Median PFS, months (range)a

6.6 (2.8–16.9)

6.3 (0.9–23.8)

0.729 7.0 (0.9–26.0)

Median treatment duration beyond initial PD, months (range)

3.8 (1.1–14.8)

– – –

Median survival beyond initial PD, months (range)

>9.1 (1.9–24.3)

3.4 (0–19.6)

0.008 6.0 (0–24.3)

Median OS, months (range)a

>25.2 (7.6–28.8)

11.2 (1.1–34.8)

0.054 14.9 (1.1–34.8)

aCalculated from the start of vermurafenib therapyPFS, progression-free survival; OS, overall survival

• Open-label, multicenter expanded access study of RO5185426 in patients with metastatic melanoma harboring the BRAF V600 mutation

• Approximately 3000 patients recruited into this study

• 140 Centers in 30 Countries

Vemurafenib (Zelboraf) expanded access study

Roche MO25515

FDA and EMA ApprovalAugust 2011 and February 2012

• The FDA has approved Zelboraf™ (vemurafenib) for the treatment of BRAF V600 mutation-positive unresectable (inoperable) or metastatic melanoma. Zelboraf is not recommended for use in patients with wild-type BRAF melanoma

• The agency has also approved the Roche cobas® 4800 BRAFV600 Mutation Test, a diagnostic test developed to identify patients eligible for treatment

[TITLE]

[TITLE]

[TITLE]

Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring

BRAFV600 or NRAS mutations

Paolo A. Ascierto,* Carola Berking, Sanjiv S. Argawala, Dirk Schadendorf, Carla van Herpen, Paola Queirolo,

Christian U. Blank, Axel Hauschild, J. Thaddeaus Beck,

Angela Zubel, Faiz Niazi, Simon Wandel, Reinhard Dummer *National Cancer Institute, Naples

Italy

MEK inhibitors: targeting RAS and BRAF mutations in cancer

70-90% pancreatic cancer

30-40% colon cancer

~30% lung cancer

~20% melanoma

50-60% melanoma

8- 12% colorectal cancer

12% ovarian cancer

36% thyroid cancer

RAS

BRAF

MEK162

Frémin C, Meloche S. J Hematol Oncol. 2010;3:8; Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329

MEK inhibitors.Study Design

Arm 1: BRAFV600E/(n = 28)MEK162 45 mg BID

Arm 1: BRAFV600E/(n = 28)MEK162 45 mg BID

Arm 2: NRAS-mutant (n = 26)MEK162 45 mg BID

Arm 2: NRAS-mutant (n = 26)MEK162 45 mg BID

Patients with advanced or metastatic unresectable

cutaneous malignant melanoma harboring

BRAFV600E/NRAS mutation

Patients with advanced or metastatic unresectable

cutaneous malignant melanoma harboring

BRAFV600E/NRAS mutation

Stratification based on metastatic stage (M1a, M1b and M1c), region, and baseline LDH (< 0.8 x ULN, 0.8–1.1 x ULN, >1.1-2 x ULN)

Best percentage change from baseline and best overall response (NRAS)

*Patients with missing best % change from baseline and unknown overall response are not included.

N=28*Progressive Disease (PD)

Stable Disease (SD)

Partial Response (PR)

Unconfirmed PR

45 mg NRAS

Ongoing pts

PFS – NRAS- /BRAF-mutant

Number of patients at risk

100

PFS

(%)

Median (months) [95% CI]: 3.65 [2.53, 5.39]Median (days) [95% CI]: 111 [77, 164]

Time (days)

0 0214437145 mg

00

20

40

60

61

80

122 183 274 365

Median (months) [95% CI]: 3.55 [2.00, 3.81]Median (days) [95% CI]: 108 [61, 116]

NRASmt

BRAFmt

[TITLE]

Rationale for Combination of BRAFi (GSK436) + MEKi (GSK212) in BRAF Mutant Tumors

1 Kefford et al., SMR 2010; 2 Lewis et al. Perspectives in Melanoma 2011

Tumor Type % BRAF Mutant

Melanoma 50%

Thyroid 50%

Cholangioca 15%

NSCLC 7-8%

Colorectal 5%

Goals of Combination

1. Improve complete response rate

2. Suppress MAP kinase dependent resistance mechanisms and improve duration of response

3. Decrease incidence of BRAFi-induced proliferative skin lesions

pERK

BRAF

MEK

Proliferation

SurvivalInvasion

Metastasis

BRAFi (GSK436)RR 77%1

Mechanistic toxicity: Hyperproliferative skin AEsMEKi (GSK212)

RR 35%2

Mechanistic toxicity: rash

RAS

IPILIMUMAB VS VEMERAFENIB PFS

Ipilimumab Vemurafenib

• Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial.

• Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred.

• Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d.

PFS and OS Rates

Median PFS 3.5 months 1-year OS 51.0%.

Pre-screening for c-Kit mutation

Pre-screening for c-Kit mutation

ScreeningScreening

Randomization 120 Patients1:1Randomization 120 Patients1:1

DTIC 850 mg/m2

IV q3weeksDTIC 850 mg/m2

IV q3weeks

ProgressionProgression

Tasigna 400 mgb.i.d.

Tasigna 400 mgb.i.d.

ProgressionProgression

Cross-over?Cross-over?

Follow for survivalFollow for survival

Follow for survivalFollow for survival

No

. Studio di fase III randomizzato . NILOTINIB vs DTIC in c-kit mutati

MELANOMA in 2012Setting EMA approval Clinical trials evidence

1° line B-Raf mutated Vemurafenib Ipilimumab +/CT

B-Raf WT CT Ipilimumab +/-CT

2 line B Raf mutated Ipilimumab Ipilimumab ?BRAFi +MTT-CT

B-Raf WT Ipilimumab