Selezione dei

pazienti affetti da melanoma

Vanna Chiarion SileniMelanoma and Skin Cancer Unit

IOV-IRCCS , Padova

Prognostic factors in metastatic melanoma

1362 pts enrolled in 8 studies ECOG in the last 25 years

Median OS 6.4 months (CI 6.1-6.9)• Multiple metastases RR= 1.3• ECOG PS >1 RR = 1.49• GI metastases RR =1.49• Liver metastases = 1.44• Pleural metastases RR =1.35• LDH RR = 1.89• FAL RR = 1.76• Previous immunotherapy RR = 0.84• Female gender RR = 0.87• Response to the treatment RR = 0.4

J Manola JCO 18; 3782-3793,2000

LDH is the most important prognostic factor

C. Balch. JCO 27:6199,2009

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

Patient selection

Factors to recommend high-dose IL-2 or immunotherapies

• Good PS (ECOG 0-1)

• Normal LDH

• Cutaneous or subcutaneous metastases only or less than three organs involved

• No brain metastases

BO 84 y protocol Ca184 EAP

Courtesy V Chiarion Sileni

BO anni 84 Ipi 3 mg/kg q 21d x 4

EORTC Protocol 16032 (Coso 059)

Jun 2005

Sep 2005

Nov 2005

EORTC Protocol 16032 (C0s0 059)courtesy V. Chiarion Sileni

Aug 2005

Nov 2005

Jan 2006

Different incidence of Braf mutation with age and sun exposure

JCO 2011

IOV-IRCCS

Cancer 2011

MOLECULAR TARGETSMELANOMA PATHWAY

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 1 2 3 4 5 6 7 8 9 10 11 12Time (months)

Overall survival (March 31, 2011 cutoff)

13 14

No. of patients at risk

DacarbazineVemurafenib

338337

302336

268334

232317

186285

145218

111178

83125

4382

2654

1222

511

04

02

00

Vemurafenib (N=337)Est 6 mo survival 83%

Median follow-up 6.2 mo

Dacarbazine* (N=338)Est 6 mo survival 63%

Median follow-up 4.5 mo

Ove

rall

surv

ival

(%

)

Hazard ratio 0.44 (95% CI; 0.33 - 0.59)

Post-progression use of ipilimumab: 17% dacarbazine patients vs 6% vemurafenib patients

Dacarbazine median OS

7.9 mo

*Dacarbazine patients who received vemurafenib after the IA (by DSMB recommendation; N=50) were censored at the date of crossover

Confirmed objective response rates (RECIST 1.1) across vemurafenib clinical trial programme

PLX 06-02 Phase I BRIM 2

BRIM-3 ORR(final analysis

at OS IA, 30 Dec 2010)

Vemurafenib

(95% CI)

56.0%

(38–74)

53.0%

(44–62)

48.4%

(42–55)

Dacarbazine

(95% CI)

– – 5.5%

(3–9)

Clinical case 1

F 21-y old Nov 2005 NM on the left arm : pT4bN2aM0

HDI 1 month iv and 6 months LDI sc Feb ‘06 Oct ‘06

Feb ‘09 subcutaneous multiple recurrences: Sur

Jan ’10 subcutaneous multiple lesions: S + RT

Mar ’10 recurrence in axillary lymph-node and iliac: DTIC+DDP x 4 NC (CT and PET scan)

Jul ’10 FMT only induction: plt G4 toxicity and pelvic PD

Nov ’10 ipilimumab 3 mg/kg x 4 well tolerated: PD

April’11 surgical resection of pelvic mass (symptomatic) and left ovary

Aug’ 11 started vemurafenib 960 mg x 2 on protocol M025515

ongoing

Tolerance: photosensitization ,weight loss, dry skin, curly hair

Aug 2011

Oct 2011

V. Chiarion Sileni courtesy

Dec 2011

Mar 2012

May 2012

V. Chiarion Sileni courtesy

Clinical case 1

resection and DC vaccination ?

radical resection alone or continuing vemu ?

ECT and to continue vemu ?

Clinical case 2

M 30-y old, May 2004 SSM in the back High IM and axillary mets pT2a N1aM0

adjuvant HDI for 1 y regular FU till Jan ‘11

Lung bilateral recurrence and mediastinal node: evaluation for S excluded

Apr ’11 he started DTIC for 8 cycles: SD followed by PD lung and bone

Oct 2011 Vemurafenib + zoledronic acid: ongoing in Sep ’12

Toxicity: photosensitization and plantar hyperkeratosis ( G2)

Oct 2011

Dec 2011 Jul 2012

Apr 2012

V.Chiarion Sileni courtesy

Clinical case 2

Options:

Continue treatment without any change ?

Stop Vemu and restart it at PD ?

Ipilimumab asap or at PD ?

Clinical case 3

F 29-y old: NM on the shoulder Mar 2010 pT4bN0

Jan ’11 lung multiple mets: DDP+DTIC x 6 Cycles: SD- PD

Sep ’11 evaluation for protocol M025515

screen failure due to elevated LFT

Jan 2011 retested, started vemuradenib

Jan 2012

Mar 2012 May 2012

V. Chiarion Sileni courtesy

Aug 2012

Jun 2012

Sep 2012

V. Chiarion Sileni courtesy

Clinical case 3

In pts who develop CNS mets during vemu should the treatment be stopped ?

Rochet N, NEJM 2011

Feb 2011 Aug 2011

B. Neyns Mel Res 2012

Conclusions (1)

• After 30 years of extensive researches two new different drugs showed an increase of OS in metastatic melanoma

• The effect of ipilimumab is not directly related to the tumor response, need time and a good PS, seems independent from disease extension and location

• Ipilimumab exerts some activity also in metastatic mucosal and ocular melanoma and in brain metastases when asymptomatic

Conclusions (2)

BRAFi exert their effect rapidly and in a large proportion of patients arboring BRAF mutation

BRAFi showed efficacy in brain metastasesCombination of BRAFi with MEKi seems to prolong

response duration Efficacy in the adjuvant setting, activity and safety in

combination with other target therapies, with other immuno-modulating agents and with anti-angiogenetic agents are undervaluation