tutor dott. alessandro minisini - aiommedia.aiom.it/userfiles/files/doc/aiom-servizi/... · •...

Dipartimento di Medicina Interna e Oncologia Clinica

Università degli Studi di Bari ‘Aldo Moro’

U.O.C. Oncologia Medica Universitaria Direttore: Prof. Franco Silvestris

Stefania Stucci Medical Oncology Unit, University of Bari

TUTOR Dott. Alessandro Minisini

CASE REPORT

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)

BRAF mutazione V600E

Targeted therapy

Immunoterapia

Inizio trattamento con NIVOLUMAB (aprile 2016)

AGOSTO 2016 La tac di controllo mostra stabilità delle lesioni secondarie

e comparsa di lesione encefalica sospetta

CASE REPORT


RMN ENCEFALO: comparsa di nove lesioni metastatiche subcentimetriche RISPOSTA ATIPICA

DA ANTI-PD1?

PROSEGUE TRATTAMENTO CON ANTI-PD1

NON EVENTI AVVERSI

CASE REPORT


STABILITA’ DELLE

LESIONI VISCERALI

CASE REPORT


STABILITA’ DELLE LESIONI ENCEFALICHE

VALUTAZIONE DELLA RISPOSTA IN ONCOLOGIA

RECIST 1.1 CRITERIA

…DURANTE L’IMMUNOTERAPIA?

4 TIPI DI RISPOSTE

TIMING: 8-12 settimane

IMMUNE-RELATED CRITERIA RESPONSE

• Melanoma brain metastases (MBM) are a common clinical presentation associated with

poor prognosis (median OS ~4-5 months)1

• Surgery and/or stereotactic radiation therapy (SRT) are widely used for oligometastatic

disease and whole brain radiation therapy (WBRT) for miliary or leptomeningeal disease

– No impact on survival or extracranial disease, significant early and late neurotoxicity

• Experience with immunotherapy is limited

– Ipilimumab (IPI): 18% disease control in 51 asymptomatic patients7

– IPI+fotemustine: 50% disease control in 20 asymptomatic patients8,9

– Pembrolizumab: 22% intracranial response in 18 asymptomatic patients10

CONCLUSIONI


CASE REPORT


CONCLUSIONI

Attivazione delle DC Induzione dell’apoptosi

Aumento della permeabilità della BEE RT aumenta l’espressione dei checkpoints

BACKGROUND

EFFETTO PRO-IMMUNOGENO DELLA RADIOTERAPIA STEREOTASSICA

BJC 2017

MONOTHERAPY WITH ANTI-PD1

The median OS was 9.9 months

RESULTS

The intracranial PFS was 5.3 months

BJC 2017

2.7 vs 7.4 m 5.7 vs 13.0 m

3.2 vs 7.4 m 4.8 vs 13.1 m

Efficacy and Safety of Nivolumab Plus Ipilimumab in

Patients with Melanoma Metastatic to the Brain: Results of the Phase II Study CheckMate 204

Hussein Tawbi,1 Peter Forsyth,2 Alain Algazi,3 Omid Hamid,4 F. Stephen Hodi,5 Stergios Moschos,6

Nikhil Khushalani,2 Rene Gonzalez,7 Christopher Lao,8 Michael Postow,9 Michael B. Atkins,10 Marc

Ernstoff,11 Igor Puzanov,11 Ragini Kudchadkar,12 Reena Thomas,13 Ahmad Tarhini,14 Joel Jiang,15

Alexandre Avila,15 Sheena Demelo,15 Kim Margolin16

1University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3University of California-San Francisco, San Francisco, CA, USA; 4The Angeles Clinic and Research Institute, Los Angeles, CA, USA;

5Dana-Farber Cancer Institute, Boston, MA, USA; 6University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 7University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 8University of Michigan, Ann Arbor, MI, USA;

9Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; 10Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA; 11Roswell Park Cancer Institute, Buffalo, NY, USA; 12Winship Cancer Institute of

Emory University, Atlanta, GA, USA; 13Stanford University Hospital, Palo Alto, CA, USA; 14University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 15Bristol-Myers Squibb, Princeton, NJ, USA; 16Department of Medical Oncology, City of Hope, Duarte, CA, USA.

Abstract Number 9507

TRIAL DESIGN (FROM ASCO 2017)


• Exclusion criteria included neurological symptoms; steroids > 10 days; WBRT; prior treatment with checkpoint inhibitors; leptomeningeal disease

• Original planned enrollment of 110 asymptomatic patients

NIVO 1 mg/kg

Q3W × 4

+

IPI 3 mg/kg

Q3W × 4

NIVO

3 mg/kg

Q2W

Treat until progression or unacceptable

toxicity (maximum of 24

months)a

Induction Maintenance •≥ 1 measurable, unirradiated MBM (0.5-3.0 cm)

•Prior SRT in ≤3 MBM

•Previous treatment with BRAFi/MEKi permitted

Key eligibilities

TRIAL DESIGN (FROM ASCO 2017)

Global Intracranial Extracranial

Best overall response, n (%)

Complete response 4 (5) 16 (21) 5 (7)

Partial response 36 (48) 25 (33) 32 (43)

Stable disease 4 (5) 4 (5) 2 (3)

Progressive diseasea 18 (24) 18 (24) 16 (21)

Not evaluableb 13 (17) 12 (16) 20 (27)

Objective response rate, % (95% CI) 53 (41−65) 55 (43−66) 49 (38−61)

Clinical benefit ratec, % (95% CI) 59 (47−70) 60 (48−71) 52 (40−64)

RESPONSE TO TREATMENT

CASE REPORT

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)

Quattro formazioni emorragiche in sede: -Parietale dx (27x9 mm) -Frontoparietale sx (17x14 mm e 9x28 mm) -Frontale sx (27x25 mm)

PAZIENTE SINTOMATICO

TERAPIA CORTICOSTEROIDEA

PAZIENTE GIOVANE

Pz di anni 38. 2012 diagnosi di melanoma nodulare stadio IIB BRAFV600E. Follow up negativo per 54 mesi.

Aprile 2017 riscontro di multiple secondarietà cerebrali, polmonari e adenopatiche.

MIGLIORAMENTO CLINICO

DABRAFENIB + TRAMETINIB

CASE REPORT


Rivalutazione TC post BRAFi + MEKi

- Parietale dx (9 mm) - Frontoparietale sx (5 mm) - Parietale posteriore sx (diam max 12 mm) - Frontale sx (11 mm)

NON EVENTI AVVERSI

- Parietale dx (7.5 mm) - Parietale posteriore sx (diam max 9 mm) - Frontale sx (9.5 mm)

DOPO 1 MESE DOPO 3 MESI

A Phase 2 Study of Combination Dabrafenib and

Trametinib in Patients With BRAF V600–Mutant

Melanoma Brain Metastases

Michael A. Davies, Caroline Robert, Georgina V. Long, Jean-Jacques Grob, Keith T. Flaherty,

Ana Arance, Vanna Chiarion-Sileni, Luc Thomas, Thierry Lesimple, Laurent Mortier, Stergios

Moschos, David Hogg, Iván Márquez Rodas, Michele Del Vecchio, Céleste Lebbé, Nicolas

Meyer, Ying Zhang, Yingjie Huang, Bijoyesh Mookerjee, Philippe Saiag

ASCO 2017,

Abstract 9506 COMBI-MB


LANCET 2017

• Primary endpoint: intracranial response (IR) rate in cohort Aa

• Secondary endpoints: IR rate in cohorts B, C, and D; extracranial response (ER) and overall response (OR) rates; intracranial, extracranial, and overall DCRs; duration of IR, ER, and OR; PFS; OS; and safety

Key eligibility criteria

•Cutaneous melanoma

metastatic to the brain

•BRAF V600D/E/K/R

mutation positive

•≤ 2 prior metastatic

melanoma systemic

treatments

•No prior BRAFi or MEKi

•Corticosteroids permitted;

stable or decreasing dose

only for cohorts A-C

Final analysis (planned)

S

C

R

E

E

N

I

N

G

Cohort A:

Interim analysis

for futility after

22 patients had

≥ 2 assessments

BRAF

V600D/E/K/R

BRAF

V600E

Dabrafenib

150 mg BID

+

Trametinib

2 mg QD

Cohort A (n = 76) • Asymptomatic

• Without prior local therapy

• ECOG PS 0-1

Cohort B (n = 16) • Asymptomatic

• With prior local therapy

• ECOG PS 0-1

Cohort D (n = 17) • Symptomatic

• With or without prior local therapy

• ECOG PS 0-2

Cohort C (n = 16) • Asymptomatic

• With or without prior local therapy

• ECOG PS 0-1

BRAF

V600D/K/R

BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; PFS, progression-free survival; QD, once daily. a Null hypothesis: IR rate of ≤ 35% in cohort A (based on activity of dabrafenib monotherapy in the BREAK-MB trial; Long GV, et al. Lancet Oncol. 2012;13:1087-1095).

Investigator-assessed efficacy was confirmed by a blinded independent review committee (BIRC). Data cutoff date: November 28, 2016.

Presented by: Michael A. Davies

ASCO 2017,



Intracranial Response


CR, complete response; SD, stable disease. a Patient had a CR in the target lesion, but best confirmed response was determined to be PD due to development of an unequivocal new lesion; b Patient had an unconfirmed CR, but best confirmed response was SD; c Investigator assessed; these results were supported by independent review.

100

50

0

-50

-100

Ma

x R

ed

uc

tio

n F

rom

BL

, %

Cohort A (n = 76)

100

50

0

-50

-100

Ma

x R

ed

uc

tio

n F

rom

BL

, %

Cohort B (n = 16)

100

50

0

-50

-100

Ma

x R

ed

uc

tio

n F

rom

BL

, %

Cohort C (n = 16) 100

50

0

-50

-100

Ma

x R

ed

uc

tio

n F

rom

BL

, %

Cohort D (n = 17)

Best Confirmed IRc: PD CR PR SD

a b

Intracranial ORR: 58%

Intracranial DCR: 78%







ASCO 2017,



Intracranial Response (cont)


a Investigator assessed; these results were supported by independent review.

Cohort A

(n = 76)

Cohort B

(n = 16)

Cohort C

(n = 16)

Cohort D

(n = 17)

Intracranial response, n (%) [95% CI]a

Overall intracranial response (CR + PR) 44 (58) [46-69] 9 (56) [30-80] 7 (44) [20-70] 10 (59)

[33-82]

Intracranial disease control (CR + PR + SD) 59 (78) 14 (88) 12 (75) 14 (82)

Intracranial CR 3 (4) 1 (6) 0 1 (6)

Intracranial PR 41 (54) 8 (50) 7 (44) 9 (53)

Intracranial SD 15 (20) 5 (31) 5 (31) 4 (24)

Intracranial PD 14 (18) 1 (6) 4 (25) 3 (18)

Not evaluable 3 (4) 1 (6) 0 0

Intracranial duration of responsea

Events, n/N (%) 29/44 (66) 6/9 (67) 4/7 (57) 8/10 (80)

Median (95% CI), mo 6.5 (4.9-10.3) 7.3 (3.6-12.6) 8.3 (1.3-15.0) 4.5 (2.8-5.9)

6-mo rate (95% CI), % 63 (45-76) 73 (28-93) 67 (19-90) 13 (1-43)

ASCO 2017,



ASCO 2017,



Progression-Free Survival


Pro

po

rtio

n R

em

ain

ing

Pro

gre

ssio

n F

ree

Months

0 2 4 6 8 10 12 14 16 18 20 24 28 22 26

No. at Risk

0.0

0.2

0.4

0.6

0.8

1.0

44%

19%

Events, n/N

(%)

Median PFS (95%

CI), mo

Cohort A 58/76 (76) 5.6 (5.3-7.4)

Cohort B 10/16 (63) 7.2 (4.7-14.6)

Cohort C 14/16 (88) 4.2 (1.7-6.5)

Cohort D 15/17 (88) 5.5 (2.8-7.3)

76 58 43 27 18 13 9 5 1 0 0 0 3 1 0 Cohort A

Cohort B 16 14 12 9 6 6 5 4 2 0 0 0 2 2 1

Cohort C 16 11 7 4 3 2 2 2 1 0 0 0 2 1 0

Cohort D 17 14 9 7 3 3 1 0 0 0 0 0 0 0 0

71%

47%

31% 16%

46%

8%

a Investigator assessed; these results were supported by independent review. +, censored.

ASCO 2017,



CONCLUSIONI

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY VS IMMUNOTERAPIA)

SCELTA DELLA TARGETED THERAPY

RISPOSTE RAPIDA

CONCOMITANZA CON TERAPIA STEROIDEA

BRAFV600 POSITIVO

IMMUNOTERAPIA

TARGETED THERAPY

NON CI SONO STUDI TESTA A TESTA

SCELTA DELLA IMMUNOTERAPIA

TEMPO DI LATENZA DELLA RISPOSTA

NON UTILIZZO DI TERAPIA STEROIDEA

CASO CLINICO 1.

TRATTAMENTO LOCO-REGIONALE (RT STEREOTASSICA) AL MOMENTO DELLA PROGRESSIONE? (OLIGOPROGRESSIONE?)

ABSCOPAL EFFECT?

CASO CLINICO 2.

STRATEGIE DI SEQUENCING : RT E TARGETED THERAPY?

EFFICACIA O NO DELLA RT WB?

OPEN QUESTIONS

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY VS IMMUNOTERAPIA)

Working Group IMI (intergruppo melanoma italiano) giovani Under 40

Dermatologo Oncologo

Medico

Chirurgo

A patologo

Radioterapista Genetista

Contatti: [email protected] [email protected]

Sito internet: www.melanomaimi.it Sito faceboook Imi-intergruppo melanoma italiano

Dipartimento di Medicina Interna e Oncologia Clinica

Università degli Studi di Bari ‘Aldo Moro’

U.O.C. Oncologia Medica Universitaria Direttore: Prof. Franco Silvestris

Stefania Stucci

Medical Oncology Unit, University of Bari IMI giovani

TUTOR Dott. Alessandro Minisini

tutor dott. alessandro minisini - aiommedia.aiom.it/userfiles/files/doc/aiom-servizi/... · •...

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