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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
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)
RMN ENCEFALO: comparsa di nove lesioni metastatiche subcentimetriche RISPOSTA ATIPICA
DA ANTI-PD1?
PROSEGUE TRATTAMENTO CON ANTI-PD1
NON EVENTI AVVERSI
CASE REPORT
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)
STABILITA’ DELLE
LESIONI VISCERALI
CASE REPORT
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)
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
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)
CASE REPORT
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)
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)
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)
• 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
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
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
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
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,
Abstract 9506 COMBI-MB
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
Intracranial Response
Presented by: Michael A. Davies
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%
Intracranial ORR: 56%
Intracranial DCR: 88%
Intracranial ORR: 59%
Intracranial DCR: 82%
Intracranial ORR: 44%
Intracranial DCR: 75%
ASCO 2017,
Abstract 9506 COMBI-MB
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
Intracranial Response (cont)
Presented by: Michael A. Davies
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,
Abstract 9506 COMBI-MB
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
ASCO 2017,
Abstract 9506 COMBI-MB
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
Progression-Free Survival
Presented by: Michael A. Davies
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,
Abstract 9506 COMBI-MB
METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (TARGETED THERAPY)
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