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Caso clinico: metastasi encefaliche in paziente con melanoma BRAFmut (immunoterapia)

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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

(2)

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

(3)

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

(4)

CASE REPORT

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)

STABILITA’

DELLE

LESIONI

VISCERALI

(5)

CASE REPORT

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)

STABILITA’

DELLE LESIONI

ENCEFALICHE

(6)

VALUTAZIONE DELLA RISPOSTA IN ONCOLOGIA

RECIST 1.1 CRITERIA

(7)

…DURANTE L’IMMUNOTERAPIA?

4 TIPI DI RISPOSTE

TIMING:

8-12 settimane

(8)

IMMUNE-RELATED CRITERIA RESPONSE

(9)

• 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 patients

7

– IPI+fotemustine: 50% disease control in 20 asymptomatic patients

8,9

– Pembrolizumab: 22% intracranial response in 18 asymptomatic patients

10

CONCLUSIONI

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)

(10)

CASE REPORT

METASTASI ENCEFALICHE IN PAZIENTE CON MELANOMA BRAFmut (IMMUNOTERAPIA)

CONCLUSIONI

(11)

Attivazione delle DC Induzione dell’apoptosi

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

BACKGROUND

EFFETTO PRO-IMMUNOGENO DELLA RADIOTERAPIA STEREOTASSICA

(12)

BJC 2017

MONOTHERAPY WITH ANTI-PD1

(13)

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

(14)

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 Margolin

16

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

(15)

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

(16)

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 disease a 18 (24) 18 (24) 16 (21)

Not evaluable b 13 (17) 12 (16) 20 (27)

Objective response rate, % (95% CI) 53 (41−65) 55 (43−66) 49 (38−61) Clinical benefit rate c , % (95% CI) 59 (47−70) 60 (48−71) 52 (40−64)

RESPONSE TO TREATMENT

(17)

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

(18)

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

(19)

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

(20)

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)

(21)

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

Max Reduction From BL, %

Cohort A (n = 76)

100

50

0

-50

-100

Max Reduction From BL, %

Cohort B (n = 16)

100

50

0

-50

-100

Max Reduction From BL, %

Cohort C (n = 16)

100

50

0

-50

-100

Max Reduction From BL, %

Cohort D (n = 17)

Best Confirmed IRc: CR PR SD PD

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)

(22)

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)

(23)

Progression-Free Survival

Presented by: Michael A. Davies

Proportion Remaining Progression Free

Months

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

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 3 1 1 0 0 0 0

Cohort A

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

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

(24)

CONCLUSIONI

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

SCELTA DELLA TARGETED THERAPY

RISPOSTE RAPIDA

CONCOMITANZA CON TERAPIA STEROIDEA

BRAF

V600

POSITIVO

IMMUNOTERAPIA TARGETED THERAPY

NON CI SONO STUDI TESTA A TESTA

SCELTA DELLA IMMUNOTERAPIA TEMPO DI LATENZA DELLA RISPOSTA NON UTILIZZO DI TERAPIA STEROIDEA

(25)

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)

(26)

Working Group IMI (intergruppo melanoma italiano) giovani Under 40

Dermatologo Oncologo

Medico

Chirurgo A patologo

Radioterapista Genetista

Contatti:

segreteria.melanomaimi@gmail.com stefania.stucci@uniba.it

Sito internet:

www.melanomaimi.it Sito faceboook

Imi-intergruppo melanoma italiano

(27)

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

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