Melanoma brain mets management

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1 Melanoma brain mets management Reinhard Dummer, Phil Cheng, Simone Goldinger, Katrin Kerl, Lars French, Joanna Mangana, Lukas Sommer, Ralph Braun, Mitch Levesque

2 Substantially worse survival in patients with brain metastases Mangana J. et al. Melanoma Res / Aug;27

3 The AJCC staging classification 8 th edition /

4 Wiesner JAMA Dermatology 2016 /

5 The oncogens of the mitogen-activated protein kinase (MAPK) pathway /

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7 ASCO /

8 Dokumentname / Autor / Abteilung / 22. Januar

9 All Patients IT and SRT pretreated, many symptomatic patients Co-comittant corticosteroids and Anti-convulsive therapy allowed PI: PD Dr S. Goldinger, Prof. R Dummer Dokumentname / Autor / Abteilung / 22. Januar

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11 B-Raf Inhibition: Comparison Day 0 Day 17 female 1948 tumor shrinkage and clinical improvement Dummer et al Eur J Cancer 2014/

12 COMBI-MB: Study Design (phase 2) 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 S C R E E N I N G BRAF V600E BRAF V600D/K/R BRAF V600D/E/K/R 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 C (n = 16) Asymptomatic With or without prior local therapy ECOG PS 0-1 Cohort D (n = 17) Symptomatic With or without prior local therapy ECOG PS 0-2 Dabrafenib 150 mg BID + Trametinib 2 mg QD Cohort A: Interim analysis for futility after 22 patients had 2 assessments Final analysis (planned) Primary endpoint: intracranial response (IR) rate in cohort A a 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 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: ). Investigator-assessed efficacy was confirmed by a blinded independent review committee (BIRC). Data cutoff date: November 28, Presented by: Michael A. Davies

13 Max Reduction From BL, % Max Reduction From BL, % Max Reduction From BL, % Max Reduction From BL, % Intracranial Response Cohort A (n = 76) Intracranial ORR: 58% Intracranial DCR: 78% Cohort B (n = 16) Intracranial ORR: 56% Intracranial DCR: 88% 0 a b Cohort C (n = 16) Intracranial ORR: 44% Intracranial DCR: 75% Cohort D (n = 17) Intracranial ORR: 59% Intracranial DCR: 82% 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. Best Confirmed IR c : CR PR SD PD Presented by: Michael A. Davies

14 Proportion Remaining Progression Free Progression-Free Survival 1.0 Events, n/n (%) Median PFS (95% CI), mo Cohort A 58/76 (76) 5.6 ( ) % 46% 44% 47% Cohort B 10/16 (63) 7.2 ( ) Cohort C 14/16 (88) 4.2 ( ) Cohort D 15/17 (88) 5.5 ( ) 19% % 16% 8% No. at Risk Months Cohort A Cohort B Cohort C Cohort D a Investigator assessed; these results were supported by independent review. +, censored. Presented by: Michael A. Davies

15 Patterns of Disease Progression Progression Category, n (%) a Cohort A (n = 76) Cohort B (n = 16) Progression Patterns in Cohort A Cohort C Cohort D Total (n = 16) Intracranial (n and = Extracranial 17) (N = 125) Intracranial only 36 (47) 10 (63) 10 (63) 10 (59) 66 (53) Intracranial and extracranial 19 (25) 1 (6) 3 (19) 5 (29) 28 (22) Intracranial Only n = 36 n = 19 Extracranial Only n = 7 Extracranial only 7 (9) 1 (6) 3 (19) 0 11 (9) No progression 14 (18) 4 (25) 0 2 (12) 20 (16) No Progression n = 14 a Pattern of disease progression is described for all enrolled patients, including those who did not have disease progression while on study treatment. Presented by: Michael A. Davies

16 Proportion Alive Preliminary Overall Survival % Events, n/n (%) Median OS (95% CI), mo 81% Cohort A 44/76 (58) 10.8 ( ) 79% Cohort B 7/16 (44) 24.3 (7.9-NE) Cohort C 13/16 (81) 10.1 ( ) 69% Cohort D 13/17 (76) 11.5 ( ) % 46% % 44% No. at Risk Months Cohort A Cohort B Cohort C Cohort D , censored. Presented by: Michael A. Davies

17 Dokumentname / Autor / Abteilung / 22. Januar

18 Dynamic heterogeneity of tumors is determined by transcriptional cycling Between proliferative, melanocytic and invasive (stem cell like, inflammatory, senescent) profiles The phenotype switch hypothesis Alternating growth & invasion to drive disease progression /

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20 The cancer immunity cycle: adaptive, flexible, self adjusting Release of tumour-specific antigens 1 T Vec Sting/ TLR ag 2 Tumour-specific antigen presentation Killing of tumour cells Anti-PD1/PDL1 Anti CSF, Anti LAG3 Recognition of tumour cells by T cells Priming and activation of T cells Anti-CTLA4 Vaccines,Tim3, Trafficking of T cells to tumours 5 Infiltration of T cells into tumours Adapted from Chen DS, Mellman I. Immunity 2013;39:1 10;and Raaijmakers et al. Immunobiology 2014 /

21 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 1 University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2 Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3 University of California-San Francisco, San Francisco, CA, USA; 4 The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 5 Dana-Farber Cancer Institute, Boston, MA, USA; 6 University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 7 University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 8 University of Michigan, Ann Arbor, MI, USA; 9 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; 10 Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA; 11 Roswell Park Cancer Institute, Buffalo, NY, USA; 12 Winship Cancer Institute of Emory University, Atlanta, GA, USA; 13 Stanford University Hospital, Palo Alto, CA, USA; 14 University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 15 Bristol-Myers Squibb, Princeton, NJ, USA; 16 Department of Medical Oncology, City of Hope, Duarte, CA, USA. Abstract Number 9507

22 Demographic and Patient Characteristics All patients (N = 75) Male, n (%) 53 (71) Median age, years (range) 59 (22 79) BRAF mutation, n (%) 41 (55) NRAS mutation, n (%) 5 (7) LDH > ULN, n (%) 31 (41) LDH > 2x ULN, n (%) 11 (15) Prior systemic cancer therapy, n (%) 12 (16) Dabrafenib/Trametinib 6 (8) Vemurafenib 2 (3) Prior SRT, n (%) 7 (9) Median of median target lesion diameters, mm (IQR) 9.0 ( ) Target lesions, n (%) 1-2 lesions 59 (79) >3 lesions 16 (21) IQR = interquartile range 21

23 Patients Swimmer Plot: Time to and Duration of Intracranial Response N = 41 Time to response, a median (range), months Duration of response, a median (95% CI), months 2.8 ( ) NR (NR-NR) Ongoing response 38/41 among responders a (93%) On treatment Off treatment First response (CR/PR) Ongoing response Progression a Minimum follow-up of 6 months from date of first dose; 1 patient undergoing further evaluation and not present on plot NR = not reached Time (Weeks) First tumor assessment was at 6 weeks (+/- 2 weeks) 9

24 PFS (%) PFS Events/patients Median (95% CI) 100 Intracranial 24/75 NR (7.5 NR) 90 Extracranial 15/75 NR (NR NR) 80 Global 25/75 NR (6.5 NR) % Intracranial Extracranial Global Months Number of patients at risk Intracranial Extracranial Global

Study Design Melanoma Brain Metastases 5mm & < 40mm No previous Anti-CTLA-4 Anti-PD-1 or -PD-L1 agents Previous BRAFi+MEKi allowed ECOG PS 0-2 No serious autoimmune disease No

Rate PFS (Intracranial, Extracranial, Overall) OS A No prior local brain Rx & asymptomatic n=30 Nivolumab 1mg/kg + Ipilimumab 3mg/kg Q3W X4 Nivolumab 3mg/kg Q2W B No prior local

25 Study Design Melanoma Brain Metastases 5mm & < 40mm No previous Anti-CTLA-4 Anti-PD-1 or -PD-L1 agents Previous BRAFi+MEKi allowed ECOG PS 0-2 No serious autoimmune disease No corticosteroids (Cohort C < 10mg prednisone allowed) R 1:1 Primary Endpoint: Intracranial Response Rate week 12 Secondary Endpoints: Extracranial Response Rate Overall Response Rate PFS (Intracranial, Extracranial, Overall) OS A No prior local brain Rx & asymptomatic n=30 Nivolumab 1mg/kg + Ipilimumab 3mg/kg Q3W X4 Nivolumab 3mg/kg Q2W B No prior local brain Rx & asymptomatic n=30 Nivolumab 3mg/kg Q2W C Previously treated or symptomatic or leptomeningeal, with MRI progression n=15 Nivolumab 3mg/kg Q2W Presented by Georgina V. Long

26 Best Intracranial RECIST Response A: Ipi+Nivo N=26 B: Nivo N=25 C: Nivo N=16 Intracranial Response, n (%) 11 (42%) 5 (20%) 1 (6%) CR 4 (15%) 3 (12%) 0 PR 7 (27%) 2 (8%) 1 (6%) SD 2 (8%) 1 (4%) 4 (25%) PD 12 (46%) 18 (72%) 11 (69%) NE* 1 (4%) 1 (4%) 0 Median duration of intracranial response not reached in any arm NE = Not Evaluable *Pts who deceased prior to wk 12 = PD Leptomeningeal, previous local treatment or symptoms Presented by Georgina V. Long

Change from Baseline (%) Intracranial Response 200 All Patients 150 Cohort A: Nivo+Ipi IC RR = 42% Cohort B: Nivo alone IC RR = 20% 100 50 0-50 * * * * * * * * * *

27 Change from Baseline (%) Intracranial Response 200 All Patients 150 Cohort A: Nivo+Ipi IC RR = 42% Cohort B: Nivo alone IC RR = 20% * * * * * * * * * * * * IC RR = 50% IC RR = 21% 100 Drug Treatment Naive * * * * * * * * * -100 * Deceased prior to week 12 assessment Presented by Georgina V. Long

28 Choice of first-line systemic drug therapy for patients with advanced melanoma. / Long et al, Current Opin Oncol 2017

29 Melanoma brain mets management The Zürich approach Patients to be discussed in the interdisciplinary tumorboard No pretreatment in stage IV: systemic therapy (+ early or delayed SRT) Consider Neurosurgery to collect tissue for biobanking In case of mixed response: SRT of PD lesions Avoid whole brain irradiation! Dokumentname / Autor / Abteilung / 22. Januar

Overview: Immunotherapy in CNS Metastases

Overview: Immunotherapy in CNS Metastases Manmeet Ahluwalia, MD, FACP Miller Family Endowed Chair in Neuro-Oncology Director Brain Metastasis Research Program Cleveland Clinic Disclosures Consultant- Monteris