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TRANSCRIPT
Sessione Polmone
Daniela Iacono
UOSD Pneumologia Oncologica
Ospedale San Camillo Forlanini, Roma
1 TUTOR: Dr. Alessandro Inno
Congresso Nazionale AIOM Giovani 2017
Perugia, 7-8 Luglio 2017
Agenda
• The problem
• Activity of Immunotherapy on CNS
• Radiotherapy + Immunotherapy
• Medical Therapy for Brain metastases
• Corticosteroids and Immunotherapy
• Take Home Messages
2
The Problem
Central nervous system (CNS) metastases occur in 20–40% of patients with advanced NSCLC
Brain or leptomeningeal metastases represent a poor prognostic factor (median OS ≈ 7 months)
The onset of CNS metastases often matches with the worsening of the performance status
3
Once upon a time…
Whole Brain Radiation Therapy (WBRT)
Stereotactic radiation therapy
Neurosurgery
STOP WHATEVER YOU ARE DOING!
4
Today
Target therapies beyond progression integrated with locoregional treatment
Delay locoregional treatment and use new generation target therapies
IMMUNOTHERAPY
5
Activity of Immunotherapy
on CNS
6
Nivolumab in Patients With Advanced NSCLC and
Central Nervous System Metastases
Jonathan W. Goldman,1 Lucio Crinò,2 Everett E. Vokes,3 Esther Holgado,4 Karen Reckamp,5 Adam Pluzanski,6 David Spigel,7 Martin Kohlhaeufl,8 Marina Garassino,9 Laura QM Chow,10 Scott Gettinger,11 David E. Gerber,12 Libor Havel,13 Suresh S. Ramalingam,14
Grace K. Dy,15 Xuemei Li,16 Ang Li,16 Anne Blackwood-Chirchir,17 Diane Healey,16 Julie Brahmer18
1UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA; 2University Hospital of Perugia, Perugia, Italy; 3University of Chicago Medical Center, Chicago, IL, USA; 4Hospital de Madrid, Norte Sanchinarro, Spain; 5City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 6Maria Sklodowska-Curie
Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; 7Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 8Robert-Bosch-Krankenhaus, Stuttgart, Germany; 9Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 10University of Washington, Seattle, WA, USA; 11Yale Comprehensive Cancer Center, New Haven, CT, USA; 12UT Southwestern Medical Center, Dallas, TX, USA; 13Nemocnice Na Bulovce, Prague, Czech
Republic; 14Winship Cancer Institute of Emory University, Atlanta, GA, USA; 15Roswell Park Cancer Institute, Buffalo, NY, USA; 16Bristol-Myers Squibb, Princeton, NJ, USA; 17Innovators BioPharma Consulting, LLC, Woodside, CA, USA; 18Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,
Baltimore, MD, USA
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Journal of Thoracic Oncology Vol. 11 No.10S Abstract 9038
Nivolumab in Patients With Advanced NSCLC and
Central Nervous System Metastases
This analysis pooled data from the following pivotal Nivolumab studies
CheckMate 063 (NCT01721759): Single-arm phase II trial of nivolumab in patients with advanced squamous (SQ) NSCLC7
CheckMate 017 (NCT01642004): Randomized, phase III trial of nivolumab vs docetaxel in patients with advanced SQ NSCLC5
CheckMate 057 (NCT01673867): Randomized, phase III trial of nivolumab vs docetaxel in patients with advanced non-SQ NSCLC
Efficacy and safety of nivolumab in two distinct populations with advanced NSCLC and CNS metastases
Patients with previously treated, asymptomatic CNS metastases at baseline
Patients with untreated, asymptomatic CNS metastases at baseline
8 Journal of Thoracic Oncology Vol. 11 No.10S Abstract 9038
Pooled Analysis of Nivolumab in Patients With Pretreated CNS
Metastases
9
aThis pooled analysis used the primary database locks: CheckMate 063 – July 2014 (minimum follow-up: 8.0 months);7 CheckMate 017 – December 2014 (minimum follow-up: 11.0 months);5 CheckMate 057 – March 2015 (minimum follow-up: 13.2 months)6
bIncludes patients with ≥1 documented, pretreated asymptomatic CNS lesion at baseline tumor assessment
mets = metastases
Without documented CNS mets
n = 385
Docetaxel 75 mg/m2 Q3W (n = 427)
Endpoints analyzed:
• Baseline characteristics and prior treatment
• Disposition
• Safety: nervous system AEs
• Efficacy: OS, rate of new CNS lesions, time to new CNS lesions
Patients from CheckMate 063/017/057 (N = 971)
Without documented CNS mets
n = 498
With CNS metsb
n = 42 With CNS metsb
n = 46
Nivolumab 3 mg/kg Q2W (n = 544)
Journal of Thoracic Oncology Vol. 11 No.10S Abstract 9038
Efficacy: OS in Patients With Pretreated CNS Metastases
10
0 2 4 9 16 23 27 37 46 Nivolumab
No. of patients at
risk
– 0 1 7 11 17 21 30 42 Docetaxel
OS
(%
)
Time (Months)
100
80
60
40
0
20
24 21 18 15 12 9 6 3 0
Nivolumab
Docetaxel
Nivolumab
n = 46
Docetaxel
n = 42
mOS, months
(95% CI)
8.4
(4.99, 11.6)
6.2
(4.4, 9.23)
No. of events 36 35
Among patients with pretreated CNS metastases, median OS was longer in the nivolumab group (8.4 months; 95% CI: 4.99, 11.6) than the docetaxel group (6.2 months; 95% CI: 4.4, 9.23) Among patients without documented pretreated CNS metastases, median OS (95% CI) was 10.4 months (9.1, 12.9) vs 8.4 months (7.33, 9.33) with nivolumab vs docetaxel, respectively
Journal of Thoracic Oncology Vol. 11 No.10S Abstract 9038
Cumulative New CNS Lesion Rate
and Time to New CNS Lesion
11
Nivolumab
3 mg/kg Q2W
Docetaxel
75 mg/m2 Q3W
Nivolumab
3 mg/kg Q2W
Docetaxel
75 mg/m2 Q3W
With CNS mets
n = 46 With CNS mets
n = 42
Without documented
CNS mets n = 498
Without documented
CNS mets n = 385
Patients with a new CNS lesion, n (%)
Within 3 months
Within 6 months
Overall
3 (7)
6 (13)
8 (17)
5 (12)
7 (17)
9 (21)
21 (4)
28 (6)
33 (7)
17 (4)
25 (7)
31 (8)
Time to new CNS lesion, months
n
Median (range)
8
3 (1.9–10.4)
9
2 (0.5–8.0)
33
2 (0.2–20.9)
31
3 (0.4–13.6)
The frequency of and time to new CNS lesions were similar
across treatment groups
Journal of Thoracic Oncology Vol. 11 No.10S Abstract 9038
CheckMate012 Arm M: NSCLC and Untreated CNS Metastases
CheckMate 012 (NCT01454102) is a phase I, multicohort study evaluating the safety and tolerability of nivolumab alone or in combination with other therapies for the treatment of patients with advanced NSCLC
12
Endpoints analyzed:
• Baseline characteristics and prior treatment
• Disposition
• Safety: nervous system AEs
• Efficacy: OS, PFS, intracranial best overall response
Nivolumab 3 mg/kg Q2W until progression
CheckMate 012 Arm M (N = 12)
• Stage IV NSCLC (any histology), ECOG PS 0–1
• ≥1 asymptomatic CNS metastasis, with no prior local therapy
Goldman et al. Nivolumab in patients with advanced NSCLC and central nervous system
metastases. ASCO Annual Meeting Proceedings Chicago, IL (2016).
CheckMate012 Arm M
CNS-Specific Patient Eligibility Criteria in CheckMate 012 Arm M
Asymptomatic, stable CNS metastases
Prior systemic anticancer therapy allowed, but no prior local therapy for CNS metastases
≤4 active CNS metastases, each ≤30 mm in size
≥1 measurable target CNS lesion 5–30 mm in diameter and/or 2 measurable CNS target lesions >3 mm visible on contrast MRI
CNS lesions <10 mm that could be accurately measured in ≥1 dimensions could be considered measurable
1–2 measurable CNS lesions were reported as target lesions
No evidence of significant cerebral edema
No use of systemic corticosteroids for ≥10 days before initiation of study treatment
13 Goldman et al. Nivolumab in patients with advanced NSCLC and central nervous system
metastases. ASCO Annual Meeting Proceedings Chicago, IL (2016).
Results: NSCLC and Untreated CNS Metastases
Efficacy
Median OS was 8.0 months (95% CI: 1.38, 15.50)
Median PFS was 1.6 months (95% CI: 0.92, 2.50)
Two patients had intracranial responses
There were no treatment-related nervous system AEs reported
14
NIvolumab 3 mg/kg Q2W (N = 12)
Intracranial best overall response
ORR, % (95% CI) 16.7 (2.1, 48.4)
CR, n (%) 1 (8)
PR, n (%) 1 (8)
SD, n (%) 0
PD, n (%) 10 (83)
Goldman et al. Nivolumab in patients with advanced NSCLC and central nervous system
metastases. ASCO Annual Meeting Proceedings Chicago, IL (2016).
Conclusions
Nivolumab appears to be tolerable in patients with preexisting CNS metastases
No additional treatment-related neurologic toxicities (eg, cerebral edema) were observed
In patients with pretreated CNS metastases, nivolumab resulted in longer OS than docetaxel (median OS [95% CI]: 8.4 months [4.99, 11.6] vs 6.2 months [4.4, 9.23])
The risk of developing a new CNS lesion was similar in the nivolumab and docetaxel treatment groups
In CheckMate 012 Arm M, 2 of 12 patients (16.7%) with untreated CNS metastases achieved intracranial responses, including one intracranial CR lasting >10.5 months
These results support further investigation of nivolumab monotherapy in patients with NSCLC and asymptomatic CNS metastases
15 Goldman et al. Nivolumab in patients with advanced NSCLC and central nervous system
metastases. ASCO Annual Meeting Proceedings Chicago, IL (2016).
Nsq Italian NSCLC Nivolumab EAP- Subpopulations: Brain Mets
Median OS 8.3 months (5.7-10.9)
WCLC, 2016 16
General Population (n = 1585)
Brain Metastasis (n = 409)
BORR, n (%) 284/1585 (18) 69/409 (17)
Complete response 10 (<1) 3 (<1)
Partial response 274 (17) 66 (16)
Stable disease 398 (25) 86 (21)
Progressive disease 18 (1) 6 (1)
Mixed response 664 (42) 186 (46)
Unable to determine 221 (14) 62 (15)
About Pembro..
A Phase II Trial of Pembrolizumab
for Untreated Brain Metastases
from Non-Small Cell Lung Cancer
Sarah B. Goldberg, Scott N. Gettinger, Amit Mahajan, Roy Herbst, Anne
Chiang, Apostolos J. Tsiouris, Alexander Vortmeyer, Lucia Jilaveanu, Stephanie
Speaker, Matthew Madura, Elin Rowen, Heather Gerrish, Xiaopan Yao,
Veronica Chiang, Harriet Kluger
16th World Conference on Lung Cancer
Denver, Colorado
September 9, 2015
17 Glodberg et al. Lancet Oncol. 2016 Jul; 17(7):976-83.
18
Study Design
Glodberg et al. Lancet Oncol. 2016 Jul; 17(7):976-83.
Results
19 Glodberg et al. Lancet Oncol. 2016 Jul; 17(7):976-83.
Conclusions
Pembrolizumab appears to have activity in the CNS in patients with NSCLC and untreated brain metastases Brain metastasis response rate of 33% Of the 6 patients with a systemic response, 5 also had a response in
the CNS CNS responses were durable, with 4 out of 5 confirmed responses
ongoing at the time of data analysis
Treatment has been well-tolerated – There have been no neurologic adverse events greater than grade 1
Systemic immunotherapy for select patients with small, asymptomatic brain metastases may be an alternative to radiation and warrants further study
Patient enrollment and biomarker analysis for this trial are ongoing
20 Glodberg et al. Lancet Oncol. 2016 Jul; 17(7):976-83.
*TC1/2/3 or IC1/2/3 includes TC3 or IC3 1. Lukas et al. WCLC 2016. Poster P2.03b–014
• Although the incidence of new CNS lesions is similar between arms, the time to
development of new CNS lesions is longer in patients treated with atezolizumab1
• No additional toxicities with atezolizumab were observed in patients with CNS mets1
In favor of docetaxel Hazard Ratio
In favor of atezolizumab
0
5
10
15
20
25
No CNS mets
CNS mets
0.75 0.97
0.54 0.61
0.73 0.93
0.2 1
2
ITT
PFS HR OS HR
No CNS mets
CNS mets
Doc (n = 47)
Doc (n = 378)
Atezo (n = 38)
Atezo (n = 387)
TC0 and IC0
TC1/2/3 or IC1/2/3*
TC3 or IC3
PD-L1 expression
Gadgeel et al. WCLC 2016
ATEZOLIZUMAB in OAK trial: Efficacy in CNS mets subgroup
23
Radiotherapy +
Immunotherapy
22
Data from melanoma experience
23
Data from melanoma experience
24
Brand new..
25
NSCLC Patients
26
Concomitant or Sequential?
46 patients were identified who received Ipi and underwent single-fraction SRS for melanoma BMs
15 patients received SRS during Ipi
19 received SRS before Ipi
12 received SRS after Ipi
Overall survival (OS) was significantly associated with the timing of SRS/Ipi
Patients treated with SRS during or before Ipi had better OS and less
regional recurrence than those treated with SRS after Ipi [1-year OS 65% vs
56% vs 40% p=.008]
SRS during Ipi also yielded a trend toward less local recurrence than SRS
beforeor after Ipi (1-year local recurrence 0% vs 13% vs 11%, p=.21)
On magnetic resonance imaging, an increase in BM diameter to >150%
was seen in 50% of patients treated during or before Ipi but in only 13% of
patients treated after Ipi
27
Kiess et al. Int J Radiation Oncol Biol Phys, Vol. 92, No. 2, pp. 368e375, 2015
Ongoing clinical research on NSCLC
28
Medical Treatment for Brain
Metastases
29
Principles of treatment
Definitive treatment directed against the tumor itself
WBRT
SRS
Surgical resection
Supportive treatment to help reduce symptoms
glucocorticoids
antiepileptic drugs (AEDs)
(anticoagulants)
30
Lin and DeAngelis, JCO 33:3475-3484
Corticosteroids Improve neurologic symptoms in up to 75% of patients with
cerebral edema and are indicated in any symptomatic patient
Dexamethasone is generally considered the corticosteroid of choice because of its minimal mineralocorticoid effect and long half-life
One study suggested that 4 or 8 mg of dexamethasone is as effective as 16 mg1; hence, most guidelines support an initial dexamethasone dose of 4 to 8 mg per day in two divided doses2
31
1 Vecht CJ, Hovestadt A, Verbiest HB, et al: Dose-effect relationship of dexamethasone on Kar- nofsky
performance in metastatic brain tumors: A randomized study of doses of 4, 8, and 16 mg per day. Neurology
44:675-680, 1994
2 Ryken TC, McDermott M, Robinson PD, et al: The role of steroids in the management of brain metastases: A
systematic review and evidence- based clinical practice guideline. J Neurooncol 96: 103-114, 2010
Corticosteroids and
Immunotherapy
32
Immunosuppressant and Immunotherapy
Due to their immunosuppressive role, corticosteroids are suspected to lower the immunotherapy efficacy
Preliminary data seem to show that systemic immunosuppressants used for irAEs might not have such a negative impact on efficacy
As observed in melanoma with nivolumab, patients who received systemic immunosuppressive therapy show a similar time to response and ORR compared with those who have not
33
Champiat et al. Annals of Oncology 00: 1–16, 2016
34
Response and Corticosteroid Use to Manage Immuno-R AEs
Survival and Corticosteroid Use to Manage Immuno-R AEs
Take Home Messages
Nivolumab, Pembrolizumab and Atezolizumab appears to have activity in the CNS in patients with NSCLC and untreated brain metastases
Immunotherapy seems to have no protective effect on new CNS lesions
Systemic immunotherapy for select patients with small, asymptomatic brain metastases may be a therapeutic option to evaluate case by case
Combination of radiotherapy and immunotherapy: no data on NSCLC. Consider each case individually!
No worries using corticosteroids for symptomatic brain metastases during immunotherapy!
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