congresso nazionale aiom giovani 2017media.aiom.it/userfiles/files/doc/aiom-servizi/... ·...

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

7

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)


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


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


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


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


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


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


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


*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!

36

37 [email protected]

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