Il management della progressione cerebrale e la terapia steroidea in corso di immunoterapia

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Sessione Polmone

Daniela Iacono

UOSD Pneumologia Oncologica

Ospedale San Camillo Forlanini, Roma TUTOR: Dr. Alessandro Inno

1 Congresso Nazionale AIOM Giovani 2017

Perugia, 7-8 Luglio 2017

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Agenda

• The problem

• Activity of Immunotherapy on CNS

• Radiotherapy + Immunotherapy

• Medical Therapy for Brain metastases

• Corticosteroids and Immunotherapy

• Take Home Messages

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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

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Once upon a time…

 Whole Brain Radiation Therapy (WBRT)

 Stereotactic radiation therapy

 Neurosurgery

STOP WHATEVER YOU ARE DOING!

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Today

 Target therapies beyond progression integrated with locoregional treatment

 Delay locoregional treatment and use new generation target therapies

 IMMUNOTHERAPY

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Activity of

Immunotherapy on CNS

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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

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Nivolumab in Patients With Advanced NSCLC and

Central Nervous System Metastases

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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

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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

Journal of Thoracic Oncology Vol. 11 No.10S Abstract 9038 8

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Pooled Analysis of Nivolumab in Patients With Pretreated CNS

Metastases

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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 mets^b n = 42 With CNS mets^b

n = 46

Nivolumab 3 mg/kg Q2W (n = 544)

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Efficacy: OS in Patients With Pretreated CNS Metastases

10 0

2 4

9 16

23 27

37 Nivolumab 46

No. of patients at risk

– 0

1 7

11 17

21 30

Docetaxel 42

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

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Cumulative New CNS Lesion Rate

and Time to New CNS Lesion

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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

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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).

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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

Goldman et al. Nivolumab in patients with advanced NSCLC and central nervous system 13 metastases. ASCO Annual Meeting Proceedings Chicago, IL (2016).

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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).

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Conclusions

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Nivolumab appears to be tolerable in patients with preexisting CNS metastases

 No additional treatment-related neurologic toxicities (eg, cerebral edema) were observed

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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

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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

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These results support further investigation of nivolumab monotherapy in patients with NSCLC and asymptomatic CNS metastases

Goldman et al. Nivolumab in patients with advanced NSCLC and central nervous system 15 metastases. ASCO Annual Meeting Proceedings Chicago, IL (2016).

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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)

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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

16^th World Conference on Lung Cancer Denver, Colorado

September 9, 2015

Glodberg et al. Lancet Oncol. 2016 Jul; 17(7):976-83. 17

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Study Design

Glodberg et al. Lancet Oncol. 2016 Jul; 17(7):976-83.

• 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

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Radiotherapy Immunotherapy +

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Data from melanoma experience

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Data from melanoma experience

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Brand new..

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NSCLC Patients

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Concomitant or Sequential?

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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

Kiess et al. Int J Radiation Oncol Biol Phys, Vol. 92, No. 2, pp. 368e375, 2015 27

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Ongoing clinical research on NSCLC

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Medical

Treatment for Brain Metastases

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²

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

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Corticosteroids Immunotherapy and

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Immunosuppressant and Immunotherapy

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Due to their immunosuppressive role, corticosteroids are suspected to lower the immunotherapy efficacy

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Preliminary data seem to show that systemic

immunosuppressants used for irAEs might not have such a negative impact on efficacy

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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

Champiat et al. Annals of Oncology 00: 1–16, 2016 33

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Response and Corticosteroid Use to Manage Immuno-R AEs

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Survival and Corticosteroid Use to Manage Immuno-R AEs

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Take Home Messages

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Nivolumab, Pembrolizumab and Atezolizumab appears to have activity in the CNS in patients with NSCLC and

untreated brain metastases

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Immunotherapy seems to have no protective effect on new CNS lesions

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Systemic immunotherapy for select patients with small, asymptomatic brain metastases may be a therapeutic option to evaluate case by case

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Combination of radiotherapy and immunotherapy: no data on NSCLC. Consider each case individually!

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No worries using corticosteroids for symptomatic brain metastases during immunotherapy!

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dani.iacono@gmail.com

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