Immuno-Oncology Approaches to Brain...

Immuno-Oncology Approaches to Brain Metastases

David A. Reardon, MDProfessor of Medicine, Harvard Medical School

Clinical Director, Center for Neuro-OncologyDana-Farber Cancer Institute

[email protected]

9th Annual Brain Metastases Research and Emerging Therapy Conference

Marseille, FranceOctober 4, 2019

Disclosures

• Advisory board (paid to me): Abbvie, Advantagene, Agenus, Amgen, BMS, Cavion, Celldex, EMD Serono, Genentech/Roche, Inovio, Juno Pharmaceuticals, Merck, Midatech, Momenta Pharmaceuticals, Novartis, Novocure, Oncorus, Oxigene, Regeneron, Stemline Therapeutics

• Lab Research Support (paid to Dana-Farber): Acerta Pharma, Agenus, Celldex Therapeutics, EMD Serono, Incyte, Inovio, Midatech, Tragara

• Speaker (paid to me): Genentech/Roche, Merck

Overview: 2019 Key Answers and Questions

2019 Key Answer: Modest benefit of single agent ICB for some patients/some tumor types validates this therapeutic strategy

2019 Ongoing Key Questions1. Can we increase breadth and depth of benefit?

a. Combination therapy: chemotherapy, targeted therapy, RT, additional ICB

b. CNS mets beyond melanoma?c. Who benefits?

2. Prevention: Fantasy or fiction?

Iorgulescu et al. Ca Immunol Res 6:1039, 2018

The Immune Checkpoint Era: Impact for Brain Metastases Patients

Metastatic Melanoma: ICB Improves Risk-Adjusted Survival

Methods1. National Cancer Database (70% all newly dx’d cancers in US): 2010-2015 (2011

initial US FDA approvals of ICB)2. OS analysis via risk-adjusted proportional hazards and Kaplan-Meier3. “Real-life” treatment analysis of metastatic melanoma patients4. Limitations: only reports outcome of newly diagnosed patients and outcome

after initial therapy

Results1. 7,689 of 220,439 (3.5%) newly diagnosed cutaneous melanoma had distant

metastases 2. 2,753 of those with metastatic disease had brain metastases (35.8%)3. 1039 (39.7%) only had brain metastases, while 1,660 (60.3%) had extracranial

and brain metastases


Metastatic Melanoma: ICB Improves Risk-Adjusted Survival


All Metastatic Patients Including Brain Metastases

No 1st Line ICB 1st Line ICB P value

Median OS (months)

5.2 12.4 <0.001

OS-48 11.1% 28.1% <0.001

Brain Metastases Only: ICB Improves Risk-Adjusted Survival


No 1st Line ICB 1st Line ICB

Median OS (months) 7.7 56.4

OS-48 16.9% 51.5%

Patients With Only Brain Metastases

Brain Metastases: ICB Improves Survival With Resection


Resection without 1st Line ICB

Resection with 1st Line ICB

Median OS (months) 12.6 Not reached

OS-48 23.2% 57.6%

Brain Metastatic Patients Who Underwent Resection

Single Agent anti-CTLA-4 (Ipilimumab):Advanced Melanoma

No CNS Mets*

# patients 137

ORR 11%

Median OS (months) 10.1 (95% CI: 8,13.8)

OS-12 45.6%

*Hodi NEJM 363:711, 2010; 10.9% had CNS mets at baseline

Single Agent anti-CTLA-4 (Ipilimumab):Advanced Melanoma

No CNS Mets* CNS Mets**

# patients 137 51

ORR 11% 16%

Median OS (months) 10.1 (95% CI: 8,13.8) 7.0 (95% CI: 4,1,10.8)

OS-12 45.6% 31% (95%CI: 18,44)

*Hodi NEJM 363:711, 2010; 10.9% had CNS mets at baseline** Margolin Lancet Oncol 13:459, 2012

Single Agent anti-PD-1 (nivolumab):Advanced Melanoma

NIVOLUMAB No CNS Mets*

# patients 316

ORR 45%

Median OS (months) 36.9 (95% CI: 28.3,NR)

OS-12 75% (approx)*Hodi Lancet Oncol 19:1480, 2018

Single Agent anti-PD-1 (nivolumab):Advanced Melanoma

NIVOLUMAB No CNS Mets* CNS Mets**

# patients 316 25

ORR 45% 20% (95% CI: 7,41)

Median OS (months) 36.9 (95% CI: 28.3,NR) 18.5 (95% CI: 6.9,NR)

OS-12 75% (approx) Not reported*Hodi Lancet Oncol 19:1480, 2018** Long Lancet Oncol 19:672, 2018

Single Agent anti-PD-1 (nivolumab): Advanced MelanomaNo CNS Mets: Median OS = 36.9 mthsOS-24: 67% (approx.)

Hodi Lancet Oncol 19:1480, 2018

+ CNS Mets: Median OS = 18.5 mthsOS-24: 50% (approx.)

Long Lancet Oncol 19:672, 2018

Nivo+ipi

Nivo

Single Agent anti-PD-1 (pembrolizumab):Advanced Melanoma

*Robert NEJM 372:2521, 2015

PEMBROLIZUMAB No CNS Mets*

# patients 279

ORR 33%

Median OS (months) Not reached (NR)

OS-12 74%

Single Agent anti-PD-1 (pembrolizumab):Advanced Melanoma

*Robert NEJM 372:2521, 2015** Kluger JCO 37:52, 2018

PEMBROLIZUMAB No CNS Mets* CNS Mets**

# patients 279 23

ORR 33% 26%

Median OS (months) Not reached (NR) 17 (95% CI: 10,NR)

OS-12 74% Not reported

Single Agent anti-PD-1 (pembrolizumab): Advanced Melanoma

Schachter Lancet 390:185, 2017

No CNS Mets: Median OS not reachedOS-24: 59% (approx.)

Kluger JCO 37:52, 2018

+ CNS Mets: Median OS = 17 monthsOS-24: 48% (approx.)

Single Agent anti-PD-1:Advanced Melanoma

NIVOLUMAB No CNS Mets* CNS Mets**

# patients 316 25

ORR 45% 20% (95% CI: 7,41)

Median OS (months) 36.9 (95% CI: 28.3,NR) 18.5 (95% CI: 6.9,NR)

OS-12 75% (approx) Not reported

*Robert NEJM 372:2521, 2015** Kluger JCO 37:52, 2018

PEMBROLIZUMAB No CNS Mets* CNS Mets**

# patients 279 23

ORR 33% 26%

Median OS (months) Not reached (NR) 17 (95% CI: 10,NR)

OS-12 74% Not reported

*Hodi Lancet Oncol 19:1480, 2018** Long Lancet Oncol 19:672, 2018

Overview: 2019 Key Answers and Questions

2019 Key Answer: Modest benefit of single agent ICB for some patients/some tumor types validates this therapeutic strategy

2019 Ongoing Key Questions1. Can we increase breadth and depth of benefit?

a. Combination therapy: chemotherapy, targeted therapy, RT, additional ICB

b. Who benefits?

2. Prevention: Fantasy or fiction?

Retrospective Data: Improved Benefit of ICB Plus Radiation Therapy

Achaya et al. Adv Radiat Oncol 2:572, 2017

Methods: n = 72 melanoma patients with brain mets 2006-2016 (233 brain metastases); Primary endpoint = distant intracranial control rate

Results:

Retrospective Data: Improved Benefit of ICB Plus Radiation TherapyChen et al. IJROBP 100:916, 2018

Methods: n = 260 melanoma, NSCLC, RCC patients with brain mets 2006-2016 who underwent SRS/SRT(623 brain metastases); concurrent ICB = +/- 2 weeks of SRS/SRT

Results: Median OS (mths)

24.714.512.9


Shepard et al. J Neurosurg , July 26, 2019Methods: Matched cohort NSCLC + brain mets; SRS +/- concurrent (3 months) ICB

No ICB Concurrent ICB P value

# patients 34 17

# mets 92 45

Concurrent steroids 62% 59%

ORR 63% 100% 0.003

CR Rate 16% 50% 0.012

Median OS (mths) 15.9 Not reached 0.99

Local control-12 mths 85% 100% 0.31

Distant CNS PD 24% 41% 0.19

Local necrosis/hemorrhage

3% 6% 0.99


Kotecha R et al. Neuro-Oncol 21:1060, 2019

Methods: n = 150 consecutive brain mets (variety of primary tumor types) patients 2010-2017 (1003 brain metastases); best overall response and response durability

Results: SRS Alone/delayed

ICBSRS + Immediate*

ICBP value

CR rate 32% 50%

CR/PR-12 71% 94% <0.001*Immediate = within 1 half-life of ICB agent

Conclusions of Retrospective Data: Require Prospective Validation

1. Concurrent ICB appears to generate better benefit than delayed ICB;

2. Concurrent ICB:

A. Higher CR rate and durability of CR (Kotecha 2019; Shepard 2019)

B. Improves distant intracranial control (Achaya 2017)

C. Improves OS (Achaya 2017; Chen 2018)

3. Prospective trials critically needed!

What are Prospective Trials to Validate Role of ICB + RT for Brain Mets?

(search of clinicaltrials.gov 9/2/19)

1. NCT02978404: Phase 2 Nivolumab + SRS for NSCLC and RCC brain metsPrimary outcome: intracranial PFS# patients: 60Lead site: Centre Hospitalier de l’Universite de Montreal

Key message: More prospective clinical trials are needed!!

Can combination ICB Therapy Improve Outcome?

Combination anti-CTLA-4 (ipilimumab) plus anti-PD-1 (nivolumab): Advanced Melanoma

*Hodi NEJM 2010**Hodi Lancet Oncol 2018*** Wolchok NEJM 377:1345, 2017

Ipilimumab* Nivolumab** Ipilimumab/Nivolumab***

# patients 137 316 314

Median Follow-up (mths)

-- -- 38.0

ORR 11% 45% 58% (95% CI: 53, 64)

Median Survival (mths)

10.1 36.9 Not reached


*NEJM 377:1345, 2017

No CNS Mets*

Wolchok, 2017*

# patients 314

Median follow-up (mths)

38.0

ORR 58% (95% CI: 53, 64)

Median OS (mths) Not reached


*NEJM 377:1345, 2017**Lancet Oncol 19:672, 2018***NEJM 379:722, 2018 (updated ASCO 2019)

No CNS Mets* + CNS Mets (asymptomatic)

Wolchok, 2017* Long, 2018** Twabi, 2018***

# patients 314 36 101


38.0 17 20.6

ORR 58% (95% CI: 53, 64) 46% (95% CI: 29, 63) 56%

Median OS (mths) Not reached Not reached Not reached


Wolchok NEJM 2017 – No CNS Mets

Tawbi NEJM 2017Long Lancet Oncol 2018Nivo+ipiNivo

+ CNS Mets, asymptomatic

Efficacy and Safety of the Combination of Nivolumab Plus Ipilimumab in Patients With Melanoma and Asymptomatic or Symptomatic Brain Metastases

(CheckMate 204)Hussein Tawbi,1 Peter Forsyth,2 F. Stephen Hodi,3 Christopher Lao,4 Stergios Moschos,5

Omid Hamid,6 Michael B. Atkins,7 Karl Lewis,8 Reena P. Thomas,9 John A. Glaspy,10

Sekwon Jang,11 Alain Algazi,12 Nikhil I. Khushalani,2 Michael A. Postow,13 Anna C. Pavlick,14

Marc Ernstoff,15 David A. Reardon,3 Agnes Balogh,16 Jasmine Rizzo,16 Kim Margolin171University of Texas, MD Anderson Cancer Center, Houston, TX; 2Moffitt Cancer Center and Research Institute, Tampa, FL; 3Dana-

Farber Cancer Institute, Boston, MA; 4University of Michigan, Ann Arbor, MI; 5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; 6The Angeles Clinic and Research Institute, Los Angeles, CA; 7Georgetown Lombardi Comprehensive

Cancer Center, Washington, DC; 8University of Colorado Comprehensive Cancer Center, Aurora, CO; 9Stanford University Hospital, Palo Alto, CA; 10Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; 11Inova Schar Cancer Institute, Virginia

Commonwealth University, Fairfax, VA; 12University of California, San Francisco, San Francisco, CA; 13Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; 14New York University Langone Medical Center, New York, NY; 15Roswell Park

Cancer Institute, Buffalo, NY; 16Bristol-Myers Squibb, Princeton, NJ; 17City of Hope, Duarte, CA

Abstract Number 9501

ASCO 2019

Study Overview

• Clinically meaningful intracranial efficacy has been reported for NIVO+IPI1

– 94 patients with asymptomatic brain metastases not requiring steroid therapy

• Intracranial clinical benefit rate (CBR) of 57%

• Median PFS not reached at median 14 months’ follow-up

• Here, we report updated efficacy and safety results for the full data set of 101 asymptomatic patients, with a median follow-up of 20.6 months

1. Tawbi HA, et al. N Engl J Med. 2018;379:722−730.

ASCO 2019, CheckMate 204

CheckMate 204 Study Design

32CBR, clinical benefit rate; CR, complete response; EC, extracranial; IC, intracranial; MBM, melanoma brain metastases; PR, partial disease; SD, stable disease; SRT, stereotactic radiosurgery.aPatients with grade 3–4 adverse events (AEs) during NIVO+IPI induction could resume NIVO when toxicity resolved and all patients who discontinued proceeded to follow-up;bUsing modified RECIST v1.1.

NIVO1 mg/kgQ3W × 4

+IPI

3 mg/kgQ3W × 4

NIVO3 mg/kg

Q2W

Treat until progression or toxicity

(max. 24 months)a

EndpointsPrimary: IC CBR (CR + PR +

SD ≥ 6 months)b

Secondary: safety, PFS, OS, EC and global CBR

Follow for 3 years from first dose

Induction

Maintenance• ≥ 1 measurable, unirradiated MBM (0.5–3.0 cm)

• Prior SRT in ≤ 3 MBM

• Previous treatment with BRAFi/MEKipermitted

• No prior checkpoint inhibitors in metastatic setting

Key eligibilities

• Asymptomatic patients

• ECOG PS 0/1• No steroids

Cohort eligibilities


Data cutoff date of May 1, 2018

Median follow-up = 20.6 mo

Demographic and Patient Characteristics – Asymptomatic Patients

aNine patients did not have extracranial disease.

Patients (n = 101)a

Male, n/N (%) 68/101 (67)

Median age, years (range) 59.0 (22−81)

BRAF mutation, n/N (%) 66/99 (67)

NRAS mutation, n/N (%) 7/26 (27)LDH > ULN, n/N (%) 41/101 (41)

LDH > 2 × ULN, n/N (%) 11/101 (11)

PD-L1 expression, n/N (%)≥ 1%< 1%

44/81 (54)37/81 (46)

Prior SRT, n/N (%) 9/101 (9)

Median of sum of intracranial target lesion diameters, mm (range) 15 (5−91)

Intracranial target lesions, n (%)1–2 lesions≥ 3 lesions

78/100 (78)22/100 (22)


Response to Treatment – Asymptomatic Patients

Patients (n = 101)

Intracranial Extracranial Global

Best overall response, n (%)

Complete response 29 (29) 11 (11) 11 (11)

Partial response 26 (26) 38 (38) 40 (40)

Stable disease ≥ 6 months 4 (4) 6 (6) 4 (4)

Progressive disease 27 (27) 16 (16) 28 (28)

Not evaluable

Death prior to first on-study assessmentEarly discontinuation due to toxicityStable disease < 6 monthsOther

15 (15)

3 (3)0 (0)8 (8)4 (4)

30 (30)a

3 (3)1 (1)

15 (15)11 (11)

18 (18)

2 (2)1 (1)

10 (10)5 (5)

ORR, n/N (%)(95% CI)

55/101 (54) (44−64)

49/101 (49)(38−59)

51/101 (51)(40−61)

CBRb, n/N % (95% CI)

59/101 (58)(48−68)

55/101 (54) (44−64)

55/101 (54)(44−64)

aSeven of these patients did not have extracranial disease at baseline; bClinical benefit rate = complete response + partial response + stable disease ≥ 6 months.


Best

redu

ctio

n fro

m b

asel

ine

in

intra

cran

ial t

arge

t les

ion

(%)

100

75

50

25

0

-25

-50

-75

-100

Patients

Intracranial Tumor Burden Change and Characteristics of Intracranial Response –Asymptomatic Patients

Median change: -57.1%

N = 101

Median time to response, months, (range) 1.6 (1.1-12.5)

Median duration of response, months (95% CI) Not reached

Ongoing response among responders 48/55 (87%)


Progression-Free Survival –Asymptomatic Patients

Events/patients Median (95% CI)

Intracranial 38/101 NR (6.5–NR)

Extracranial 30/101 NR (13.9–NR)

Global 41/101 NR (6.5–NR)

PFS

(%)

1009080

7060

504030

2010

0


61%

63%

72%

656264

464245

383338

342933

302530

211921

181617

109

10

Number of patients at risk:Intracranial: 101

Extracranial: 101Global: 101

878

222

000

0Months

3 6 9 12 15 18 21 24 27 30 33


Overall Survival – Asymptomatic Patients

0

92 89 80 74 67 58 47 35 22 15 8 2 0


Asymptomatic 23/101 NR (NR–NR)

OS

(%)

1009080

7060

504030

2010

0Median follow-up = 20.6 mo

3 6 9 12 15 18 21 24 27 30 33 36 39Months

93%82%

75%

Number of patients at risk:Asymptomatic: 101


Summary − Asymptomatic Patients• ORR was 54%, with an estimated 6-month PFS rate of 63%

• At a median follow-up of 20.6 months, median OS has not yet been reached

• These results are paralleled and confirmed in an independent Australian study1

• Patients in this study cohort were a select population without any neurologic symptoms or steroid therapy

• Questions concerning symptomatic patients led to an amendment to allow enrollment of up to 20 patients with symptomatic disease to explore NIVO+IPI in these patients

1. Long GV, et al. Lancet Oncol. 2018;19:672−681.


Background – Symptomatic Cohort

• Patients with symptomatic MBM are more challenging to treat– Patients tend to deteriorate quickly – Steroid use may reduce the

effectiveness of immunotherapy

1. Margolin K, et al. Lancet Oncol. 2012;13:459−465; 2. Long GV, et al. Lancet Oncol. 2018;19:672−681; 3. Davies MA, et al. Lancet Oncol. 2017;18:863−873.

Treatment Patients ORR DOR

IPI1 21 5% Notreported

NIVO2 16 6% Notreached

Dabrafenib+Trametinib3 17a 59% 4.5 mo

aBRAF mutant patients.

• Here we provide the first report of safety and efficacy of NIVO+IPI in patients with MBM who are symptomatic and/or on steroids

.


CheckMate 204 Study Design with Cohort B

CBR, clinical benefit rate; CR, complete response; EC, extracranial; IC, intracranial; MBM, melanoma brain metastases; PR, partial disease; SD, stable disease; SRT, stereotactic radiosurgery.aPatients with grade 3–4 adverse events (AEs) during NIVO+IPI induction could resume NIVO when toxicity resolved and all patients who discontinued proceeded to follow-up;bUsing modified RECIST v1.1.

NIVO1 mg/kgQ3W × 4

+IPI

3 mg/kgQ3W × 4

NIVO3 mg/kg

Q2W


(max. 24 months)a


SD ≥ 6 months)b



Induction





Key eligibilities

Cohort A:• Asymptomatic

patients• ECOG PS 0/1• No steroids

Cohort B:• Symptomatic

patients • ECOG PS 0−2• ≤ 4 mg

dexamethasone or equivalent/ day allowed


Median follow-up = 5.2 mo Data cutoff date of May 1, 2018



CheckMate 204 Study Design with Cohort B

41

CBR, clinical benefit rate; CR, complete response; EC, extracranial; IC, intracranial; MBM, melanoma brain metastases; PR, partial disease; SD, stable disease; SRT, stereotactic radiosurgery.aPatients with grade 3–4 adverse events (AEs) during NIVO+IPI induction could resume NIVO when toxicity resolved and all patients who discontinued proceeded to follow-up;bUsing modified RECIST v1.1.

NIVO1 mg/kgQ3W × 4

+IPI

3 mg/kgQ3W × 4

NIVO3 mg/kg

Q2W


(max. 24 months)a


SD ≥ 6 months)b



Induction





Key eligibilities

Cohort A:• Asymptomatic

patients• ECOG PS 0/1• No steroids

Cohort B:• Symptomatic

patients • ECOG PS 0−2• ≤ 4 mg

dexamethasone or equivalent/ day allowed


Median follow-up = 5.2 mo Data cutoff date of May 1, 2018



Demographic and Patient Characteristics – Symptomatic Patients

Patients (n = 18)a

Male, n/N (%) 13/18 (72)

Median age, years (range) 59.5 (29−80)

BRAF mutation, n/N (%) 8/16 (50)

NRAS mutation, n/N (%) 1/2 (50)LDH > ULN, n/N (%) 8/17 (47)

LDH > 2 × ULN, n/N (%) 2/17 (12)

PD-L1 expression, n/N (%)≥ 1%< 1%

6/10 (60)4/10 (40)

Prior SRT, n/N (%) 0

Median of sum of intracranial target lesion diameters, mm (range) 26 (7−86)

Intracranial target lesions, n/N (%)1–2 lesions≥ 3 lesions

11/18 (61)7/18 (39)

Steroid use at baseline, n/N (%) 11/18 (61)

aOne patient did not have extracranial disease.


Response to Treatment – Symptomatic Patients

Patients (n = 18)

Intracranial Extracranial Global

Best overall response, n (%)

Complete response 2 (11) 0 0

Partial response 2 (11) 4 (22) 4 (22)

Stable disease ≥ 6 months 0 0 0

Progressive disease 10 (56) 6 (33) 8 (44)

Not evaluable

Death prior to first on-study assessmentEarly discontinuation due to toxicityStable disease < 6 monthsOther

4 (22)

2020

8 (44)a

1043

6 (33)

1023

ORR, n/N (%)(95% CI)

4/18 (22) (6−48)

4/18 (22)(6−48)

4/18 (22) (6−48)

CBR,b n/N (%) (95% CI)

4/18 (22) (6−48)

4/18 (22) (6−48)

4/18 (22) (6−48)

a One of these patients did not have extracranial disease at baseline; bClinical benefit rate = complete response + partial response + stable disease ≥ 6 months.


Symptomatic Cohort Responders

Intracranialresponse BRAF status

NIVO+IPI induction doses

Maintenance doses

Steroid use at baseline

CR Mutant 4 37 Yes

CR Wild type 1 23 No

PR Mutant 4 23 No

PR Not reported 3 0a No

aPatient discontinued treatment due to toxicity.

• Median time to intracranial response of 4.1 (1.0−6.9) months; median duration of response not reached

• 3 of 4 (75%) with ongoing responses


Progression-Free Survival – Symptomatic Patients

19%

29%

33%



Intracranial 13/18 1.2 (0.7−1.3)

Extracranial 10/18 2.2 (0.8−NR)

Global 11/18 1.2 (0.8−NR)

PFS

(%)

1009080

7060

504030

2010

00 3 6 9 12

Months15 18 21 24

355

233

233

122

111

111

000

000

Number of patients at risk:Intracranial: 18Extracranial: 18

Global: 18


OS

(%)

1009080

7060

504030

2010

00 3 6 9 12

Months15 18 21 24

Overall Survival − Symptomatic Patients

66%


Symptomatic 8/18 8.7 (1.8−NR)


10 9 4 4 3 2 0 0Number of patients at risk:

Symptomatic: 18


Summary – Symptomatic Patients• NIVO+IPI showed intracranial antitumor activity in symptomatic patients

– ORR was 22% (2 CRs and 2 PRs)– Median OS was 8.7 months, with a 6-month survival rate of 66%

• Median number of NIVO+IPI doses received was 1 (range 1−4; 10 of 18 patients with one dose)– 4 patients entered the maintenance phase


Safety Summary − Both Cohorts

n (%)

Asymptomatica

n = 101Symptomatic

n = 18

Any grade Grade 3−4 Any grade Grade 3−4

Treatment-related AEs 97 (96) 55 (54) 16 (89) 10 (56)

Treatment-related nervous system AEs 35 (35) 7 (7) 3 (17) 3 (17)

Treatment-related AEsleading to discontinuation

29 (29) 19 (19) 2 (11) 0

Treatment-related nervous system AEs leading to discontinuation

2 (2) 2 (2) 0 0

aOne death reported: treatment-related grade 5 myocarditis (previously reported).1

1. Johnson DB, et al. N Engl J Med. 2016;375:1749−1755.


Treatment-Related Neurologic AEs –Both Cohorts

Events reported in ≥ 2% of patients, n (%)

Asymptomatica

n = 101Symptomatic

n = 18Any grade Grade 3−4 Any grade Grade 3−4

Patients with any AEs 35 (35) 7 (7) 3 (17) 3 (17)Headache 20 (20) 3 (3) 1 (6) 1 (6)Paresthesia 4 (4) 0 0 0Dysgeusia 3 (3) 0 0 0Peripheral sensory neuropathy 3 (3) 0 0 0Aphasia 2 (2) 0 0 0Brain edema 2 (2) 2 (2) 0 0Intracranial hemorrhage 2 (2) 1 (1) 0 0Seizure 2 (2) 0 0 0Amnesia 0 0 1 (6) 1 (6)Dysarthria 0 0 1 (6) 1 (6)Lethargy 0 0 1 (6) 0Partial seizures 0 0 1 (6) 1 (6)Syncope 1 (1) 1 (1) 1 (6) 1 (6)

aOne death reported: treatment-related grade 5 myocarditis (previously reported).1

1. Johnson DB, et al. N Engl J Med. 2016;375:1749−1755.



*NEJM 377:1345, 2017**Lancet Oncol 19:672, 2018***NEJM 379:722, 2018 (updated ASCO 2019)**** ASCO, 2019

No CNS Mets Asymptomatic CNS Mets Symptomatic CNS Mets

Wolchok, 2017* Long, 2018** Twabi, 2018*** Twabi, 2019****

# patients 314 36 101 18


38.0 17 20.6 5.2

ORR 58% (95% CI: 53, 64)

46% (95% CI: 29, 63)

56% 22%

Median OS (mths)

Not reached Not reached Not reached 8.7

Conclusions

• The safety profile of NIVO+IPI for asymptomatic and symptomatic patients with MBM was similar to that of patients without brain metastases1,2

• The durable intracranial responses observed in patients with asymptomatic brain metastases supports the use of NIVO+IPI as first-line therapy

• Symptomatic patients remain difficult to treat, but some can benefit from NIVO+IPI

• Further studies in patients with symptomatic brain metastases need to

– Facilitate and accelerate the screening phase to enable rapid treatment– Evaluate the incorporation or sequencing of radiation therapy– Incorporate targeted therapies and/or steroid-sparing agents

1. Hodi FS, et al. Lancet Oncol. 2016;17:1558−1568; 2. Hodi FS, et al. Lancet Oncol. 2018;19:1480−1492.


Who Benefits?: Absolute Lymphocyte Count

Chen et al. IJROBP 100:916, 2018Methods: n = 260 melanoma, NSCLC, RCC patients with brain mets 2006-2016 who underwent SRS/SRT(623 brain metastases); concurrent ICB = +/- 2 weeks of SRS/SRT

Univariate Cox Regression Multivariate Cox Regression

P Value HR (95% CI) P Value HR (95% CI)

ALC ≥ 1000 0.57 0.57 (0.31, 1.20) 0.001 0.27 (0.13, 0.57)

Pike et al. IJROBP 103:142, 2019Methods: n = 100 metastatic melanoma, NSCLC, RCC patients undergoing palliative RT +/- ICB

Steroid Use and Immune Checkpoint Blockade

Cohort A: no steroids (n=51)Median OS: 7.0 mths

Cohort B: on steroids (n=21)Median OS: 3.7 mths

Margolin Lancet Oncol 13:459, 2012Steroids significantly reduce OS of melanoma brain mets patients treated with ipilimumab

Steroids significantly reduce OS of melanoma brain mets patients treated with anti-PD-1Parakh BJC 116:1558, 2017

Median OSOn steroids: 4.8 mthsNot on steroids: 13.1 mths

p=0.039

Who Benefits?: Steroid Use

Arharya Adv Rad Oncol 2:572, 2017Methods:n = 72 melanoma patients with brain mets 2006-2016 (233 brain metastases); Primary endpoint = distant intracranial control rate

Univariate Cox Regression Multivariate Cox Regression

P Value HR (95% CI) P Value HR (95% CI)

Steroids Before SRS <0.001 2.07 (1.42, 2.99) 0.002 1.81 (1.25, 2.64)

Kotecha Neuro-Oncol 21:1060, 2019Methods: n = 150 consecutive brain mets (variety of primary tumor types) patients 2010-2017 (1003 brain metastases); best overall response and response durability

Can an immune response maintain a tumor dormant state and prevent overt metastasis?

Romero I Ca Res 74:6750, 2014

Goddard ET, Dormant tumour cells, their niches and the influence of immunity. Nat Cell Biol 20:1240, 2018

ConclusionsI. Improved outcome in modern era for brain metastases patients coincides

with approvals for immune checkpoint therapy

II. Retrospective data suggests added benefit of concurrent ICB with RT (less benefit if ICB delayed) compared to RT alone

III. Combined blockade of PD-1 and CTLA-4 modestly improves benefit compared to PD-1 alone

IV. More prospective trials critically needed

V. Greater study of CNS metastases beyond melanoma also needed

VI. Evaluation of potential biomarkers of benefita. ALC?b. Concurrent dexamethasonec. CD8+ TIL

VII. Is prevention via prolonging tumor dormancy possible?

Neuro-OncologyRameen Berhoukim, MD, PhDUgonma Chukwuede, MDMeghan Cifrino, RNLisa Doherty, NPBrittney Fontana, RNSarah Hogan, RNDeb LaFrankie, RNEudocia Quant Lee, MD, MPHLakshmi Nayak, MDDavid Reardon, MD (Clinical Director)Mik Rinne, MD, PhDJenn Stefanick, NPChrissy Taubert, NPAleks Torres, PAPatrick Wen, MD (Director)

Neuro-SurgeryOssama Al-Mefty, MDOmar Arnaout, MDAli Aziz-Sultan, MDJohn Chi, MD, MPHNino Chiocca, MD, PhD (Chair)Elizabeth Claus, MD, PhDRees Cosgrove, MD, PhDRose Du, MD, PhDAlexandra Golby, MDEdward Laws, MDPierpaolo Peruzzi, MD, PhDTim Smith, MD, PhD

Radiation OncologyAyal Aizer, MDBrian Alexander, MD, MPHDaniel Cagney, MDDaphne Haas-Kogen, MD (Chair)Shyam Tanguteri, MD DFCI Neuro-Onc Research

Brenda Acevedo, CRCMarie Allen, CRCLauren Bello-Matricaria, Clin Res SpecShawna Bilton, CRCJennifer Bruno, Clin Res SpecGina Cach, CRCMyriam Debruyne, Clin Res SpecNicole Devaney, CRCBrittany Fisher-Longden, Clin Res SpecSarah Gaffey, Clin Res SpecJack Geduldig, CRCNorris Guscott, RegulatoryJulia Hayden, CRCCorey Laforest-Royes, CRCSwati Madhok (Asst manager)Christine McCluskey, Clin Res SpecAlexa Myers, CRCAmanda Spearman, CRCPoonam Thakur, Reg SpecialistFiona Watkinson, CRCChristian Widmer, CRCCiara Williams, Clin Res Spec

NeuropathologyUmberto De Girolami, MDKeith Ligon, MD, PhD (Chair)Neal Lindeman, MDDavid Meredith, MDSandro Santagata, MD, PhD

Neuro-ImagingRay Huang, MDSrinivasan Mukundan, MD, PhD (Section Head)Geoff Young, MD, PhD

Laboratory ResearchNathalie Agar, PhDWilliam Hahn, MD, PhDWilliam Kaelin, MDSean Lawler, PhDDavid Mooney, PhDHiroshi Nakashima, PhDTom Roberts, PhDKhalid Shah, MS, PhDChuck Stiles, PhDRosiland Segal, PhDMario Suva, PhD

Broad InstituteMaegan Harden, PhDSachet Shukla, PhDJing Sun, PhD

Funding Support:Team Brain Aid: Jimmy Fund WalkNCI Brain SPORE DF/HCC

Ben and Catherine Ivy Foundation

Erica’s Entourage/Pan Mass Challenge

Blavatnik Family Foundation

Immuno-OncologyAnna Anderson, PhDGordon Freeman, PhDStephen Hodi, MDBryan Iorgulescu, MDVijay Kucheroo, PhDCarl Novina, PhDPatrick Ott, MD, PhDScott Rodig, MD, PhDArlene Sharpe, PhDKeerthi Shetty, PhDCatherine Wu, MDKai Wucherpfennig, PhD (Chair)Oriol Olive Noguer, Sr Reg Coord

Center for Neuro-Oncology: Dana-Farber/Brigham Women’s Hospital

David Hovey Family CRUS11 Tour

Experimental Therapeutics Core(Belfer Institute)Prafulla Gokhale, PhDKristen JonesPaul Kirschmeier, PhDAmy Saur

Merci Beaucoup!

(Thank you)

Background

• Brain metastases are a major cause of morbidity/death from melanoma1

– More than half of all patients with metastatic melanoma are expected to have a brain metastasis during the course of their disease

– Historically, patients with melanoma metastatic to the brain have had a median overall survival (OS) of ~4−5 months1

– Strategies for managing brain metastases have traditionally been limited to surgery and radiation therapy2

• In patients with melanoma brain metastases (MBM) who are asymptomatic and do not require steroids, immunotherapy has been proven tolerable, and has clinical benefit:

– Single agent ipilimumab (IPI) has a CNS ORR of 16%3

– Both nivolumab (NIVO) and pembrolizumab have a CNS ORR of ~ 20%4,5

59

• CheckMate 204

1. Davies MA, et al. Cancer. 2011;117:1687−1696; 2. Chukwueke U, et al. J Oncol Pract. 2016;12:536−542; 3. Margolin K, et al. Lancet Oncol. 2012;13:459−465; 4. Long GV, et al. Lancet Oncol. 2018;19:672−681; 5. Kluger HM, et el. J Clin Oncol. 2019;37:52−60.

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