Overview: Immunotherapy in CNS Metastases

Manmeet Ahluwalia, MD, FACPMiller Family Endowed Chair in Neuro-Oncology

Director Brain Metastasis Research ProgramCleveland Clinic

Disclosures

§Consultant- Monteris Medical, BMS, Abbvie, AstraZeneca, Kadmonpharmaceuticals, Dattar Genetics, CBT pharmaceuticals

§Honorarium- Elsevier

§Research Funding- Novartis, Novocure Inc, Tracon Pharmaceuticals, Spectrum Pharmaceuticals, Incyte, Astrazeneca, International Gamma Knife Research Foundation, BMS, Cures within Reach, MusellaFoundation, Case Comprehensive Cancer Center, Velasano

*Incidence increasing with better systemic Rx and improved survival

Annual US incidence: >170KRatio mets/primary: 10:1All cancer patients: 15%–30%Autopsy incidence: 10%–30%Mean age: 60 yearsMedian survival: 4–6 months

Relative prevalence of brain metastases*

Other known primary: 13%

Lung: 48%

Breast: 15%

Unknown primary: 11%

Melanoma: 9%

Colon: 5%

Primary tumor

Epidemiology of brain metastases

Courtesy: John Suh. Wen PY, et al. In: DeVita VT Jr, et al, eds.

Cancer: Principles & Practice of Oncology. 2001:2656-2670. Presented by: Manmeet Ahluwalia, MD, FACP

Goals of Treatment§ Control

§ Macroscopic disease§ Microscopic disease§ Systemic disease

§ Preserve§ Neurologic function§ QOL

Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial

Margolin K. Lancet Oncol. 2012 May;13(5):459-65

Disease control

12 /51 in cohort A (24%)

2/21 cohort B (10%)

Margolin K. Lancet Oncol. 2012 May;13(5):459-65

Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial

Disease control 12 /51 in cohort A (24%)2/21 cohort B (10%)

Margolin K. Lancet Oncol. 2012 May;13(5):459-65

Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial

Primary endpoint: brain metastasis response rate

Secondary endpoints: overall response rate, safety, PFS, OS

Safety evaluation at 4 weeks:§ Brain MRI

Response evaluation every 8 weeks:§ Brain MRI§ CT chest/abdomen/pelvis

Key eligibility:§ Advanced NSCLC or melanoma§ At least one untreated or

progressive brain metastasis 5–20 mm

§ No neurologic symptoms or steroid requirement

§ PS 0–1§ PD-L1 expression from tumor

biopsy after most recent systemic therapy

Pembrolizumab 10 mg/kg q2w

Brain metastasis PD

Consider radiation or surgery to progressing lesions

Brain metastasis CR, PR, or SD

Continue pembrolizumabif systemic control achieved

Phase II trial of pembrolizumab for untreated brain metastases

Courtesy: Harriet Kluger.

CT, computed tomography; PD-L-1, programmed cell death ligand-1; PS, performance status; q2w, every 2 weeks; SD, standard deviation.

Presented by: Manmeet Ahluwalia, MD, FACP

Lung Cancer brain metastasis response by mRECIST

Note: 4 patients were unevaluable in the brain due to rapid systemic progression

Courtesy: Sarah Goldberg.Presented by: Manmeet Ahluwalia, MD, FACP

Safety and activity of Pembrolizumab in melanoma patients with untreated brain metastases

Baseline

After 1 dose,Headaches

A BC D

FEG H

Courtesy: Harriet Kluger

• Original planned enrollment of 110 asymptomatic patients; amended to include 20 symptomatic patients

• Patients with grade 3-4 AEs during NIVO+IPI induction could resume NIVO when toxicity resolved

aAll patients who discontinued proceeded to follow-up

NIVO1 mg/kgQ3W × 4

+IPI

3 mg/kgQ3W × 4

NIVO3 mg/kg

Q2W (up to 2 years)

Treat until progression or unacceptable

toxicity

Induction Maintenance

11

Allowed:• ≥1 measurable, unirradiatedMBM (0.5-3.0 cm)

• Prior SRT in <3 MBM• BRAF/MEK inhibitorsNot allowed:• Neurologic symptoms or steroids >10 days

• WBRT, IPI, or anti-PD-1/PD-L1

• Leptomeningeal disease

Key eligibility

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with Melanoma Metastatic to the Brain:

Results of the Phase II Study CheckMate 204

Tawbi H et. al Abstract 9507, ASCO Annual Meeting 2017Presented by: Manmeet Ahluwalia, MD, FACP

Response to Treatment – All Patients (N=75)Global Intracranial Extracranial

Best overall response, n (%)Complete response 4 (5) 16 (21) 5 (7)Partial response 36 (48) 25 (33) 32 (43)Stable disease 4 (5) 4 (5) 2 (3)Progressive disease 7 (9) 6 (8) 5 (7)Not evaluable 24 (32) 24 (32) 31 (41)

Objective response rate, % (95% CI) 53 (41−65) 55 (43−66) 49 (38−61)Clinical benefit rate*, % (95% CI) 59 (47−70) 60 (48−71) 52 (40−64)Median time to objective response, months (range) 2.5 (1−14) 2.8 (1−11) 2.6 (1−15)

Median duration of objective response has not been reached*Clinical benefit rate = complete response + partial response + stable disease > 6 months

Tawbi H et. al Abstract 9507, ASCO Annual Meeting 2017Presented by: Manmeet Ahluwalia, MD, FACP

Swimmer Plot: Time to and Duration of Response Intracranial

Patie

nts

0 8 16 24 32 40 48 56 64 72 80 88Time (Weeks)

On treatmentOff treatmentLast doseLast dose when subject off treatment

First response (CR/PR)CensoredProgressionDeath

23/75 (31%) patients had radiographic progression; 14/75 (19%) intracranially, 1/75 (1%) extracranially, 8/75 (11%) intra- and extracranially

Tawbi H et. al Abstract 9507, ASCO Annual Meeting 2017

Presented by: Manmeet Ahluwalia, MD, FACP

A randomized phase II study of nivolumab or nivolumabcombined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration

Long G et al. J Clin Oncol 35, 2017 (suppl; abstr 9508)

A N = 25 nivo+ipi

B N = 25

nivo

C N = 16

nivo

ICR % (95% CI) 44 (24, 65) 20 (7, 41) 6 (0, 30)

ICR Complete Response 16 (24, 65) 12 (7, 41) 0

ECR % (95% CI) 38 (18, 62) 26 (10, 48) 21 (5, 50)

6-mo PFS % (95% CI) 50 (33, 75) 29 (15, 56) 0

6-mo OS % (95% CI) 76 (59, 97) 59 (41, 86) 44 (25, 76)

A, B - RT naïve, C-failed RT/ symptomatic/ leptomeningeal

Presented by: Manmeet Ahluwalia, MD, FACP

Slide 11

Presented By Georgina Long at 2017 ASCO Annual Meeting

A Randomized Phase II Study of Pembrolizumab plus Either Reduced Dose Ipilimumab or Epacadostat (INCB024360) for

Advanced Melanoma Metastatic to the BrainPrincipalInvestigator:AhmadTarhini,MD,PhD

N=50subjectsArmA:Thecombinationofpembrolizumab andepacadostat

oPembrolizumab 200mgIVinfusionevery3weeksoEpacadostat 100mgorallyBID

ArmB:Thecombinationofpembrolizumab andreduceddoseipilimumab

oPembrolizumab 200mgIVinfusionevery3weeksoIpilimumab 1mg/kgIVinfusionevery3weeks

DiagnosiswithmetastaticmelanomatothebrainwithatleastonemeasurablebrainmetastaticlesionbyMRI(>0.5cmand<3cminlongestdiameter)that

either(1)hasnotbeenpreviouslyexposedtoradiationtherapyor(2)alesionthatwaspreviouslytreatedwithradiosurgeryandhasdefinitivelyprogressedasassessedbyneurosurgeryand/orradiationoncologymaybeconsideredasatargetlesion

PatientmustbeasymptomaticorminimallysymptomaticBMnotrequiringsteroids

Primary Objective:Evaluate the objective response rate of melanoma metastases in the brain (by MRI

utilizing modified RECIST 1.1)

• Previously untreated CNS metastases (Cohort A)

• Progressive brain metastases (cohort B)

• Measurable CNS disease

Pembrolizumab 200mg q3 wks

Primary endpointl CNS response rate

Secondary endpointsl CNS PFSl Systemic PFS (RECIST and

irRC)l ORR (RECIST and irRC)l Safety

Exploratory endpointsl Correlation of response with

biomarkers l Duration of responsel First site of progressionl Patient reported outcomes

• Baseline brain MRI• Circulating biomarkers (including

CTCs, cell-free DNA)

• Brain MRI and systemic staging q6wks• Circulating biomarkers q3wks

CNS or systemic

progression

PhaseIItrialofpembrolizumab inbrainmetastases(CohortAandB)

PI: Priscilla Brastianos, MD Massachusetts General Hospital

Future directions: takeaway points §Control

–Macroscopic disease: immune therapy (asymptomatic pts)–Microscopic disease: immune therapy–Systemic disease: immune therapy

§Preserve–Neurologic function

§Selection of therapy for BM: multidisciplinary approach

Clinical trials are critical to define care in BM

Presented by: Manmeet Ahluwalia, MD, FACP

Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center

Multidisciplinary approach to provide individualized care