Overview: Immunotherapy in CNS Metastases

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1 Overview: Immunotherapy in CNS Metastases Manmeet Ahluwalia, MD, FACP Miller Family Endowed Chair in Neuro-Oncology Director Brain Metastasis Research Program Cleveland Clinic

2 Disclosures Consultant- Monteris Medical, BMS, Abbvie, AstraZeneca, Kadmon pharmaceuticals, 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, Musella Foundation, Case Comprehensive Cancer Center, Velasano

3 Epidemiology of brain metastases Primary tumor Colon: 5% Melanoma: 9% Unknown primary: 11% Relative prevalence of brain metastases* Annual US incidence: >170K Ratio mets/primary: 10:1 All cancer patients: 15% 30% Autopsy incidence: 10% 30% Mean age: 60 years Median survival: 4 6 months Other known primary: 13% Breast: 15% Lung: 48% *Incidence increasing with better systemic Rx and improved survival Presented by: Manmeet Ahluwalia, MD, FACP Courtesy: John Suh. Wen PY, et al. In: DeVita VT Jr, et al, eds. Cancer: Principles & Practice of Oncology. 2001:

4 Goals of Treatment Control Macroscopic disease Microscopic disease Systemic disease Preserve Neurologic function QOL

5 Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial Margolin K. Lancet Oncol May;13(5):459-65

6 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 May;13(5):459-65

7 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 May;13(5):459-65

8 Phase II trial of pembrolizumab for untreated brain metastases 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 Brain metastasis CR, PR, or SD Consider radiation or surgery to progressing lesions Continue pembrolizumab if systemic control achieved Safety evaluation at 4 weeks: Brain MRI Response evaluation every 8 weeks: Brain MRI CT chest/abdomen/pelvis Primary endpoint: brain metastasis response rate Secondary endpoints: overall response rate, safety, PFS, OS 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 Courtesy: Harriet Kluger.

9 Lung Cancer brain metastasis response by mrecist Note: 4 patients were unevaluable in the brain due to rapid systemic progression Presented by: Manmeet Ahluwalia, MD, FACP Courtesy: Sarah Goldberg.

10 Safety and activity of Pembrolizumab in melanoma patients with untreated brain metastases Baseline After 1 dose, Headaches A C E G B D F H Courtesy: Harriet Kluger

11 Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with Melanoma Metastatic to the Brain: Results of the Phase II Study CheckMate 204 Key eligibility Allowed: 1 measurable, unirradiated MBM ( cm) Prior SRT in <3 MBM BRAF/MEK inhibitors Not allowed: Neurologic symptoms or steroids >10 days WBRT, IPI, or anti-pd-1/pd- L1 Induction NIVO 1 mg/kg Q3W 4 + IPI 3 mg/kg Q3W 4 Maintenance NIVO 3 mg/kg Q2W (up to 2 years) Treat until progression or unacceptable toxicity Leptomeningeal disease a All patients who discontinued proceeded to follow-up 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 Presented by: Manmeet Ahluwalia, MD, FACP Tawbi H et. al Abstract 9507, ASCO Annual Meeting

12 Response to Treatment All Patients (N=75) Best overall response, n (%) Global Intracranial Extracranial 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) *Clinical benefit rate = complete response + partial response + stable disease > 6 months Median duration of objective response has not been reached Presented by: Manmeet Ahluwalia, MD, FACP Tawbi H et. al Abstract 9507, ASCO Annual Meeting 2017

13 Swimmer Plot: Time to and Duration of Response Intracranial Patients On treatment Off treatment Last dose Last dose when subject off treatment First response (CR/PR) Censored Progression Death 23/75 (31%) patients had radiographic progression; 14/75 (19%) intracranially, 1/75 (1%) extracranially, 8/75 (11%) intra- and extracranially Time (Weeks) Presented by: Manmeet Ahluwalia, MD, FACP Tawbi H et. al Abstract 9507, ASCO Annual Meeting 2017

14 A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration 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 Long G et al. J Clin Oncol 35, 2017 (suppl; abstr 9508)

15 Slide 11 Presented By Georgina Long at 2017 ASCO Annual Meeting

16 A Randomized Phase II Study of Pembrolizumab plus Either Reduced Dose Ipilimumab or Epacadostat (INCB024360) for Advanced Melanoma Metastatic to the Brain Principal Investigator: Ahmad Tarhini, MD, PhD N = 50 subjects Arm A: The combination of pembrolizumab and epacadostat opembrolizumab 200 mg IV infusion every 3 weeks oepacadostat 100 mg orally BID Arm B: The combination of pembrolizumab and reduced dose ipilimumab opembrolizumab 200 mg IV infusion every 3 weeks oipilimumab 1 mg/kg IV infusion every 3 weeks Diagnosis with metastatic melanoma to the brain with at least one measurable brain metastatic lesion by MRI (> 0.5 cm and < 3 cm in longest diameter) that either (1) has not been previously exposed to radiation therapy or (2) a lesion that was previously treated with radiosurgery and has definitively progressed as assessed by neurosurgery and/or radiation oncology may be considered as a target lesion Patient must be asymptomatic or minimally symptomatic BM not requiring steroids Primary Objective: Evaluate the objective response rate of melanoma metastases in the brain (by MRI utilizing modified RECIST 1.1)

17 Phase II trial of pembrolizumab in brain metastases (Cohort A and B) PI: Priscilla Brastianos, MD Massachusetts General Hospital Baseline brain MRI Circulating biomarkers (including CTCs, cell-free DNA) Brain MRI and systemic staging q6wks Circulating biomarkers q3wks Previously untreated CNS metastases (Cohort A) Progressive brain metastases (cohort B) Measurable CNS disease Pembrolizumab 200mg q3 wks CNS or systemic progression Primary endpoint l CNS response rate Secondary endpoints l CNS PFS l Systemic PFS (RECIST and irrc) l ORR (RECIST and irrc) l Safety Exploratory endpoints l Correlation of response with biomarkers l Duration of response l First site of progression l Patient reported outcomes

18 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

19 Rose Ella Burkhardt Brain Tumor and Neuro- Oncology Center Multidisciplinary approach to provide individualized care