Targeted/Immunotherapy & Molecular Profiling – State-of-the-art in Cancer Care

Manmeet Ahluwalia, MD, FACP Miller Family Endowed Chair in Neuro-Oncology Director Brain Metastasis Research Program Cleveland Clinic

1 Outline

• Role of Molecular Profiling in the management of brain metastases • Targeted/Immunotherapy in Management of brain metastases • Management of brain metastases in the coming 3–5 years

2 Epidemiology of brain metastases

Primary tumor Relative prevalence of brain metastases* Colon: 5% Annual US incidence: >170K Ratio mets/primary: 10:1 All cancer patients: 15%–30% Melanoma: 9% Autopsy incidence: 10%–30% Mean age: 60 years Unknown primary: 11% Median survival: 4–6 months

Other known primary: 13%

Breast: 15%

Lung: 48%

*Incidence increasing with better systemic Rx and improved survival Courtesy: John Suh. Wen PY, et al. In: DeVita VT Jr, et al, eds. 3 Cancer: Principles & Practice of Oncology. 2001:2656-2670. Incidence of brain metastasis is increasing

Incidence of brain metastasis is increasing1: • Improvements in imaging (e.g. MRI) • Clinical trial screening • Improvements in systemic cancer control (brain is a sanctuary site)

• Rates of brain metastasis may be influenced by Brain metastases may be changing treatments underdiagnosed • Autopsy results reveal brain – 25% of lung cancer patients have brain metastasis at initial metastases that were not presentation diagnosed clinically2 • Clinical trial screening reveals – 80% of lung cancer patients patients with asymptomatic surviving >2 years will develop brain metastases1

brain metastases 1. Ba JL et al. Oncology 2015; 29: 250-257; 2. Ahluwalia MS, Winkler F. ASCO 2015: MRI, magnetic resonance imaging. http://meetinglibrary.asco.org/content/115000067-156. 4 Brain metastasis treatment: multidisciplinary strategy individualized for the patient1

Goals of treatment: Treatment strategies: Factors used to • Control • Corticosteroids assess therapy: – Macroscopic disease • WBRT • Number of metastases – Microscopic disease • Surgery +/- WBRT • Size of lesion(s) – Systemic disease • Surgery +/- localized radiation • Location • Preserve • WBRT + radiation sensitizers • Neurological deficits – Neurologic function • WBRT + • Age/KPS – Quality of life • SRS +/- WBRT • Primary tumor/stage • Chemotherapy • Extracranial disease • +/- WBRT • Patient’s input • Immunotherapy+/- SRS

KPS, Karnofsky Performance Status; 1. Ahluwalia MS, Winkler F. ASCO 2015: SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy. 5 http://meetinglibrary.asco.org/content/115000067-156. Graded prognostic assessment tool for NSCLC BM

Prognostic Scores for each factor variables 0 1 1.5 Age >60 50–59 <50

Age KPS <70 70–80 90–100

ECM Present – Absent

Number Number of >3 2–3 1 of BM BM Median survival 0–1 = 3 1.5–2 = 5.5 2.5–3 = 9.4 3.5–4 = 14.8 (months) by GPA EM (+/-) KPS

EM, extracranial metastases; Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005; GPA, graded prognostic assessment; NSCLC, non-small-cell lung cancer. 6 Sperduto PW, et al. Int J Radiat Oncol Biol Phys. 2010;77(3):655-661. Impact of EGFR and ALK mutation on the Outcomes of Non-small cell Lung cancer (NSCLC) Patients with Brain Metastases

NSCLC Patient Characteristics Mutation+ (M+) Wild Type (WT) Factors P-value (N=91) (N=257) Age 60.0(29.8,82.6) 60.8(37.3,92.8) 0.059 KPS 0.90

• < 70 9 (10.2) 28 (11.9) • 70-80 35 (39.8) 109 (46.2) • > 80 44 (50.0) 99 (41.9) Brain Mets 2.0(1.00,99.0) 2.0(1.00,99.0) 0.23 • 1 34 (37.4) 118 (46.5) • 2 – 3 24 (26.4) 70 (27.6) • > 3 33 (36.3) 66 (26.0) Symptomatic • Asymptomatic 33 (37.1) 68 (27.6) 0.036 • Symptomatic 56 (62.9) 178 (72.4) Synchronous • No 39 (42.9) 97 (37.7) <0.001 • Yes 52 (57.1) 160 (62.3) Extracranial Metastases (ECM) • No 26 (28.6) 104 (40.6) 0.041 • Yes 65 (71.4) 152 (59.4) 7 Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005 Multivariate analysis – without ECM

Overall survival

Mutation + Wild type HR (95%CI ) P-value HR (95%CI ) P-value Age ( <50 vs 50–60 vs >60) 1.28 (0.88, 1.86) 0.20 1.05 (0.84, 1.33) 0.65 KPS (<70 vs 70–80 vs >80) 0.35 (0.22, 0.55) <0.001 0.70 (0.56, 0.89) 0.004 Brain mets (1 vs 2–3 vs >3) 0.95 (0.69, 1.31) 0.74 1.31 (1.08, 1.59) 0.006 Symptomatic 0.87 (0.48, 1.60) 0.66 0.97 (0.67, 1.40) 0.85 Synchronous 0.69 (0.40, 1.19) 0.18 0.83 (0.60, 1.15) 0.25

8 Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005 Multivariate analysis – including ECM

Overall survival

Mutation+ Wild type HR (95% CI) P-value HR (95% CI) P-value Age ( <50 vs 50–60 vs >60) 1.28 (0.88, 1.88) 0.20 1.06 (0.84, 1.34) 0.62 KPS (<70 vs 70–80 vs >80) 0.35 (0.22, 0.55) <0.001 0.69 (0.54, 0.87) 0.002 Brain mets (1 vs 2–3 vs >3) 0.95 (0.69, 1.31) 0.76 1.20 (0.99, 1.46) 0.063 Symptomatic 0.87 (0.48, 1.60) 0.66 1.09 (0.75, 1.59) 0.65 Synchronous 0.69 (0.40, 1.18) 0.18 0.80 (0.58, 1.11) 0.18 ECM (yes / no) 0.97 (0.54, 1.74) 0.91 1.95 (1.37, 2.77) <0.001

9 Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005 The Effect of Gene Alterations and Inhibition on Survival and Cause of Death in 1521 Patients With Adenocarcinoma of the Lung and Brain Metastases

1.0 ALK positive (n=86, MST=45) EGFR positive (n=235, MST=23) KRAS positive (n=211, MST=12) 0.8 EGFR & ALK neg (n=284, MST=14) Unknown (n=705, MST=12)

0.6

0.4 Proportionsurviving 0.2

0 0 12 24 36 48 60

Months from start of BM treatment

10 Sperduto P et al. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2):406-13. Management of brain metastases in TKI-naïve EGFR mutation- positive NSCLC: retrospective analysis

• 351 EGFR-mutant NSCLC BM from six institutions • SRS followed by EGFR-TKI (n=100) • WBRT followed by EGFR-TKI (n=120) • EGFR-TKI followed by SRS or WBRT at progression (n=131) • OS and IC-PFS were measured from the date of brain metastases

EGFR-TKI, epidermal inhibitor; IC-PFS, intracranial progression-free survival. 11 Magnuson WJ, et al. J Clin Oncol. 2017;35(10):1070-1077. Management of brain metastases in TKI-naïve EGFR mutation- positive NSCLC: overall survival

• The median OS for the SRS, WBRT, and EGFR-TKI cohorts was 46, 30, and 25 months respectively (p<0.001)

12 Magnuson WJ, et al. J Clin Oncol. 2017;35(10):1070-1077. EGFR inhibitors and RT

Number of Intracranial PFS OS Study Design Combination patients (months) (Months)

Welsh, et al. Phase II + WBRT 40 8 11.8

Arm A: WBRT Arm A: 40 1.6 2.9 Lee, et al. Phase II Arm B: WBRT + erlotinib Arm B: 40 1.6 3.4

Arm A: WBRT + SRS Arm A:44 8.1 13.4

RTOG-0320 Phase III Arm B: WBRT + SRS + TMZ Arm B:40 4.6 6.3

Arm C: WBRT +SRS + erlotinib Arm C: 41 4.8 6.1

Zhou, et al. Phase I Icotinib + WBRT 15 18.9 NR

Sperduto PW, et al. Int J Radiat Oncol Biol Phys. 2013;85(5):1312-1318; Welsh JW, et al. J Clin Oncol. 2013;31:895-902; 13 Zhou L, et al. Lung Cancer. 2016;96:93-100. ALK inhibitors and BM

Loco-regional ALK inhibitor Study design Number of patients control (ORR)

Post-hoc analysis 22 18% of PROFILE-1005 and 1007 18 33%

Post-hoc analysis of 98 ( ALK pretreated) 50% ASCEND-1 26 (ALK naïve) 69% Phase I/II study 34 56% Phase II study 13 69%

Costa DB, et al. J Clin Oncol. 2015;33(17):1881-1888. Shaw E, et al. Neuro-Oncology. 2014;16(suppl 5):v39; Gadgeel SM, et al. Lancet Oncol. 2014;15(10):1119-1128; 14 Kerstein D, et al. Ann Oncol. 2015;26(suppl1):i60-i61. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive NSCLC

15 Gadgeel SM, et al. J Clin Oncol. 2016;34(34):4079-4085. Phase II trial of for untreated brain metastases

Key eligibility: • Advanced NSCLC or melanoma • At least one untreated or Brain metastasis Consider radiation or surgery progressive brain metastasis PD to progressing lesions Pembrolizumab 10 5–20 mm mg/kg • No neurologic symptoms or steroid q2w requirement Brain metastasis Continue pembrolizumab • PS 0–1 CR, PR, or SD if systemic control achieved • PD-L1 expression from tumor biopsy after most recent systemic therapy

Safety evaluation at 4 weeks: Primary endpoint: • Brain MRI brain metastasis response rate

Response evaluation every 8 weeks: • Brain MRI Secondary endpoints: • CT chest/abdomen/pelvis 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. 16 Courtesy: Harriet Kluger. Best brain metastasis response by mRECIST

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

17 Courtesy: Sarah Goldberg. CNS response to in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials

• The CNS ORR was 54% (95% CI 39, 68) Patients evaluable for CNS response (n=50)

• Median best percentage change from baseline in CNS ORR*, % 54 (95% CI 39, 68) CNS target lesion size was -53% (range: -100% – +80%) Complete response, n (%) 6 (12) Partial response, n (%) 21 (42)

100 Stable disease ≥6 weeks, n (%) 19 (38) Progressive disease, n (%) 3 (6) 80 Not evaluable, n (%) 1 (2)

60 CNS DCR, % 92 (95% CI 81, 98) 40 CNS response based on prior brain RT status* 20 *

0 Prior RT ≤6 months before first dose, n 19 / 50

-20 CNS ORR, % 32 (95% CI 13, 57) Complete response / partial response, % 11 / 21 -40 Complete response -60 Partial response No prior RT or RT >6 months before first dose, n 31 / 50 Stable response -80 Progressive response CNS ORR, % 68 (95% CI 48, 83) Best change from baseline in target lesion size (%) size lesion target in baseline from changeBest Not evaluable -100 Complete response / partial response, % 13 / 55

Population: evaluable for response. Scans were performed every 6 weeks *represents imputed values Goss G et al. Presented at WCLC 2016 CI, confidence interval J Thorac Oncol 2017; 12(suppl):S440-S441 (abstr MA16.11) 18 PFS benefit in AURA3 patients with CNS metastases at baseline

With CNS metastases Without CNS metastases Median PFS, months (95% CI) Median PFS, months (95% CI) 1.0 Osimertinib (n=93) 8.5 (6.8, 12.3) 1.0 Osimertinib (n=186) 10.8 (8.3, 12.5) Platinum-pemetrexed (n=51) 4.2 (4.1, 5.4) Platinum-pemetrexed (n=89) 5.6 (4.2, 6.8)

0.8 0.8 HR 0.32 HR 0.40 (95% CI 0.21, 0.49) (95% CI 0.29, 0.55)

0.6 0.6 free survival free survival

0.4 0.4 Probability of Probability of progression - progression - 0.2 0.2

0 0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 Months Months No. at risk Osimertinib 93 80 46 27 14 4 0 186 160 116 61 36 9 0 Platinum- 51 32 9 4 2 0 0 89 61 35 13 5 1 0 pemetrexed Papadimitrakopoulou V et al. Presented at WCLC 2016 (J Thorac Oncol 2017; 12(suppl): S5-S6 (abstr PL03.03) Mok TS et al. NEJM 2017; 376:629-640 19 Breast Cancer BM

. 10-30% of breast cancer develop BM

. HER2 positive: 30-55% chance of BM

. HER2 positive: , , , trastuzumab-emtansine (T-DM1),

. Triple negative : 25-45% chance of BM

. Triple negative: may be amenable to targeted therapy PARP inhibitor

Lim E, Lin NU. Oncology (Williston Park).2014 Jul;28(7):572-8.

20 Targeted therapy Before and After WBRT

Lapatinib/capecitabine N Response rate*(%)

Progression after WBRT1 50 20

Before WBRT2 45 66

*≥50% volumetric reduction of CNS lesions

1Lin, Clin Cancer Res, 2009 2Batchelot, Lancet Oncology 2013

21 Ongoing trials in BCBM

Study Design Targeted therapy Local Estimated therapy enrollment

NCT01622868 Phase 2, randomized, Lapatinib WBRT/SRS 143 multicenter

NCT01494662 Phase 2, open label, Neratinib and capecitabine None 105 multicenter

NCT01934894 Phase 2, open label, Cabazitaxel and lapatinib None 11 multicenter

NCT02135159 Phase 1, open label, T-DM1 WBRT 36 single center

NCT02614794 Phase 2, randomized, ONT-380 vs placebo Plus None 180 double blinded, capecitabine and multicenter trastuzumab

NCT01305941 Phase 2, open label, + trastuzumab + None 35 single center vinorelbine

NCT01783756 Phase 1b/2, open label, Lapatinib+ Everolimus + None 47 single center Capecitabine 22 Melanoma BM

. Up to 40% of melanoma pts →BM

. MBM: median survival is 6 months

. CTLA4 MoAb:

. BRAF - : ,

. MEK - : Trematinib,

. Anti PD1: Pembrolizumab,

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

Margolin K. Lancet Oncol. 2012 May;13(5):459-65 24 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 25 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 26 Phase II Trial of Pembrolizumab for Untreated Brain Metastases

Key Eligibility: Consider radiation or •Advanced NSCLC or melanoma Brain surgery to progressing •At least 1 untreated or progressive metastasis lesions brain metastasis 5-20mm PD •No neurologic symptoms or Pembrolizumab steroid requirement 10mg/kg q2 weeks •PS 0-1 Brain

•PD-L1 expression from tumor metastasis Continue pembrolizumab biopsy after most recent systemic CR, PR, or SD if systemic control therapy achieved

Safety evaluation at 4 weeks: •Brain MRI

Response evaluation every 8 weeks: •Brain MRI Primary Endpoint: •CT chest/abdomen/pelvis Brain Metastasis Response Rate

Secondary Endpoints: Overall response rate, safety, PFS, OS

27 Courtesy: Harriet Kluger Safety and activity of Pembrolizumab in melanoma patients with untreated brain metastases

Baseline A B C D After 1 dose, Headaches E F G H Courtesy: Harriet Kluger 28 Future directions: takeaway points

• Control – Macroscopic disease: SRS, WBRT? Number • Targeted/immune therapy (radiation sensitizers?) – Microscopic disease: targeted/immune therapy – Systemic disease: targeted/immune therapy • Preserve – Neurologic function: primary endpoint in clinical trials, appropriate tests, time point • Selection of therapy for BM: multidisciplinary approach • Clinical trials are critical to define care in BM

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