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 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 3 Courtesy: John Suh. Wen PY, et al. In: DeVita VT Jr, et al, eds. Cancer: Principles & Practice of Oncology. 2001:2656-2670.
Incidence of brain metastasis is increasing Incidence of brain metastasis is increasing 1 : 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 changing treatments 25% of lung cancer patients have brain metastasis at initial presentation 80% of lung cancer patients surviving >2 years will develop brain metastases MRI, magnetic resonance imaging. 4 Brain metastases may be underdiagnosed Autopsy results reveal brain metastases that were not diagnosed clinically 2 Clinical trial screening reveals patients with asymptomatic brain metastases 1 1. Ba JL et al. Oncology 2015; 29: 250-257; 2. Ahluwalia MS, Winkler F. ASCO 2015: http://meetinglibrary.asco.org/content/115000067-156.
Brain metastasis treatment: multidisciplinary strategy individualized for the patient 1 Goals of treatment: Control Macroscopic disease Microscopic disease Systemic disease Preserve Neurologic function Quality of life Treatment strategies: Corticosteroids WBRT Surgery +/- WBRT Surgery +/- localized radiation WBRT + radiation sensitizers WBRT + chemotherapy SRS +/- WBRT Chemotherapy Targeted therapy +/- WBRT Immunotherapy+/- SRS Factors used to assess therapy: Number of metastases Size of lesion(s) Location Neurological deficits Age/KPS Primary tumor/stage Extracranial disease Patient s input KPS, Karnofsky Performance Status; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy. 5 1. Ahluwalia MS, Winkler F. ASCO 2015: http://meetinglibrary.asco.org/content/115000067-156.
Graded prognostic assessment tool for NSCLC BM Prognostic variables Scores for each factor 0 1 1.5 Age Age >60 50 59 <50 KPS <70 70 80 90 100 ECM Present Absent Number of BM Number of BM >3 2 3 1 EM (+/-) KPS Median survival (months) by GPA 0 1 = 3 1.5 2 = 5.5 2.5 3 = 9.4 3.5 4 = 14.8 EM, extracranial metastases; GPA, graded prognostic assessment; NSCLC, non-small-cell lung cancer. 6 Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005; 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 Factors Mutation+ (M+) Wild Type (WT) (N=91) (N=257) P-value 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 Mutation + HR (95%CI ) Overall survival P-value Wild type HR (95%CI ) 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 P-value 8 Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005
Multivariate analysis including ECM Mutation+ HR (95% CI) Overall survival P-value Wild type HR (95% CI) 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 P-value 9 Balasubramanian SK et al. J Clin Oncol 2016; 34 (suppl): abstr 2005
The Effect of Gene Alterations and Tyrosine Kinase Inhibition on Survival and Cause of Death in 1521 Patients With Adenocarcinoma of the Lung and Brain Metastases Proportion surviving 1.0 0.8 0.6 0.4 ALK positive (n=86, MST=45) EGFR positive (n=235, MST=23) KRAS positive (n=211, MST=12) EGFR & ALK neg (n=284, MST=14) Unknown (n=705, MST=12) 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 mutationpositive 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 growth factor receptor tyrosine kinase 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 mutationpositive 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 Study Design Combination Number of patients Intracranial PFS (months) OS (Months) Welsh, et al. Phase II Erlotinib + WBRT 40 8 11.8 Lee, et al. Phase II Arm A: WBRT Arm A: 40 1.6 2.9 Arm B: WBRT + erlotinib Arm B: 40 1.6 3.4 RTOG-0320 Phase III Arm A: WBRT + SRS Arm A:44 8.1 13.4 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 13 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; Zhou L, et al. Lung Cancer. 2016;96:93-100.
ALK inhibitors and BM ALK inhibitor Study design Number of patients Crizotinib Ceritinib Post-hoc analysis of PROFILE-1005 and 1007 Post-hoc analysis of ASCEND-1 Loco-regional control (ORR) 22 18% 18 33% 98 ( ALK pretreated) 50% 26 (ALK naïve) 69% Alectinib Phase I/II study 34 56% Brigatinib Phase II study 13 69% 14 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; 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 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. 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 osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials The CNS ORR was 54% (95% CI 39, 68) Median best percentage change from baseline in CNS target lesion size was -53% (range: -100% +80%) 80 60 40 20 0-20 -40-60 -80-100 Best change from baseline in target lesion size (%) 100 * Complete response Partial response Stable response Progressive response Not evaluable Patients evaluable for CNS response (n=50) CNS ORR*, % Complete response, n (%) Partial response, n (%) Stable disease 6 weeks, n (%) Progressive disease, n (%) Not evaluable, n (%) 54 (95% CI 39, 68) 6 (12) 21 (42) 19 (38) 3 (6) 1 (2) CNS DCR, % 92 (95% CI 81, 98) CNS response based on prior brain RT status* Prior RT 6 months before first dose, n 19 / 50 CNS ORR, % Complete response / partial response, % 32 (95% CI 13, 57) 11 / 21 No prior RT or RT >6 months before first dose, n 31 / 50 CNS ORR, % Complete response / partial response, % 68 (95% CI 48, 83) 13 / 55 Population: evaluable for response. Scans were performed every 6 weeks *represents imputed values CI, confidence interval 18 Goss G et al. Presented at WCLC 2016 J Thorac Oncol 2017; 12(suppl):S440-S441 (abstr MA16.11)
PFS benefit in AURA3 patients with CNS metastases at baseline With CNS metastases Without CNS metastases 1.0 Median PFS, months (95% CI) Osimertinib (n=93) 8.5 (6.8, 12.3) Platinum-pemetrexed (n=51) 4.2 (4.1, 5.4) 1.0 Median PFS, months (95% CI) Osimertinib (n=186) 10.8 (8.3, 12.5) Platinum-pemetrexed (n=89) 5.6 (4.2, 6.8) Probability of progression-free survival 0.8 0.6 0.4 0.2 HR 0.32 (95% CI 0.21, 0.49) Probability of progression-free survival 0.8 0.6 0.4 0.2 HR 0.40 (95% CI 0.29, 0.55) No. at risk Osimertinib Platinumpemetrexed 0 0 3 6 9 12 15 18 Months 93 51 80 32 46 9 27 4 14 2 4 0 0 0 19 0 0 3 6 9 12 15 18 Months 186 89 160 61 116 35 61 13 36 5 9 1 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 0 0
Breast Cancer BM 10-30% of breast cancer develop BM HER2 positive: 30-55% chance of BM HER2 positive: Trastuzumab, Lapatinib, Neratinib, trastuzumab-emtansine (T-DM1), pertuzumab 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 WBRT 1 50 20 Before WBRT 2 45 66 * 50% volumetric reduction of CNS lesions 1 Lin, Clin Cancer Res, 2009 2 Batchelot, Lancet Oncology 2013 21
Ongoing trials in BCBM Study Design Targeted therapy Local therapy Estimated enrollment NCT01622868 NCT01494662 NCT01934894 NCT02135159 Phase 2, randomized, multicenter Phase 2, open label, multicenter Phase 2, open label, multicenter Phase 1, open label, single center Lapatinib WBRT/SRS 143 Neratinib and capecitabine None 105 Cabazitaxel and lapatinib None 11 T-DM1 WBRT 36 NCT02614794 Phase 2, randomized, double blinded, multicenter ONT-380 vs placebo Plus capecitabine and trastuzumab None 180 NCT01305941 Phase 2, open label, single center Everolimus+ trastuzumab + vinorelbine None 35 NCT01783756 Phase 1b/2, open label, single center Lapatinib+ Everolimus + Capecitabine None 47 22
Melanoma BM Up to 40% of melanoma pts BM MBM: median survival is 6 months CTLA4 MoAb: Ipilimumab BRAF - : Vemurafenib, Dabrafenib MEK - : Trematinib, Cobimetinib Anti PD1: Pembrolizumab, Nivolumab 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: Advanced NSCLC or melanoma At least 1 untreated or progressive brain metastasis 5-20mm No neurologic symptoms or steroid requirement PS 0-1 PD-L1 expression from tumor biopsy after most recent systemic therapy Pembrolizumab 10mg/kg q2 weeks 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 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 Courtesy: Harriet Kluger 28 G H
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 29