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Targeted/Immunotherapy & Molecular Profiling – State-Of-The-Art in Cancer 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 + chemotherapy • Age/KPS – Quality of life • SRS +/- WBRT • Primary tumor/stage • Chemotherapy • Extracranial disease • Targeted therapy +/- 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 Tyrosine Kinase 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 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 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 Erlotinib + 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% Crizotinib of PROFILE-1005 and 1007 18 33% Post-hoc analysis of 98 ( ALK pretreated) 50% Ceritinib ASCEND-1 26 (ALK naïve) 69% Alectinib Phase I/II study 34 56% Brigatinib 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 pembrolizumab 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 osimertinib 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 Best change Not evaluable -100 Complete response / partial response, % 13 / 55 Population: evaluable for response.
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