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Targeted Therapies and Immunotherapies
For Brain Metastases
Patrick Y. Wen, M.D.
Center For Neuro-Oncology Dana Farber/Brigham and Women’s Cancer Center
Division of Neuro-Oncology, Department of Neurology Brigham and Women’s Hospital
Harvard Medical School
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DISCLOSURES
Research Support•Agios, Astra Zeneca, Beigene, Eli Lily, Genentech/Roche, Kadmon, Karyopharm, Kazia, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines
Advisory Board•Abbvie, Astra Zeneca, Cortice Bioscience, Eli Lilly, Genentech/Roche, GW Pharmaceuticals, Immunomic Therapeutics, Puma, Vascular Biogenics, Taiho, DecipheraSpeaker•MerckDSMB•Monteris, TocagenEditor•UpToDate, Elsevier
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Outline
• Overview and Challenges• Targeted Therapies
– Melanoma– NSCLC– Breast Cancer
• Immunotherapies– Melanoma– NSCLC
• Future Strategies
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Incidence of Brain Metastases
Glitza Oliva et al. Ann Oncol 2018;29: 1509–1520 Barnholtz-Sloan et al. J. Clin Oncol. 2004;22(14):2865–72 Schouten et al. Cancer. 2002;94(10):2698–705 Chamberalin et al. Neuro-Oncology. 2017;19(1):i1–i24
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Challenges
• Blood-brain barrier
• Genetic Heterogeneity
• Tumor Microenvironment
• Exclusion from Clinical Trials
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Kim et al., Pharm Res 2018;35:177
• Importance controversial• Less intact than GBM• Nonetheless not completely
open• Heterogenous drug
distribution
Blood-Brain Barrier
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2010;16:5664-78
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Lapatinib
Heterogeneity of BBB disruption and lapatinib concentration in mouse model of breast cancer
2 hr
12 hr
Texas Red 3kd dextran 14C-Lapatinib
Taskar et al. Pharm Res. 2012;29(3):770–81
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2015;5:30
Uptake of 11C-Lapatinib
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Genetic Heterogeneity in Brain Metastases
Bergoff and Brastianos Seminar Neurol 2018;35:95-103
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Cancer Discovery 2015
• 53% of brain metastases have genetically distinct molecular drivers compared to primary tumor
• Little intralesional heterogeneity
• Molecular drivers in different metastases in the same patient are relatively similar
• Evidence of upregulation of PI3Kinase and CDK pathways
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Brain-Specific Microenvironment
PTEN loss induced by astrocyte-derived exosomal microRNA primes brain metastasis outgrowth via functional cross-talk between disseminated tumour cells and brain metastatic microenvironment
Zhang et al. Nature 2015; 527(7576): 100–104
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• Pts with treated or stable brain mets• Pts with treated or stable brain mets who are stable for 4 weeks are eligible for all phases of
clinical trials
• Pts with active brain mets• Pts with active brain mets should be considered early in clinical development if there is a strong
scientific rationale for likelihood of benefit based on molecular pathway, histology or preclinical data
• For therapies with less robust preclinical data, inclusion of brain met pts should still be considered esp if BM common in the intended population. Consider brain met specific cohort.
• Leptomeningeal Disease• Inclusion of LMD cohort encouraged in early phase trials if CNS activity expected and when
relevant in specific disease type under study• CSF PK measurement encouraged• Consider LMD cohort in later phase trials
2017
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2018;19:e20
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Targeted Molecular Therapies
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Melanoma
• Columbino et al. J Clin Oncol 2012; 30(20): 2522–2529
• Paired tissue samples from primary tumors and metastases showed an 80% genetic concordance (lower than that between the primary tumor and metastases to the draining lymph node (93%) and visceral organs (96%).
• More MBM than primary tumors harbored BRAF (48% versus 43%) or NRAS (23% versus 15%) mutations.
• Chen et al. Clin Cancer Res 2014;20(21): 5537–5546
• Extracranial metastases and found that all 16 sample pairs were concordant for BRAF and NRAS mutations and other genetic alterations
• Zhang et al. Nature 2015; 527(7576): 100–104
• Loss of PTEN, upregulation of pAKT
Glitza Oliva et al. Ann Oncol 29: 1509–1520, 2018
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Kim et al. Pharm Res 2018;35:177
v v
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Melanoma
Glitza Oliva et al. Ann Oncol 29: 1509–1520, 2018
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• 146 patients were treated• Cohort 1 (untreated)-90• Cohort 2 (previously
treated)-56• Intracranial BORR:
• Cohort 1 by IRC was 18% (2 CRs, 14 PRs)
• Median PFS (brain only, investigator-assessed) was 3.7 months in cohort 1 and 4.0 months in cohort 2
• Median OS was 8.9 months in cohort 1 and 9.6 months in cohort 2
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Melanoma
Glitza Oliva et al. Ann Oncol 29: 1509–1520, 2018
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No previous treatment for BM
Previous treatment for BM
Response rate in BRAFV600K mutations 15%
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• Multicenter, multicohort, open-label phase II study• Dabrafenib 150mg bid and trematinib 2mg qd
• Group A (76pt) : BRAFv600E +ve, asymptomatic melanoma BM, no previous local brain therapy, ECOG 0 or 1
• Overall intracranial response (CR+PR=58%)
• Group B (16 pt): BRAFv600E +ve, asymptomatic melanoma BM, previous local brain therapy, ECOG 0 or 1
• Overall intracranial response (CR+PR=56%)
• Group C (16 pt): BRAFv600D/K/R +ve, asymptomatic melanoma BM, with or without previous brain therapy, ECOG 0 or 1
• Overall intracranial response (CR+PR=44%)
• Group D (17 pt): BRAFv600D/E/K/R +ve, symptomatic melanoma BM, with or without previous brain therapy, ECOG 0,1 or 2
• Overall intracranial response (CR+PR=59%)
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• Intracranial response appears to be shorter than extracranial response • ? Upregulation of PI3K pathway • Potentially combinations of MAPKi and PI3Ki maybe beneficial
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Lung Cancer
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Kim et al. Pharm Res 2018;35:177
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NSCLC (EGFR mutated)
Ulahannan et al. Ann Oncol 28: 2923–2931, 2017
vv
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• Pulsatile erlotinib (1500mg 1x/week)
Grommes et al. Neuro-Oncol 2011;13:1364–1369
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Lancet Resp Med 2017;5:891
AZD3759 (EGFR mutant kinase inhibitor) has high passive permeability and is not a P-gpor BCRP transporter substrate
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Lancet Resp Med 2017;5:891
• 15/18 (83%) BM pts who had not received prior EGFRi had a response
• ¼ LM pts had a response
Pretreated with EGFRi
Not Pretreated with EGFRi
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• Osimertinib is a EGFR-TKI selective for both EGFR-TKI–sensitizing and EGFR T790M–resistance mutations with good BBB penetration.
• Patients with asymptomatic, stable CNS metastases were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed.
• Preplanned sub-group analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review.
• Primary objective for this analysis was CNS objective response rate (ORR).
• Of 116/419 patients had CNS lesions, including 46 patients with measurable CNS lesions.
2018;36:2702-2709
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• Pt with measurable lesions:
• CNS ORR was:
• 70% with osimertinib
• 31% with platinum-pemetrexed
• (odds ratio, 5.13; 95% CI, 1.44 to 20.64; P = .015)
2018;36:2702-2709
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• Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was:– 8.9 months for osimertinib– 5.7 months for platinum-pemetrexed
• Median CNS progression-free survival was:– 11.7 months for osimertinib– 5.6 months for platinum-premetrexed (HR, 0.32; 95% CI, 0.15 to 0.69; P = .004)
2018;36:2702-2709
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2018 (epub)
• 556 pts randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib)
• Patients with asymptomatic or stable CNS metastases were included.
• Preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or non-measurable CNS lesions (IRR)
• 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions
• 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with > one measurable CNS lesion.
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2018 (epub)
• CNS ORR were 91% with osimertinib and 68%with EGFR-TKI in patients with > one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066)
• CNS ORR was 66% for osimertinib and 43% for EGFR-TKI in patients with measurable and/or nonmeasurable CNS lesions (OR, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively.
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2018 (epub)
• Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (HR, 0.48; 95% CI, 0.26 to 0.86; P = .014.
• Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs.
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Lancet Resp Med 2017
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Median OS:- SRS = 46 mo - WBRT = 30 mo- EGFR-TKI = 25 mo
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NSCLC (ALK+)
Ulahannan et al. Ann Oncol 28: 2923–2931, 2017
Intracranial Resonse RatesAlectinib: 81%Ceritinib: 73%Crizotinib: 50-57%Brigatinib: 53%Lorlatinib: 44%
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LC, leptomeningeal carcinomatosis.
N~125
▪ Prior RT to brain ▪ Prior ALK inhibitor ▪ No evidence of LC
Arm 1 (N ~30)
▪ No prior RT to brain ▪ Prior ALK inhibitor ▪ No evidence of LC
Arm 2 (N ~30)
▪ No prior RT to brain ▪ No prior ALK inhibitor ▪ No evidence of LC
Arm 4 (N ~30)
▪ LC with or without active metastasesArm 5
(N ~5)
Ceritinib 750 m
g QD
28-day cycles
▪ Prior RT to brain ▪ No prior ALK inhibitor ▪ No evidence of LC
Arm 3 (N ~30)
Gadolinium-enhanced Brain MRI
ALK+ NSCLC •Aged ≥18 years •Locally advanced or metastatic disease •Confirmed ALK+ by FISH •Active (measurable or non-measurable) metastases to the brain and/or leptomeningeal carcinomatosis
ASCEND-7 Phase 2 Study in Patients with NSCLC Brain Metastases: CLDK378A2205
ENROLLING
Clinicaltrials.gov identifier: NCT02336451
• Primary endpoint Whole body ORR • Secondary endpoints Whole body Disease Control Rate (DCR), intracranial ORR, DCR, Time To
Response, and Duration Of Response; Whole body TTR, Duration Of Response, and PFS; OS, safety, PK
Clinical Trial Protocol CLDK378A2205. EUDRACT 2014-000578-20; 29 Jul 2014.41
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2017;377:829-38
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Breast Cancer
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v v
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Kim et al. Pharm Res 2018;35:177
v vv
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Biodistribution of 89Zr-trastuzumab and PET Imaging of HER-2-Positive Lesions in Patients With Metastatic Breast Cancer
Dijkers, et al Clin Pharmacol & Ther 2010
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Lin et al (ASCO 2017, Abstr 2074 ): PATRICIA TRIAL
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Trastuzumab-Emtansine (TDM1)
• Bartsch et al (Clin Exp Metastasis 2015)
– 10 pt; 3PR (30%), 2SD > 6 mo
– Median intracranial PFS 5 mo
• Jacot et al (Breast Ca Res Treat 2016)
– Retrospective review of 39 pt (CNS ORR 44%)
– Median PFS 6.1 mo
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Lapatinib For Brain Metastases
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Lapatinib and Capecitabine For Brain Metastases
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Neratinib
• Oral, irreversible-binding inhibitor of the erbB TKI• Single agent activity in brain metastases: ORR 8% in patients pretreated
with WBRT or SRS (Freedman et al, J Clin Oncol 2016)• Neratinib + capecitabine (Friedman et al (ASCO 2017): CNS ORR 49%
% reduction in volume of CNS lesion
• Median time to CNS progression = 5.5 mo
• 6M-PFS= 38%
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• Tucatinib (ONT-380), HER2 inhibitor with good BBB penetration • 12 patients treated at the recommended phase 2 dose had measurable brain
mets• 5 (42%) of these patients achieved brain-specific objective response
2018;4(9):1214-1220
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• MTD 300mg bid• 50 pt with brain met
– Median PFS was 6.7 months (95% CI, 4.1-10.2 months)
• 14/30 pt with measurable brain met– Brain-specific objective response rate was 36% (2 CR, 3 PR, 7 SD, and 2
nonevaluable).
Lancet Oncol 2018
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Ongoing HER2 TKI Trials
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AO71701 (Brastianos et al)
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Immunotherapy
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Immune Checkpoint Blockade
Postow et al. J Clin Oncol 33:1974, 2015
Cytotoxic T Lymphocyte Antigen – 4 (CTLA-4)
Programmed Death – 1 (PD-1/PD-L1)
Initial T cell activation
Later/after T cell activation
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59
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Kaplan–Meier Estimates of Survival.
Wolchok JD et al. N Engl J Med 2017;377:1345-1356
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Glitza Oliva et al. Ann Oncol 29: 1509–1520, 2018
Melanoma BM immunotherapy trials
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2012;13:459
• 72 patients with melanoma and brain metastases enrolled into 2 cohorts:
– Cohort A (51 pt) were neurologically asymptomatic and not receiving corticosteroid treatment at study entry
– Cohort B (21 pt) were symptomatic and on a stable dose of corticosteroids.
• Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks.
• Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every12 weeks
• Primary endpoint was the proportion of patients with disease control, defined as CR, PR or SD after 12 weeks
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Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial
Margolin K. Lancet Oncol. 2012 May;13(5):459-65
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Disease control 12/51 in cohort A (24%) 2/21 cohort B (10%)
Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial
Margolin K. Lancet Oncol. 2012 May;13(5):459-65
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2016;17:976
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Goldberg Lancet Oncol 2016
Generally well-tolerated
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Goldberg Lancet Oncol 2016
Response was achieved in:
•4 (22%) of 18 patients with melanoma
•6 (33%) of 18 patients with NSCLC
•Responses were durable
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Courtesy: Sarah Goldberg.
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• 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/kg Q3W × 4
+ IPI
3 mg/kgQ3W × 4
NIVO 3 mg/kg
Q2W (up to 2 years)
Treat until progression or unacceptable
toxicity
Induction Maintenance
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Allowed: •≥1 measurable, unirradiated MBM (0.5-3.0 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 •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 2017
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2018;379:722-730
• Open label single arm phase II study (94 pts)
• At least one measurable, non-radiated BM, no neurologic symptoms
• 26% CR, 30% PR, SD for at least 6 months 2%
• 57% intracranial benefit
• Extracranial clinical benefit 56%
• 55% Gr ¾ adverse events; 7% CNS
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Tawbi et al. NEJM 2018;379:722-730
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Lancet Oncol 2018
• Asymptomatic brain metastases with no previous local brain therapy were randomly assigned to:
• Cohort A (nivolumab plus ipilimumab)
• Cohort B (nivolumab)
• Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease
• Cohort C : (nivolumab)
• Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks
• Patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks.
• Primary endpoint was intracranial response from week 12
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Lancet Oncol 2018
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Lancet Oncol 2018
Treatment-related grade 3/4 AEs occurred in 54% (combination) and 15% (nivolumab) of patients, and 26% and 5% of patients, respectively, discontinued due to an AE.
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Summary of Results of Immune Checkpoint Blockade for Melanoma
Checkpoint inhibitor ORR
Ipilimumab 16% (Margolin, Lancet Oncol 2012)
Pembrolizumab 22% (Goldberg, Lancet Oncol 2016)
Nivolumab 20% (Long; Lancet Oncol 2018)
Nivolumab + Ipilimumab 56% (Tawbi; NEJM 2018)46-56% (Long; Lancet Oncol 2018)
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2018
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Future Studies
• Combination of TKI + immunotherapy• Atezolizumab combined with cobimetinib and vemurafenib• Ipilimumab with or without dabrafenib, trametinib, and/or nivolumab• Pembrolizumab plus dabrafenib and trametinib• Nivolumab in combination with dabrafenib and/or trametinib
• Immunotherapy + RT
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Selected Ongoing Immunotherapy Trials in Brain Metastases
Lauko et al. Curr Neurol Neuroscience Rep 2018;18:70
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Radiotherapy + PD1 Blockade
Vanpouille-Box et al. CCR 2017
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Radiation and Immunotherapy
• RT can augment the immune response through a variety of mechanisms
– RT can cause inflammatory cell death, priming the immune system to tumor derived antigens, converting tumor into an in situ vaccine
– RT can modulate tumor vasculature and enhance T-cell extravasation, increasing the number of tumor infiltrating lymphocytes
– RT improves recognition and killing of tumor cells by CD8+ cytotoxic T cells by increasing in a dose dependent manner the number of MHC molecules on tumor cell surface, by upregulating death receptors, and promoting exposure of NK cell-activating ligands
Sahebjam J Neuro-Ocol 2017;134:531 Vanpouille-Box CCR 2017
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Maude et al. Blood 2015 Maus and June CCR 2016
FDA Approved of tisagenlecleucel-T (Kymriah) for leukemia and axicabtagene ciloleucel (Yescarta ) for lymphoma in 2017
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Abramson et al. NEJM 2017;377;8
DLBCL refractory to multiple therapies showing response to CD19 CAR-T-Cell therapy
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2017
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• CDK4/6 inhibitors stimulates production of type III interferons and hence enhances tumour antigen presentation
• CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells
• Synergy with PD1 inhibitors
Nature 2017
Example of immunotherapy using combination of targeted molecular agent and PD1 antibody
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85
CombinationofCDK4/6iandPD1blockade
CT26modelGoelandDeCristoetal,Nature2017
Combination of CDK4/6 inhibitor abemaciclib and PD1 antibody produces complete tumor regression
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• Synergistic antitumor activity with PD1 blockade for breast cancer brain metastases
Targeting CDK4/6 potentially integrates targeted molecular therapy and immunotherapy
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Summary
• Growing evidence of therapeutic benefit of targeted therapies and immunotherapies for brain metastases, especially for melanoma. EGFR mutated NSCLC, and HER2+ breast cancer
• Optimal combinations of targeted agents and immunotherapies, and with RT remained to be defined
• Need for more randomized trials focused on brain metastases
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Thank You!
Funding: NIH/NCI P50 CA165962, R01CA129371, U01 CA137433, RO1FD004400, Ivy Consortium for Early Phase Trials for Glioblastomas, NBTS, ABC2
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2016;34:4079-4085
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2016;34:4079-4085