scholarly journals ACTR-10. PHASE 0 TRIAL OF CERITINIB IN BRAIN METASTASES AND RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi14-vi14
Author(s):  
Roberto Fiorelli ◽  
Jing Li ◽  
Xun Bao ◽  
Alanna DeRogatis ◽  
Chelsea Pennington-Krygier ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Tissue ◽  
Tumor Resection ◽  
Immunohistochemical Analysis ◽  
Recurrent Glioblastoma ◽  
Drug Binding ◽  
Drug Concentrations ◽  
Orally Bioavailable ◽  
Cns Penetration

Abstract BACKGROUND Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical reports suggest ceritinib activity in central nervous system (CNS) malignancies, yet there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in brain metastases and recurrent glioblastoma patients. METHODS Ten patients with brain metastases (n=3) or glioblastoma (n=7) exhibiting high expression of pSTAT5b/pFAK/pIGFR1 were treated with 10 days of oral ceritinib (750 mg daily) prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues. RESULTS Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one brain metastasis patient, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor and CSF concentration as compared to all other patients. In all patients, no pharmacodynamic response was detected in sampled tumor tissue. CONCLUSION Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations in brain metastasis and glioblastoma appear insufficient for target modulation. Despite recent reports of clinical response, our findings suggest no role for ceritinib in treating glioblastoma and an unfavorable profile for brain metastases.

scholarly journals OS4.2 Phase 0 trial of Ceritinib in brain metastasis and recurrent glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii10-iii10
Author(s):  
R Fiorelli ◽  
J Li ◽  
X Bao ◽  
A DeRogatis ◽  
C Pennington-Krygier ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Tumor Resection ◽  
Immunohistochemical Analysis ◽  
Recurrent Glioblastoma ◽  
Drug Binding ◽  
Drug Concentrations ◽  
Molecule Inhibitor ◽  
Tumor Tissues ◽  
Orally Bioavailable ◽  
Cns Penetration

Abstract BACKGROUND Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical data suggest that ceritinib has activity in central nervous system (CNS) malignancies, but to date there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in recurrent glioblastoma and brain metastasis patients. MATERIALS AND METHODS Three brain metastasis and seven glioblastoma patients with high expression of pSTAT5b/pFAK/pIGFR1 were enrolled and treated with oral ceritinib daily (750 mg) for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues. RESULTS Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one patient with brain metastasis, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor concentration and CSF concentration as compared to those in glioblastoma patients. In all patients, no changes in PD markers were detected. CONCLUSION Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastasis and glioblastoma are unlikely sufficient for target modulation.

Gamma Knife surgery for multiple brain metastases from a malignant schwannoma of the penis

2006 ◽  
Vol 105 (Supplement) ◽  
pp. 238-240 ◽  
Author(s):  
Albertus T. C. J. van Eck ◽  
Gerhard A. Horstmann
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Gamma Knife ◽  
De Novo ◽  
Tumor Resection ◽  
Gamma Knife Surgery ◽  
Malignant Schwannoma ◽  
Efficacy And Safety ◽  
Single Brain Metastasis ◽  
Therapy Option

✓The occurrence of brain metastases from a malignant schwannoma of the penis is extremely rare. In patients with a single brain metastasis, microsurgical extirpation is the treatment of choice and verifies the diagnosis. In cases of multiple or recurrent metastases, radiosurgery is an effective and safe therapy option. Gamma Knife surgery was performed in a patient who had previously undergone tumor resection and who presented with recurrence of the lesion and three de novo brain metastases. This first report on brain metastasis from a malignant penile schwannoma illustrates the efficacy and safety of radiosurgical treatment for these tumors.

scholarly journals MNGI-01. A PHASE 0 TRIAL OF RIBOCICLIB IN AGGRESSIVE MENINGIOMA PATIENTS INCORPORATING A TUMOR PHARMACODYNAMIC- AND PHARMACOKINETIC-GUIDED EXPANSION COHORT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi139-vi139
Author(s):  
An-Chi Tien ◽  
Jing Li ◽  
Xun Bao ◽  
Alanna DeRogatis ◽  
Yoko Fujita ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Tumor Tissue ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Who Grade ◽  
Drug Concentrations ◽  
Grade Ii ◽  
Expansion Cohort ◽  
Pharmacologically Active

Abstract BACKGROUND New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. METHODS Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an expansion cohort for preliminary assessment of progression-free survival. RESULTS The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At 14 months, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. CONCLUSION Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

scholarly journals OS8.1 A phase 0/2 clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii15-iii16
Author(s):  
A Tien ◽  
J Li ◽  
X Bao ◽  
A DeRogatis ◽  
Y Fujita ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Tumor Tissue ◽  
Tumor Resection ◽  
Who Grade ◽  
Forkhead Box M1 ◽  
Drug Concentrations ◽  
Grade Ii ◽  
Rb Phosphorylation ◽  
Pharmacologically Active

Abstract BACKGROUND New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. MATERIAL AND METHODS Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory Phase 2 cohort. RESULTS The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. CONCLUSION Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

CTNI-48. A PHASE 0 ‘TRIGGER’ TRIAL OF CDK4/6 PLUS ERK1/2 INHIBITORS IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi71
Author(s):  
Nader Sanai ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
Anita DeSantis ◽  
Mackenna Elliott ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Drug Dose ◽  
Recurrent Glioblastoma ◽  
Optimal Time ◽  
Time Interval ◽  
Tumor Proliferation ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Recurrent Gbm ◽  
Dual Drug

Abstract BACKGROUND This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. METHODS Adult recurrent GBM patients (n=10) with intact RB expression, > 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. RESULTS No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. CONCLUSION Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.

Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2012-2012 ◽  
Author(s):  
Timothy Francis Cloughesy ◽  
Paul S. Mischel ◽  
Antonio Marcilio Padula Omuro ◽  
Michael Prados ◽  
Patrick Y. Wen ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Tumor Resection ◽  
Recurrent Glioblastoma ◽  
Pi3k Inhibitor ◽  
Post Dose ◽  
Inhibition Of Proliferation ◽  
Tumor Sample ◽  
Ffpe Tumor ◽  
Pathway Inhibition ◽  
Early Phase Clinical Trials

2012 Background: XL765 is a potent pan PI3K inhibitor with activity against mTOR and XL147 is a potent pan-PI3K inhibitor. Inhibition of the PI3K/mTOR pathway may be beneficial in the treatment of GBM. Methods: Patients with GBM who were candidates for a surgical resection were eligible for this exploratory study. Cohorts of 6-10 patients were treated with one of three regimens: Cohort 1: XL765 50mg twice daily (BID), Cohort 2: XL147 200mg once daily (QD), Cohort 3: XL765 90mg QD for >10 days prior to undergoing tumor resection. Tumor tissue was obtained at ~12, 24 and 3 hours after the last dose, respectively. Frozen tumor tissue and blood were analyzed for drug concentration (PK) and pathway modulation was analyzed in post-dose frozen tumor tissue and compared to reference tumor samples from GBM patients not treated with XL765 or XL147. Pharmacodynamic impact (PD) on the pathway, apoptosis and proliferation was examined by immunohistochemistry (IHC) in an FFPE tumor sample from each patient and compared to an archived tumor sample from an earlier surgery. Results: Enrollment is complete with 21 patients enrolled; 6, 6 and 7 were evaluable for the PK/PD analysis in cohorts 1, 2 and 3, respectively. The toxicity profiles for both drugs were consistent with previous studies. PK analyses revealed a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2. PD analysis by IHC revealed reduction compared to archived tumor in pS6K1 in 4/6 and 7/7 patients in cohorts 1 and 3 and 6/6 patients in cohort 2. Reduction in Ki67 was observed in 6/6 and 5/7 patients in cohorts 1 and 3 and 4/6 patients in cohort 2. Conclusions: XL765 when given on a QD or BID schedule to patients with glioma yields moderately higher distribution of XL765 into CNS tumor compared to XL147 based on tumor to plasma ratios. Decreases in pS6K1, consistent with pathway inhibition, and decreases in Ki67, consistent with inhibition of proliferation, were observed following treatment with both XL147 and XL765. Clinical trial information: NCT01240460.

scholarly journals RADI-11. Evaluating the Tissue Effects of Dose-escalated Pre-operative Stereotactic Radiotherapy for Resectable Brain Metastasis

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii20-iii20
Author(s):  
Rupesh Kotecha ◽  
Raees Tonse ◽  
Miguel A Ramirez Menendez ◽  
Andre Williams ◽  
Zuanel Diaz ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Stereotactic Radiotherapy ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Biological Effects ◽  
Immunohistochemical Analysis ◽  
Time Interval ◽  
Primary Tumors ◽  
Paired Difference

Abstract Background Although the classic radiobiologic principles of radiotherapy are well understood, the unique effects of the large fractional does that characterize stereotactic radiotherapy (SRT), specifically in terms of antitumor immune cellular processes, vascular damage, tumor necrosis, and apoptosis on brain metastasis have yet to be adequately demonstrated. The objective of this study is to provide the first in-human evaluation of the biological effects of SRT in resected brain metastasis. Methods All paired primary tumors and metastases for patients who underwent dose-escalated preoperative SRT followed by resection were evaluated for tumor necrosis using hematoxylin-eosin staining. T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), vessel density (CD31+), and apoptotic factors (caspase-3) were determined by immunohistochemical analysis. Results Fifteen patients with brain metastases from solid tumors received a median preoperative SRT dose of 18 Gy (range: 15–18 Gy) in 1 fraction, with 2 patients receiving 27–30 Gy in 3–5 fractions, followed by resection within a median interval of 90 hours (Range: 17.1–260 hours). The rate of necrosis was found to be significantly higher in irradiated brain metastases than in non-irradiated primary tumor samples (mean paired difference: 30.47, SD: 29.28, p=0.001). A decrease in all immunomodulatory cell populations was found in irradiated metastasis: CD3 (mean paired difference -19.4, SD: 31.7, p=0.03), CD4 (-10.0, SD: 20, p=0.01), and CD8 (-17.4, SD: 22.1, p=0.008). While irradiated samples had numerically lower CD 31+, CD 56+, and caspase-3 scores, the difference was not statistically significant. Time interval from SRT to surgery had no effect on these parameters. Conclusions There is complex interplay between tumor-associated cells and the unique radiobiological effects of SRT on tumor tissue. Although time interval from SRT to surgery was associated with increased tumor necrosis, differences in immunomodulatory factors may be multifactorial, including concurrent corticosteroids or the immunosuppressive effect of SRT.

Tumor recurrence and survival following gamma knife surgery for brain metastases

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 287-288 ◽  
Author(s):  
Thomas Mindermann
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Gamma Knife ◽  
Tumor Recurrence ◽  
Patient Survival ◽  
Gamma Knife Surgery ◽  
Recurrence Rates ◽  
Term Survival ◽  
Content Type ◽  
Fine Print

Object. The authors evaluated prognostic factors for tumor recurrence and patient survival following gamma knife surgery (GKS) for brain metastasis. Methods. A retrospective review of 101 patient charts was undertaken for those patients treated with GKS for brain metastases from 1994 to 2001. Recurrence rates of brain metastasis following GKS depended on the duration of patient survival. Long-term survival was associated with a higher risk of tumor recurrence and shorter-term survival was associated with a lower risk. The duration of survival following GKS for brain metastases seems to be characteristic of the primary disease rather than the cerebral disease. Conclusions. Recurrence rates of brain metastasis following GKS are related to duration of survival, which is in turn mostly dependent on the nature and course of the primary tumor.

STEROID RECEPTOR PHENOTYPE, EXPRESSION OF HER-2/NEU, PD-1, PD-L1 AND LYMPHOCYTIC-MACROPHAGAL INFILTRATION OF ENDOMETRIAL CARCINOMAS: COMPARISON OF MODERN MOLECULAR BIOLOGICAL TYPES OF THE DISEASE (THE ROLE OF BODY MASS INDEX)

2020 ◽  
Vol 66 (1) ◽  
pp. 71-78
Author(s):  
Lev Bershteyn ◽  
Aleksandr Ivantsov ◽  
Aglaya Ievleva ◽  
A. Venina ◽  
I. Berlev
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Tumor Tissue ◽  
Immunohistochemical Analysis ◽  
The Body ◽  
Molecular Profile ◽  
Total N ◽  
Number Of Patients ◽  
Her 2

The aim of this study was to evaluate steroid receptors’ status of tumor tissue in different molecular biological types of endometrial cancer (EC), subdivided according to the current classification, and their colonization by lymphocytic and macrophage cells, taking into account body mass index of the patients. Materials and methods: Material from treatment-naive patients with EC (total n = 229) was included; the number of sick persons varied depending on the method used. The average age of patients was close to 60 years, and about 90% of them were postmenopausal. It was possible to divide the results of the work into two main subgroups: a) depending on the molecular biological type of the tumor (determined on the basis of genetic and immunohistochemical analysis), and b) depending on the value of the body mass index (BMI). The latter approach was used in patients with EC type demonstrating a defective mismatch repair of the incorrectly paired nucleotides (MMR-D) and with a type without characteristic molecular profile signs (WCMP), but was not applied (due to the smaller number of patients) in EC types with a POLE gene mutation or with expression of the oncoprotein p53. According to the data obtained, when comparing various types of EC, the lowest values of Allred ER and PR scores were revealed for POLE-mutant and p53 types, while the “triple-negative” variant of the tumor (ER-, PR-, HER2/neu-) was most common in POLE-mutant (45.5% of cases) and WCMP (19.4%) types of EC. The p53+ type of EC is characterized by inclination to the higher expression of the macrophage marker CD68 and lymphocytic Foxp3, as well as mRNA of PD-1 and SALL4. In addition to the said above, for WCMP type of EC is peculiar, on the contrary, a decrease in the expression of lymphocytic markers CD8 (protein) and PD-L1 (mRNA). When assessing the role of BMI, its value of >30.0 (characteristic for obesity) was combined with an inclination to the increase of HER-2/neu expression in the case of MMR-D EC type and to the decrease of HER-2 /neu, FOXp3 and ER expression in WCMP type. Conclusions: The accumulated information (mainly describing here hormonal sensitivity of the tumor tissue and its lymphocytic-macrophage infiltration) additionally confirms our earlier expressed opinion that the differences between women with EC are determined by both the affiliation of the neoplasm to one or another molecular biological type (subdivided according to the contemporary classification), as well as by body mass value and (very likely) the associated hormonal and metabolic attributes.

196 Checkpoint blockade therapy for brain-metastatic non-small cell lung cancer: a comparative effectiveness analysis of national data

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A211-A211
Author(s):  
Nayan Lamba ◽  
Bryan Iorgulescu
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Second Line ◽  
Newly Diagnosed ◽  
Small Cell Lung ◽  
Survival Analyses ◽  
Stage 4 ◽  
Insured Patients

BackgroundManagement of advanced non-small cell lung carcinoma (NSCLC) has been transformed by PD-1/PD-L1 immune checkpoint inhibitors (ICI), with FDA approvals in 2015 (second-line) and 2016 (first-line). Despite ~40% of NSCLC patients developing brain metastases, these patients were disproportionately excluded from the pioneering ICI trials. Thus herein we evaluate the overall survival (OS) associated with ICI in NSCLC brain metastases nationally.MethodsPatients newly-diagnosed with stage 4 NSCLC, including brain metastases, from 2010–2016 were identified from the National Cancer Database (comprising >70% of all newly-diagnosed cancers in the U.S.) Landmark survival analysis was used to address immortal time bias. Post-approval, median time from diagnosis to ICI was 58 days, and this timepoint was selected for all landmark survival analyses (OS estimated by Kaplan-Meier technique, and compared by logrank test and multivariable Cox regression) and for multivariable logistic regression to identify predictors of ICI utilization.Results50,858 patients presented with advanced NSCLC that involved the brain: representing 27.6% of all newly-diagnosed stage 4 cases. Following initial FDA approvals in 2015, ICI use in brain metastasis patients rose from 7.2% in 2015 to 12.7% in 2016. OS for NSCLC brain metastasis patients diagnosed post-approval (i.e. 2015, median 6.3 months, 95% [confidence interval] CI: 6.0–6.6) was substantially better than those diagnosed pre-approval (median 5.5 months, 95%CI: 5.4–5.7, p<0.001) and, in fact, than those diagnosed in 2014 (median 5.9 months, 95%CI: 5.6–6.1, p=0.002). Among patients diagnosed post-approval (in 2015, n=7,431), ICI receipt demonstrated substantially improved OS in landmark survival analyses (median 13.8 months, 95%CI: 12.2–15.1; vs. 8.5 months, 95%CI: 8.3–8.9, p<0.001) – benefits which persisted in multivariable landmark survival analyses (hazard ratio [HR] 0.83, 95%CI: 0.71–0.96, p=0.02), independent of patient characteristics, other therapies, and extracranial disease. For patients diagnosed post-approval, who reached the landmark timepoint, ICI receipt was independent of patient demographics, socioeconomic status, and hospital type—with the exception of Medicaid-insured patients, who were less likely than privately insured patients to receive ICI (OR 0.77, 95%CI: 0.60–0.97, p=0.03).ConclusionsNationally, the use of ICI for NSCLC brain metastasis patients is increasing, generally without significant socioeconomic barriers. Brain metastasis patients diagnosed in the post-approval second-line ICI era (2015) demonstrated significantly better OS than patients diagnosed pre-approval and even than patients diagnosed only in 2014. ICI was associated with a >60% relative increase in median OS. Together our findings from a real-world population demonstrate that the dramatic OS benefits of ICIs for advanced NSCLC also extended to brain metastasis patients.

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