Recurrent Brain Metastases Research Articles

Stereotactic reirradiation for local failure of brain metastases following previous radiosurgery: Systematic review and meta-analysis.

Local failure (LF) following stereotactic radiosurgery (SRS) of brain metastases (BM) may be treated with a second course of SRS (SRS2), though this procedure may increase the risk of symptomatic radionecrosis (RN). A literature search was conducted according to PRISMA to identify studies reporting LF, overall survival (OS) and RN rates following SRS2. Meta-analysis was performed to identify predictors of RN. Analysis included 11 studies (335 patients,389 metastases). Pooled 1-year LF was 24 %(CI95 % 19-30 %): heterogeneity was acceptable (I2 = 21.4 %). Median pooled OS was 14 months (Confidence Interval 95 %, CI95 % 8.8-22.0 months). Cumulative crude RN rate was 13 % (95 %CI 8 %-19 %), with acceptable heterogeneity (I2 = 40.3 %). Subgroup analysis showed higher RN incidence in studies with median patient age ≥59 years (13 % [95 %CI 8 %-19 %] vs 7 %[95 %CI 3 %-12 %], p = 0.004) and lower incidence following prior Whole Brain Radiotherapy (WBRT, 19 %[95 %CI 13 %-25 %] vs 7%[95 %CI 3 %-13 %], p = 0.004). SRS2 is an effective strategy for in-site recurrence of BM previously treated with SRS.

Predictors of Local Control of Brain Metastasis Treated With Laser Interstitial Thermal Therapy.

Laser Interstitial Thermal Therapy (LITT) has been used to treat recurrent brain metastasis after stereotactic radiosurgery (SRS). Little is known about how best to assess the efficacy of treatment, specifically the ability of LITT to control local tumor progression post-SRS. To evaluate the predictive factors associated with local recurrence after LITT. Retrospective study with consecutive patients with brain metastases treated with LITT. Based on radiological aspects, lesions were divided into progressive disease after SRS (recurrence or radiation necrosis) and new lesions. Primary endpoint was time to local recurrence. A total of 61 consecutive patients with 82 lesions (5 newly diagnosed, 46 recurrence, and 31 radiation necrosis). Freedom from local recurrence at 6 mo was 69.6%, 59.4% at 12, and 54.7% at 18 and 24 mo. Incompletely ablated lesions had a shorter median time for local recurrence (P<.001). Larger lesions (>6 cc) had shorter time for local recurrence (P=.03). Dural-based lesions showed a shorter time to local recurrence (P=.01). Tumor recurrence/newly diagnosed had shorter time to local recurrence when compared to RN lesions (P=.01). Patients receiving systemic therapy after LITT had longer time to local recurrence (P=.01). In multivariate Cox-regression model, the HR for incomplete ablated lesions was 4.88 (P<.001), 3.12 (P=.03) for recurrent tumors, and 2.56 (P=.02) for patients not receiving systemic therapy after LITT. Complication rate was 26.2%. Incompletely ablated and recurrent tumoral lesions were associated with higher risk of treatment failure and were the major predicting factors for local recurrence. Systemic therapy after LITT was a protective factor regarding local recurrence.

Repeated stereotactic radiosurgery for recurrent brain metastases: An effective strategy to control intracranial oligometastatic disease.

Due to improvements in systemic therapies and longer survivals, cancer patients frequently present with recurrent brain metastases (BM). The optimal therapeutic strategies for limited brain relapse remain undefined. We analyzed tumor control and survival in patients treated with salvage focal radiotherapy in our center. Thirty-three patients with 112 BM received salvage stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) for local or regional recurrences. Local progression was observed in 11 BM (9.8 %). After 1 year, 72 % of patients were free of distant brain failure, and the 2-year overall survival (OS) was 37.7 %. No increase in toxicity or neurologically related deaths were observed. The 2- and 3-year whole brain radiation therapy free survival (WFS) rates were 92.9 % and 77.4 %, respectively. Hence, focal radiotherapy is a feasible salvage of recurrent BM in selected group of patients with limited brain disease, achieving a maintained intracranial control and less neurological toxicity.

Laser Interstitial Thermal Therapy in the treatment of brain metastases and radiation necrosis.

Stereotactic Radiosurgery has become the main treatment for patients with limited number of brain metastases (BM). Recently, with the increasing use of this modality, there is a growth in recurrence cases. Recurrence after radiation therapy can be divided in changes favoring either tumor recurrence or radiation necrosis (RN). Laser Interstitial Thermal Therapy (LITT) is minimally invasive treatment modality that has been used to treat primary and metastatic brain tumors. When associated with real-time thermometry using Magnetic Resonance Imaging, the extent of ablation can be controlled to provide maximum coverage and avoid eloquent areas. The objective of this study was to investigate the use of LITT in the treatment of BM. An extensive review of the relevant literature was conducted and the outcome results are discussed. There is an emphasis on safety and local control rate of patients treated with this modality. The findings of our study suggest that LITT is a viable safe technique to treat recurrent BM, especially in patients with deep-seated lesions where surgical resection is not an option.

Laser interstitial thermal therapy for in-field recurrence of brain metastasis after stereotactic radiosurgery: does treatment with LITT prevent a neurologic death?

Brain metastasis (BM) affects up to one-third of adults with cancer and carries a historically bleak prognosis. Despite advances in stereotactic radiosurgery (SRS), rates of in-field recurrence (IFR) after SRS range from 10 to 25%. High rates of neurologic death have been reported after SRS failure, particularly for recurrences deep in the brain and surgically inaccessible. Laser interstitial thermal therapy (LITT) is an emerging option in this setting, but its ability to prevent a neurologic death is unknown. In this study, we investigate the causes of death among patients with BM who undergo LITT for IFR after SRS. We conducted asingle institution retrospective case series of patients with BM who underwent LITT for IFR after SRS. Clinical and demographic data were collected via chart review. The primary endpoint was cause of death. Between 2010 and 2018, 70 patients with BM underwent LITT for IFR after SRS. Median follow-up after LITT was 12.0months. At analysis, 49 patients died; a cause was determined in 44. Death was neurologic in 20 patients and non-neurologic in 24. The 24-month cumulative incidence of neurologic and non-neurologic death was 35.1% and 38.6%, respectively. Etiologies of neurologic death included local recurrence (n = 7), recovery failure (n = 7), distant progression (n = 5), and other (n = 1). Among our patient population, LITT provided the ability to stabilize neurologic disease in up to 2/3 of patients. For IFR after SRS, LITT may represent a reasonable treatment strategy for select patients. Additional work is necessary to determine the extent to which LITT can prevent neurologic death after recurrence of BM.

PCN16 RESECTION FOR RECURRENT BRAIN METASTASES: A SYSTEMATIC REVIEW AND META-ANALYSIS

There is recurrence at some point following initial resection or radiosurgery in about 50% of patients previously treated for brain metastases (BMs); yet, little is known about the optimal management of recurrent BMs. To better understand the management of recurrent brain metastases, we carried out a systematic review and meta-analysis to describe outcomes of craniotomy for recurrent BMs after resection or stereotactic radiosurgery, with particular attention to recurrence in the previous resection cavity.

Surgical bed stereotactic radiotherapy of brain metastases: Clinical outcome and predictors of local and distant brain failure

PurposeTo retrospectively analyze the outcomes of stereotactic radiotherapy (SRT) targeted at surgical bed of brain metastases (BM) and identify patterns of local/distant brain relapses (LR/DBR). Patients/methodsSeventy patients were treated with SRT between 2008–2017. Marginal dose prescription on the 70% isodose line depended on the maximal diameter of the target volume and range between 15–18Gy for single fraction radiosurgery and 23.1–26Gy in 3–5 fractions for fractionated SRT. ResultsAt 12 months, the overall survival (OS) was 69% [CI 95%=59%–81%]. At 6 and 12 months, the cumulative incidence functions (CIF) of local relapse were 4% [1%–13%] and 15% [8%–26%], respectively. According to univariate analysis, factors associated with LR were an initial volume larger than 7cc (hazard ratio: 4.6 [1.0–20.8], P=0.046) and a positive resection margin [hazard ratio: 3.6 [1.1–12.0], P=0.037. DBR occurred in 54.3% of patients with a median time of 8 months. None of the variables tested (histology, location or number of lesions) were found correlated with the DBR. Leptomeningeal disease occurred in 12.9% of cases. Salvage whole brain radiotherapy (WBRT) was required in 45.7% of patients and delayed by a median time of 9.6 months. Symptomatic radionecrosis (RN) occurred in 7.1%. ConclusionsAdjuvant SRT was an effective and well-tolerated treatment to control the postoperative risk of recurrence of BM without compromising OS. Positive resection margins and large volumes were predictors factor of local relapse.

Bevacizumab-based treatment as salvage therapy in patients with recurrent symptomatic brain metastases.

BackgroundSalvage treatment for recurrent brain metastases (BM) of solid cancers is challenging due to the high symptomatic burden and the limited local treatment options.MethodsPatients with recurrent BM with no option for further local therapies were retrospectively identified from BM databases. Bevacizumab-based treatment was initiated as a salvage treatment. Radiological imaging before and after bevacizumab-based treatment was reevaluated for treatment response using the Response Assessment in Neuro-Oncology (RANO) BM criteria.ResultsTwenty-two patients (36.4% male) with recurrent BM from breast cancer (40.9%), colorectal cancer (31.8%), or lung cancer (27.3%) were identified. Previous BM-directed therapies were radiosurgery in 16/22 (72.7%) patients, whole-brain radiotherapy in 8/22 (36.4%), and neurosurgical resection in 11/22 (50.0%). Time since BM diagnosis to initiation of bevacizumab treatment was 16.5 months. Of 22 patients 14 (63.6%) received concurrent systemic therapies. Neurological symptom improvement could be achieved in 14/22 (63.6%) and stabilization in 6/22 (27.3%) patients, resulting in a clinical benefit in 20/22 (90.9%) patients. Steroids could be reduced or stopped in 15/22 (68.2%) patients. Rate of improvement on T1-weighted imaging was 15/19 (78.9%; median reduction: −26.0% ± 32.9) and 19/20 (95%; median reduction: −36.2% ± 22.2) on T2-weighted FLAIR imaging. According to RANO-BM best response was partial response in 7/19 (36.8%), stable disease in 9/19 (47.3%), and progressive disease in 3/19 (15.7%) patients. Median CNS-specific progression-free survival was 8 months and median overall survival after initiation of bevacizumab treatment was 17 months.ConclusionsBevacizumab-based treatment had clinically relevant intracranial activity in the vast majority of patients suffering from recurrent, symptomatic BM. The data supports a prospective clinical trial of bevacizumab as a salvage treatment in BM.

LITT and Pembrolizumab in Recurrent Brain Metastasis

LITT and Pembrolizumab in Recurrent Brain Metastasis

CMET-33. PHASE II STUDY OF PALBOCICLIB IN BRAIN METASTASES HARBORING CDK PATHWAY ALTERATIONS

Abstract BACKGROUND Up to 25% of all cancer patients will develop brain metastases and prognosis remains poor. In preclinical work, we discovered that more than 50% brain metastases genomically diverge from primary tumors and harbor alterations in genes involved with cell cycle regulation. We thus initiated a phase II study to evaluate the efficacy and safety of the cyclin dependent kinase (CDK) 4/6 inhibitor, palbociclib, in patients with recurrent brain metastases with alterations in the CDK pathway (NCT02896335). METHODS The primary endpoint of the trial is the rate of intracranial benefit (defined as CR, PR, or SD, per RANO) at 8 weeks after the start of palbociclib. A Simon two-stage design was used to compare the rate of intracranial benefit for a null rate of 10% against an alternative of 30%. Fifteen patients were to be enrolled in the first stage. If fewer than 2 responders were observed, then the study would stop for insufficient evidence of efficacy. If 6 or more responders were observed among the total of 30, this treatment regimen would be considered worthy of further study. CSF, blood samples and tumor samples were collected to elucidate the genomic determinants of response to CDK inhibitors in the brain. RESULTS A total of 14 patients have been accrued (5 with breast cancer, 4 with melanoma, 3 esophageal and 2 with non-small cell lung cancer) thus far. One or more grade-3 or higher adverse events at least possibly related to treatment were seen in six (42%) patients, the majority being hematologic toxicities. At the time of the data analysis, eight (57%) patients had achieved intracranial benefit. Therefore, the study met primary endpoint. CONCLUSIONS In this unique, genomically-guided brain metastasis trial, we demonstrate that the CDK 4/6 inhibitor, palbociclib, is well-tolerated and has activity in patients with brain metastases.

RBTT-02. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL

Abstract BACKGROUND: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. Study Design: NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.

CD138 plasma cells may predict brain metastasis recurrence following resection and stereotactic radiosurgery

We sought to identify candidate biomarkers for early brain metastasis (BM) recurrence in patients who underwent craniotomy followed by adjuvant stereotactic radiosurgery. RNA sequencing was performed on eight resected brain metastasis tissue samples and revealed B-cell related genes to be highly expressed in patients who did not experience a distant brain failure and had prolonged overall survival. To translate the findings from RNA sequencing data, we performed immunohistochemistry to stain for B and T cell markers from formalin-fixed parffin-embedded tissue blocks on 13 patients. CD138 expressing plasma cells were identified and quantitatively assessed for each tumor sample. Patients’ tumor tissues that expressed high levels of CD138 plasma cells (N = 4) had a statistically significant improvement in OS compared to low levels of CD138 (N = 9) (p = 0.01). Although these findings are preliminary, the significance of CD138 expressing plasma cells within BM specimens should be investigated in a larger cohort. Immunologic markers based on resection cavity analysis could be predictive for determining patient outcomes following cavity-directed SRS.

EP1.14-38 Prolonged Survival in a Case of NSCLC with Recurrent Brain Metastasis - A Case Report

Carcinoma lung remains the most common cause of cancer related deaths in men globally. Approximately 10 percent of newly diagnosed patients with advanced non-small cell lung cancer (NSCLC) have brain metastases. Presence of brain metastases is associated with very poor prognosis with decreased survival and compromised quality of life in patients even after intensive treatment with multimodal approach. Though the survival varies according to performance status and presence of other prognostic factors, the survival in non small cell lung cancer with brain metastasis has increased to some extent in last two decades(median survival ranges between 7 -12 months in various studies).Hereby we present our experience with a case of adenocarcinoma lung with brain metastasis on presentation who has received multiple lines of treatment approach and leading a happy and hearty life after 8 years(96 months) of diagnosis. Section not applicable CASE REPORT A 45 year old nonsmoker male presented with constant headache with memory loss and on evaluation was found to have a SOL in the left temporal region with few other small lesions at other sites in brain along with right lung mass and was diagnosed as primary lung cancer with brain metastasis. CT guided biopsy of the lung mass showed adenocarcinoma lung. EGFR and ALK were non mutated. He received palliative whole brain radiotherapy followed by four cycles of chemotherapy with pemetrexed and carboplatin regimen. Received EBRT to right lung mass. Developed relapse after one year and underwent surgery. After six months , he developed recurrence at brain, for which surgical excision of the brain lesion(metastatectomy) was done followed by reirradiation to brain. Again he developed brain recurrence following which he received six cycles of Pemetrexed and Carboplatin followed by six cycles of maintenance Inj Pemetrexed. Again developed brain recurrence after one year which was surgically resected out following which he received Tab Erlotinib+ Tab Temezolamide. Recurrence of brain lesion was again encountered after four months for which he received six cycles of Inj Bevacizumab+ Nab-Paclitaxel + Carboplatin. Evaluation with whole body PET-CT scan and MRI brain showed complete metabolic response at primary site(lung) and partial response at brain. Then he received maintenance Inj Bevacizumab for six cycles. Then after one year,on recurrence in brain with surgical excision of the tumor and subsequent evaluation it was found that he had T790M mutation and hence was planned for Tab Osimertinib. He is on Tab Osimertinib since last 26 months. Recent evaluation was done two months back in form of whole body PET-CT scan and MRI brain which showed complete response at both primary(lung) site and brain. Patient is doing fine till date with a followup period of 96 months since upfront presentation with brain metastasis. Treatment approach for NSCLC has seen a paradigm shift in last few years with the increased role of targeted therapies which has improved the survival. Hence biopsy and identifying the druggable targets have become of prime importance in managing lung malignancies. Metastatectomy and target oriented approach has always proven to be beneficial in oligometastatic settings.

P1.01-51 Micropapillary Predominant and Pathologic Stage Were Risk Factors for Postoperative Brain Metastasis in Lung Adenocarcinoma

Brain metastasis from non-small cell lung cancer following curative resection is a significant issue because it often causes critical symptoms and may require different therapeutic approaches from other recurrence. On this background, we aimed to investigate correlation between clinicopathological variables and brain metastasis in resected lung adenocarcinoma. Clinicopathological data of 358 patients who had undergone complete resection for lung adenocarcinoma at Saiseikai Utsunomiya Hospital between 2002 and 2015 were retrospectively reviewed. Brain metastasis-free survival was calculated from the date of surgery to the date when brain metastasis was diagnosed or the date of last follow-up by using Kaplan-Meier method. We analyzed the risk factors of postoperative brain metastasis by log-rank analysis and Cox regression analysis. The median follow-up period was 60.4 months (range, 1.0 - 195.6 months). Thirty-six patients developed brain metastasis after complete resection of lung adenocarcinoma during follow-up. Thirty-three patients were diagnosed as brain metastasis by contrast-enhanced brain MRI and the others were diagnosed by contrast-enhanced brain CT. Five-year brain metastasis-free survival rate was 91.4%. Log-rank analysis demonstrated that pathologic stage IB or higher (p <0.001), lymphovascular invasion (p <0.001), presence of spread through alveolar spaces (p < 0.001) and micropapillary predominant pattern (p <0.001) were significantly associated with recurrence of brain metastasis. Cox regression analysis demonstrated that pathologic stage IB or higher (p = 0.004) and micropapillary predominant pattern (p = 0.007) were independent risk factors for brain metastasis. Our findings suggest that careful follow-up may be required for patients with higher pathologic stage as well as micropapillary predominant lung adenocarcinoma after complete resection. It may also emphasize clinical significance of micropapillary subtype in resected lung adenocarcinoma.

1594TiP - Radiosurgery followed by tumour treating fields (TTFields) for brain metastases (1-10) from NSCLC in the phase III METIS trial

BackgroundTumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. Trial designNSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150kHz, > 18hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues have emerged on the study, and recommended to continue the METIS study as planned. Clinical trial identificationNCT02831959. Legal entity responsible for the studyNovocure. FundingNovocure. DisclosureM. Mehta: Advisory / Consultancy: Varian Medical Systems ; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Tocagen; Advisory / Consultancy: AbbVie; Leadership role: Oncoceutics ; Shareholder / Stockholder / Stock options, Officer / Board of Directors: Pharmacyclics; Advisory / Consultancy: Cavion, Novocure, Varian, Agenus, Insys, Remedy, IBA. M. Ahluwalia: Advisory / Consultancy: Monteris Medical ; Advisory / Consultancy: AstraZeneca ; Advisory / Consultancy: Bristol-Myers Squibb ; Advisory / Consultancy: AbbVie; Advisory / Consultancy: CBT Pharmaceuticals; Advisory / Consultancy: Kadmon ; Advisory / Consultancy: VBI Vaccines ; Shareholder / Stockholder / Stock options: MimiVax ; Honoraria (self): Prime Oncology ; Research grant / Funding (institution): Novartis ; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Boehringer Ingelheim ; Research grant / Funding (institution): Aztra zeneca; Research grant / Funding (institution): Lilly/ImClone . P. Brown: Advisory / Consultancy: Novella Clinical. All other authors have declared no conflicts of interest.

427P - Phase 0 trial of ceritinib in brain metastases and recurrent glioblastoma

BackgroundCeritinib 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. MethodsThree brain metastasis and 7 glioblastoma patients with high expression of pSTAT5b/pFAK/pIGFR1 were enrolled and treated with oral ceritinib daily (750mg) for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ∼ 4 and 24h 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. ResultsCeritinib 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. ConclusionsCeritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastasis and glioblastoma are unlikely sufficient for target modulation. Clinical trial identificationNCT02605746. Legal entity responsible for the studyThe authors. FundingThe Ben and Catherine Ivy Foundation. DisclosureAll authors have declared no conflicts of interest.

Supportive Care With or Without Repeated Whole Brain Radiotherapy in Patients With Recurrent Brain Metastases

Supportive Care With or Without Repeated Whole Brain Radiotherapy in Patients With Recurrent Brain Metastases

Hypofractionated Radiosurgery Plus Bevacizumab for Locally Recurrent Brain Metastasis with Previously High-Dose Irradiation

Selection of appropriate treatment for patients with recurrent brain metastasis (BM) remains uncertain. Recent studies have demonstrated a significant response rate and acceptable toxicity using fractionated stereotactic radiosurgery (FSRS) in patients with locally recurrent large BM. The aim of this study was to evaluate efficacy and toxicity of FSRS with bevacizumab as a new salvage treatment for locally recurrent BM with previous high-dose irradiation. Patients with recurrent BM previously irradiated were enrolled. Salvage FSRS dose was 9.5-29 Gy (2-5 fractions) with 62%-75% isodose line by CyberKnife according to the brain tumor volume, site, and previous dose. Bevacizumab was prescribed for 4 cycles (5 mg/kg, every 3 weeks). The primary objective was to identify the overall survival after salvage treatment. Secondary objectives included clinical response (Karnofsky performance scale), imaging response (magnetic resonance imaging) and treatment-related adverse events. From December 2009 to October 2016, 24 patients were enrolled. The 1-year overall survival after salvage stereotactic radiosurgery was 87.5%. Twenty-three (96%) patients had a positive imaging response with a T2 volume reduction range of 6-22 cm3 (median 14 cm3, P= 0.032, paired t test). Significant clinical improvement was achieved (best Karnofsky performance scale score, P < 0.05, paired t test). Grade 1/2 fatigue was observed in 8 (33%) patients. Grade 3 fatigue and headache occurred in 1 patient. FSRS with adjuvant bevacizumab treatment showed favorable clinical and radiologic control as a salvage treatment regimen. The diagnoses of radiation necrosis and local recurrence after salvage FSRS warrant further study.

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

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.

Significance of Programmed Death Receptor Ligand One Expression in Brain Metastases of Non-Small Cell Lung Carcinoma

Survival in patients with metastatic non-small cell lung carcinoma (NSCLC) has considerably increased in recent years, in part due to the advent of programmed death/programmed death ligand one (PD-1/PD-L1) inhibitors. There is increasing evidence that patients with NSCLC brain metastases (BMs) also benefit from these novel therapies. PD-L1 expression as assessed by immunohistochemistry is known to predict response to PD-L1/PD-1 checkpoint inhibitors. However, it is not known whether this biomarker has prognostic significance in patients with BMs. Therefore, the aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with radiotherapy or neurosurgery as well as PD-1/PD-L1 inhibitors, after adjusting for the lung-Graded Prognostic Assessment (lung-GPA). This was a multi-institutional retrospective study. Patient records from three hospitals were reviewed to identify NSCLC BM patients who were treated with PD-1/PD-L1 inhibitors after intracranial treatment (resection, SRS (stereotactic radiosurgery/radiotherapy (SRS/SRT)), or whole-brain radiotherapy) but before intracranial progression. PD-L1 expression was considered positive in case of >1% histopathological staining. Cox proportional hazards model was used to assess prognostic significance of PD-L1 expression. Forty-eight patients with available PD-L1 expression were identified; median follow-up in this cohort was 24.7 months. Intracranial treatment consisted of SRS (n = 37), SRT (n = 3), resection (n = 7), or WBRT (n = 1). Intracranial treatment for newly diagnosed BMs was given to 30 patients; while 18 were treated for a recurrent BM. PD-L1 expression was positive in 33 patients (69%). In this cohort, median survival was 21.7 months. When split by lung-GPA, median survival in months was as follows: GPA 0-1: 11.4 (n = 6), GPA 1.5 – 2: 16.3 (n = 22), GPA 2.5 – 3: median not reached (n = 17); GPA 3.5 – 4: 14.6 (n = 3). In univariate analysis, PD-L1 expression was a borderline significant predictor for overall survival (HR = 0.44; 95% CI 0.19 – 1.00; p = 0.05). In multivariate analysis, PD-L1 was prognostic for overall survival (HR = 0.36, 95% CI = 0.14 – 0.90; p = 0.03) after correcting for lung-GPA, type of intracranial treatment, and newly diagnosed vs recurrent BMs. PD-L1 expression may be a prognostic factor independent of lung-GPA in patients with NSCLC BMs who underwent treatment with PD-1/PD-L1 checkpoint inhibitors. Larger studies are required to validate this finding.