Background and aims
This retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with ...bevacizumab in a real‐world setting.
Methods
Adult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan‐Meier estimator was used to describe overall survival (OS), progression‐free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected.
Results
Seventy‐four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5‐58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval CI, 7.3‐13.4) and 6.4 months (95% CI, 3.9‐8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8‐∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6‐16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8‐12.5) in those who did (P = 0.0382, log‐rank), while median PFS values were 8.6 months (95% CI, 4.6‐9.7) and 3.7 months (95% CI, 2.7‐6.6), respectively (P = 0.0243, log‐rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab.
Conclusions
Treatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real‐world setting were comparable with those reported in prospective clinical trials.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab ...therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (
n
= 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3;
P
= 0.51) and 10.3 months (95% CI: 2.5, 14.4;
P
= 0.91) for patients who initiated non-bevacizumab containing therapy (
n
= 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Introduction Malignant glioma remains a significant therapeutic challenge, and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for ...multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. Methods D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohistochemical analysis. The three MAbs were labeled with125 I or131 I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. Results The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2×109 M−1 and 3.6×109 M−1 , and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of125 I-labeled D2C7 compared with131 I-labeled EGFR.1. Uptake of125 I-labeled D2C7 in NR6M xenografts (52.45±13.97 %ID g−1 on Day 3) was more than twice that of131 I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to131 I-labeled EGFR.1 in mice with WTT xenografts. Conclusions These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6–10 months. We conducted a phase II trial of upfront 5‐day temozolomide (TMZ) and bevacizumab (BV) in patients ...with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m2 on days 1–5, and BV at 10 mg/kg on days 1 and 15 of a 28‐day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty‐one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment‐related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.
Forty‐one patients with unresectable glioblastomas were treated with an upfront regimen of 5‐day temozolomide and bevacizumab for four cycles prior to radiation. This combination resulted in partial response or stable disease in all but one patient and had acceptable tolerability.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and ...radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.
Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.
Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.
The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
2027
Background: While circulating tumor DNA (ctDNA) is a routine tool for therapeutics in metastatic solid tumors, data in those with stable and active brain metastases (BrMs) is limited. We ...assessed genomic alterations in ctDNA from patients (pts) with solid tumor BrMs in three groups: isolated BrMs/stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs at ctDNA draw (eCNS). We also compared ctDNA alterations between pts with and without BrMs. Methods: Pts with BrMs and a Guardant 360 profile (n=253) from the Duke Molecular Registry of Tumors between 01/2014 – 12/2020 were identified. Intracranial and extracranial disease status were determined via investigator assessment (RECIST and RANO-BM criteria) within 30 days of ctDNA test. Mutant allele fraction (MAF) was defined as the % of mutant alleles divided by total alleles at a given loci. Differences in mean ranks of the MAF % maximum were compared using the Kruskal-Wallis test and pairwise comparisons with the Dwass, Steel, Critchlow-Fligner multiple comparisons post-hoc procedure. We compared differences in MAF >1% using the chi-square test. Results: Among the 253 pts with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. The two most common tumor types were breast (BC, 12.0%) and non-small cell lung cancer (NSCLC, 76.4%). Median MAF was lower in the iCNS group (1.6%) vs cCNS (4.8%) p=0.002, but eCNS did not differ (2.6%). In pts with BC BrMs, ESR1 mutations were most frequent in the iCNS group (67%), followed cCNS (54%) then eCNS (18%) (p = 0.09) as were PIK3CA mutations, iCNS(50%), cCNS (46%), and eCNS (27%), p = 0.55. In pts with NSCLC BrMs, EGFR mutations were most frequent in the iCNS followed by cCNS then eCNS (67%, 40% and 37%, p = 0.08). KRAS mutations were more frequent in cCNS followed by eCNS and iCNS (30%, 17% and 6% p = 0.031). Patients with no BrMs (n=449) included 24% breast and 76% NSCLC. In the ctDNA, ESR1 and BRCA2 mutations were more frequent in pts with BC BrMs than those without (60% vs 25%, p< 0.001) and (17% vs 5%, p=0.022), respectively. Mutations in EGFR were more frequent in pts with BrMs vs without (36% vs 17%, p<0.001). Sequencing from both BrMs tissue and ctDNA were available for 8 pts (4cCNS and 4 iCNS). 7 of these (87.5%) had identical mutations in tumor and ctDNA. Conclusions: This study illustrates the feasibility of detecting actionable mutations from ctDNA among pts with BrMs, with and without extracranial disease. A higher frequency of actionable mutations in several targetable genes was observed in ctDNA when comparing pts with and without BrMs, thus providing therapeutic opportunities. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.
2070
Background: Leptomeningeal disease (LMD) is a challenging complication of high grade glioma (HGG) and questions remain regarding risk factors, molecular associations, and optimal treatment. Here ...we report updated results on a larger cohort from our previously reported multicenter study (Shoaf 2022, Neuro-Oncology). Methods: Patients with molecularly-profiled HGG (Caris Life Sciences; Phoenix, AZ) with LMD at 3 institutions were included. NextGen Sequencing of DNA (592 gene or whole exome) and RNA (whole transcriptome) were tested. Medical records were reviewed for clinicopathologic characteristics and outcome. Kaplan-Meier estimates of survival were performed using Cox’s proportional hazard model. Mann-Whitney U or Chi-square tests were applied for molecular comparison as appropriate and adjusted for multiple comparisons. Results: Seventy-two patients (female: 20, male: 52; median age: 54.5y) were identified, comprising 65 grade 4 tumors (glioblastoma GBM: 62; gliosarcoma: 2; H3K27M diffuse midline glioma: 1), 5 grade 3 tumors (astrocytoma: 4; pleomorphic xanthoastrocytoma: 1), and 1 astrocytoma NOS. LMD diagnosed at glioma diagnosis (n=23) vs. recurrence (n=44) was associated with longer post-LMD survival pLMD-OS: 16.9m vs. 5.5m, p<0.0001 but similar overall survival mOS: 16.9m vs. 20.9m; p=0.36. Pathology-diagnosed LMD (n=15) vs. MRI-diagnosed LMD (n=54) was associated with longer post-LMD survival pLMD-OS: 15.2m vs. 6.2m, p=0.0002 but similar overall survival mOS: 16.9m vs. 20.9m; p=0.72. Post-LMD survival pLMD-OS: 8.7m vs. 6.8m, p=0.33 and overall survival mOS: 21.1m vs. 20.9m, p=0.20 were similar for supratentorial (n=45) vs. infratentorial/spinal (n=10) locations, and post-LMD survival did not significantly differ for symptomatic (n=40) vs. asymptomatic (n=22) patients pLMD-OS: 6.6m vs. 10.5m, p=0.13). pTERT mutation (73%), MGMT methylation (38%), EGFR amplification (31%), and PTEN mutation (28%) were the most prevalent molecular alterations in this group. Comparison of grade 4 LMD tumors with an independent GBM cohort (n=5431) suggested a male predominance (73.4% vs. 58.5%, p=0.016) and a trend towards more frequent mutations in RB1 (25% vs. 9.2%, p=0.002) and MDM4 (12.7% vs. 4.3%, p=0.01) and amplification of WIF1 (6.1% vs. 0.3%, p=0.006), CHIC2 (17.0% vs. 5.2%, p=0.002), and LGR5 (5.9% vs. 0.4%, p=0.012). The expression of immune checkpoint-related genes was similar, although a trend towards immunologically “colder” tumors in the LMD cohort was observed. However, these effects were not significant after correcting for multiple comparisons. Conclusions: LMD is more common in male patients and may be associated with various genomic alterations and tumor microenvironment differences. Overall survival does not differ from patients without LMD, but these differences may provide clues to the pathogenesis and treatment resistance of GBM.
Abstract
INTRODUCTION
Leptomeningeal disease (LMD) is a challenging complication of high grade glioma (HGG) and critical questions remain unanswered regarding clinicopathologic risk factors, ...molecular associations, and optimal treatment.
METHODS
Patients with molecularly-profiled HGG (Caris Life Sciences; Phoenix, AZ) with LMD at two institutions were included. Medical records were reviewed for clinicopathological characteristics, treatment, and outcome. Kaplan-Meier estimates of patient survival were performed on censored data using Cox’s proportional hazard model.
RESULTS
43 patients (male: 33, female: 10; median age: 56 years) were identified, comprising 41 grade 4 (glioblastoma: 38; gliosarcoma: 2; H3K27M diffuse midline glioma: 1) and 2 grade 3 tumors (astrocytoma: 1; pleomorphic xanthoastrocytoma: 1). LMD diagnosed at HGG diagnosis (n=18) versus recurrence (n=22) was associated with longer post-LMD survival pLMD-OS: 15.3m vs. 4.8m, HR: 0.07, 95% CI: 0.02-0.29, p=0.0004 but similar overall survival mOS: 15.3m vs. 12.3m; HR: 0.82; 95% CI: 0.36-1.85; p=0.63. Pathology-diagnosed LMD (n=15) versus MRI-diagnosed LMD (n=26) was associated with longer post-LMD survival pLMD-OS: 15.4m vs. 5.2m, HR: 14.9, 95% CI: 0.01-0.30, p=0.0004 but similar overall survival mOS: 17.1m vs. 12.3m; HR: 0.66; 95% CI: 0.3-1.58; p=0.38. Post-LMD survival was significantly prolonged for supratentorial (n=28) versus infratentorial/spinal (n=4) locations regardless of the diagnostic modality pLMD-OS: 2.6m vs. 11.3m, HR: 14.4, 95% CI: 2.73-75.7, p=0.0017, and did not significantly differ between symptomatic (n=20) and asymptomatic (n=23) patients pLMD-OS: 4.8m vs. 11.2m, HR: 1.75, 95% CI: 0.82-3.77, p=0.15). pTERT mutation (81%), EGFR amplification (43%), and MGMT methylation (33%) were prevalent but IDH1 mutation was rare (2.8%). Comparison with a separate glioblastoma cohort (n=1400) suggested more frequent amplification of CHIC2, MDM4, and KDR, higher mutation rates of RUNX1, APC, and RAD51C, colder tumor microenvironment (TME), and lower expression of immune checkpoint-related genes.
CONCLUSIONS
Clinicopathological characteristics affect post-LMD survival, and cohort comparison suggests molecular and TME differences in LMD-HGG tumors.
Abstract
BACKGROUND
Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deaths in children with a median overall survival of 9–15 ...months. In recent years, immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selection of patient population who are most likely to benefit from immunotherapeutic approaches.
MATERIAL AND METHODS
In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in pGBMs, we undertook an immunohistochemical survey on 19 recurrent pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq was also performed on a subset of 9 cases. Distribution of lymphocytes (LYMPHS) was recorded as intratumoral (IT) or perivascular (PV).
RESULTS
The analysis indicates intratumoral CD3+ LYMPHS are commonly <5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associated with PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS and PD-L1+ tumor cells were associated with longer survivals. The data were confirmed by RNA-seq analysis.
CONCLUSION
PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigation as candidates for immunotherapy.
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