Caregivers of adults with cancer often report significant distress yet remain difficult to engage in supportive services. While the field of Psychosomatic Medicine has continued to identify important ...markers of physiologic stress, and demonstrated disruption in these markers in caregiver populations, no research has investigated whether biomarker information on caregivers’ reaction to stress could impact their willingness to address their ongoing distress.
Here, we report on a qualitative study (N = 17) in which we conducted individual interviews with cancer caregivers to explore their key attitudes towards, and subjective experience of, mock stress biomarker data. A total of 17 caregivers of patients (M age = 56.1 years; SD = 12.3) with primarily metastatic brain tumors (glioblastoma) were interviewed regarding four commercially available biomarkers (telomere length; hair cortisol, activity levels and heart rate variability). Once presented with information about stress biomarkers, caregivers were asked to discuss their subjective reaction as if it was their own data as well as their motivation and willingness to seek support after receiving such information. We identified and extracted relevant themes.
Analysis utilizing the framework method revealed four emerging themes. The first theme described caregivers' ability to manage stress and willingness to engage with supportive services. Second, caregivers generally accepted the biomarker data but preferred it to be presented in a specific way. The third theme demonstrated that for some, biomarker data may actually increase their subjective distress (e.g., whether or not something could be done to improve their mental state). The last theme described how biomarkers were generally received as meaningful motivators that could increase caregivers’ willingness to engage with supportive services.
In addition to the more general identified theme of CG's willingness to engage with additional support, we gained insights into caregivers' reaction to the stress biomarkers presented. Findings will set the stage for the utility of stress biomarker information and whether it influences cancer caregivers' willingness to address their distress and motivation to engage in supportive services.
Background
Responses to bevacizumab in glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By targeting vascular ...endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor, Src, and FGF receptor pathways, ponatinib may potentially help to overcome some of the putative mechanisms of adaptive resistance.
Methods
We performed a phase II trial of ponatinib in patients with bevacizumab‐refractory GBM and variants. Adult patients with Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function received 45 mg ponatinib daily. No limit on the number of prior therapies but only one prior bevacizumab‐containing regimen was allowed. Primary endpoint was 3‐month progression‐free survival. Plasma biomarkers of angiogenesis and inflammation were evaluated before and after treatment.
Results
The study closed after the first stage. Fifteen patients enrolled: median age 61 27‐74; median KPS 80 70‐90; median number of prior relapses 2 2‐4. Three‐month progression‐free survival rate was 0, median overall survival was 98 days 95% CI 56, 257, and median PFS was 28 days 95% CI 27, 30. No responses were seen. The most common grade ≥3 adverse events included fatigue (n = 3), hypertension (2), and lipase elevation (2). Ponatinib treatment significantly increased plasma VEGF, soluble (s)VEGFR1, sVEGFR2, sTIE2, interferon gamma (IFNγ), tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐6, IL‐8, and IL‐10 and decreased sVEGFR2.
Conclusions
Ponatinib was associated with minimal activity in bevacizumab‐refractory GBM patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.
In this phase II trial, ponatinib was associated with minimal activity in bevacizumab‐refractory glioblastoma patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.
To review the existing glioma literature and National Comprehensive Cancer Network current standard–of care guidelines for recurrent high-grade glioma, which includes surgery, radiation, and systemic ...therapies.
PubMed, MedlinePlus, Science Direct, National Comprehensive Cancer Network, and Google Scholar were searched. Key words for databases were high-grade glioma, glioblastoma, recurrent, surgery, radiation, and systemic therapy.
Approved treatments for patients with recurrent high-grade glioma are limited and do not significantly impact progression-free survival rates, nor do they offer long-term benefit in symptom improvement or quality of life. Particular consideration for progression versus pseudoprogression should be evaluated before pursuing recurrent therapies.
Given the limited availability of standard-of-care treatments, clinical trials should be prioritized to maximize future treatment options. Individual performance status, genetic and molecular profiles, as well as goals of care and quality of life are important considerations in the context of treatment plans.
Abstract
Background
Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed ...death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy.
Methods
Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.
Results
Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO.
Conclusion
Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.
Although antiangiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1α/CXCR4 axis may mediate resistance to VEGFR ...inhibition. Preclinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGG.
Part 1 enrolled 23 patients with a 3 × 3 dose escalation design to a maximum planned dose of plerixafor 320 μg/kg subcutaneously on days 1 to 21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. Cerebrospinal fluid (CSF) and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular biomarkers were evaluated before and after treatment. Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue.
In Part 1, no dose-limiting toxicities were seen at the maximum planned dose of plerixafor + bevacizumab. Treatment was well tolerated. After plerixafor 320 μg/kg treatment, the average CSF drug concentration was 26.8 ± 19.6 ng/mL. Plerixafor concentration in resected tumor tissue from patients pretreated with plerixafor was 10 to 12 μg/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF-1α and placental growth factor. Progression-free survival correlated with pretreatment plasma soluble mesenchymal-epithelial transition receptor and sVEGFR1, and overall survival with the change during treatment in CD34
progenitor/stem cells and CD8 T cells.
Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with biomarker changes consistent with VEGF and CXCR4 inhibition.
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Abstract
BACKGROUND
PCNSL exhibit B-cell receptor (BCR) pathway activation due to CD79B and MYD88 mutations, concurrently with 9p24.1/PD-L1/PD-L2 copy number alterations. These genetic features ...suggest complementary approaches of targeting PD1, BCR/BTK (Bruton’s tyrosine kinase) and CD20. Pembrolizumab, ibrutinib and rituximab have each been used as monotherapy in RR PCNSL. We investigate these agents in combination to determine tolerability and synergistic efficacy.
METHODS
This is a phase 1b/2 study of pembrolizumab, ibrutinib and rituximab in RR PCNSL patients. In phase 1b, patients were accrued using a 3 + 3 design to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). Patients were treated with pembrolizumab 200mg IV every 3 weeks, ibrutinib oral daily and rituximab 375mg/m2 IV weekly (for 4 doses). Two dose levels (DL) of ibrutinib (DL1: 560 mg, DL2: 840 mg) were evaluated. Primary endpoint is progression-free survival at six months (PFS6); secondary endpoints include safety, tolerability, objective response rate (ORR), duration of response (DOR), progression-free and overall survival.
RESULTS
We completed accrual on the phase 1b part and report results of 10 evaluable patients (50% women). The median age was 74 years (38-82) and median ECOG 1 (0-1). There was 1 DLT at DL1 (grade 4 transaminases) and 2 DLTs at DL2 (hypertension, flu-like symptoms); the MTD/R2PD of ibrutinib with pembrolizumab and rituximab is 560mg. The most common grade 3/4 adverse events were elevated transaminases and decrease in lymphocyte counts. There were 13 dermatologic events, all < grade 3. Reasons for discontinuing treatment include progression (6), consent withdrawal (1), toxicity (2). The ORR is 80% (6 complete responses, 2 partial responses). As of June 2023, the median DOR is 177 days (49-619); PFS6 is 50%.
CONCLUSIONS
The combination of pembrolizumab, ibrutinib and rituximab is well-tolerated with manageable side effects and encouraging efficacy. The phase 2 portion of the study is open.
Abstract
Glioblastoma is immunologically “cold”, with little clinical response to single-agent immune-checkpoint inhibitors (ICI). Our previous randomized study of neoadjuvant and adjuvant ...pembrolizumab versus adjuvant pembrolizumab in recurrent glioblastoma identified a molecular signature for ICI and suggested that neoadjuvant pembrolizumab improved survival (PMID30742122). We extended these original findings with a single-arm expansion cohort of glioblastoma patients at first or second relapse undergoing surgical resection for recurrent disease. Eligibility was identical to the original study. Patients receiving > 4mg dexamethasone, or with prior immunotherapy or anti-angiogenic therapy were excluded. The primary objective was to determine the effect of neoadjuvant pembrolizumab on cell cycle/cancer proliferation genes. Secondary objectives were PFS-6 and OS. Twenty-five patients received neoadjuvant pembrolizumab followed by tumor resection and adjuvant pembrolizumab until progression or unacceptable toxicity. The median age of participants was 60 years and median KPS was 90. Ninety-six percent of tumors were IDH wild-type and 48% were MGMT promoter methylated. Neoadjuvant pembrolizumab continued to induce alterations in the tumor microenvironment (T-cell/IFN upregulation, cell cycle downregulation; molecular responders (MR)), but the proportion of MR in this trial was 36% compared with 70% in the original treatment cohort. Median OS was 6.8 months. There were no CTCAE grade 4-5 AEs attributable to pembrolizumab. Further analysis of prognostic differences between stage 1 and 2 subjects is underway, as are additional immune and genotypic correlates to further define molecular changes induced by pembrolizumab. Anti-PD1 monotherapy triggers an intra-tumoral genetic signature associated with interferon-γ response and suppression of cell cycle/cancer proliferation in recurrent glioblastoma, though does not extend OS. This surgical window-of-opportunity paradigm allows for attribution of molecular effects to single agents. Future work will evaluate the differences in patient population, tumor characteristics, and address additional immune checkpoints and/or signaling pathways that can be targeted to augment the effectiveness of anti-PD1 in glioblastoma.
Abstract
BACKGROUND
The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and ...complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM.
METHODS
We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3).
RESULTS
Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference.
CONCLUSIONS
Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.
Caregivers of adults with cancer often report significant distress yet remain difficult to engage in supportive services. While the field of Psychosomatic Medicine has continued to identify important ...markers of physiologic stress, and demonstrated disruption in these markers in caregiver populations, no research has investigated whether biomarker information on caregivers' reaction to stress could impact their willingness to address their ongoing distress.
Here, we report on a qualitative study (
= 17) in which we conducted individual interviews with cancer caregivers to explore their key attitudes towards, and subjective experience of, mock stress biomarker data. A total of 17 caregivers of patients (
age = 56.1 years;
= 12.3) with primarily metastatic brain tumors (glioblastoma) were interviewed regarding four commercially available biomarkers (telomere length; hair cortisol, activity levels and heart rate variability). Once presented with information about stress biomarkers, caregivers were asked to discuss their subjective reaction
as well as their motivation and willingness to seek support after receiving such information. We identified and extracted relevant themes.
Analysis utilizing the framework method revealed four emerging themes. The first theme described caregivers' ability to manage stress and willingness to engage with supportive services. Second, caregivers generally accepted the biomarker data but preferred it to be presented in a specific way. The third theme demonstrated that for some, biomarker data may actually increase their subjective distress (e.g., whether or not something could be done to improve their mental state). The last theme described how biomarkers were generally received as meaningful motivators that could increase caregivers' willingness to engage with supportive services.
In addition to the more general identified theme of CG's willingness to engage with additional support, we gained insights into caregivers' reaction to the stress biomarkers presented. Findings will set the stage for the utility of stress biomarker information and whether it influences cancer caregivers' willingness to address their distress and motivation to engage in supportive services.
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