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  • 1
    Online Resource
    Online Resource
    Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti–PD-1 Monotherapy
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 21 ( 2021-11-01), p. 5993-6000
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 21 ( 2021-11-01), p. 5993-6000
    Abstract: Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti–PD-1 monotherapy remains unclear. Experimental Design: In this multicenter retrospective analysis, patients treated with anti–PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti–PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. Results: Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti–PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10–13.70; P & lt; 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20–16.09; P & lt; 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04–2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15–3.39; P = 0.01] . Similar findings were also observed in the 26-week landmark analysis for post–irAE-PFS but not for post–irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. Conclusions: Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti–PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-1283
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    Online Resource
    Online Resource
    Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study
    Oxford University Press (OUP) ; 2022
    In:  British Journal of Dermatology Vol. 187, No. 3 ( 2022-09-01), p. 401-410
    Details
    In: British Journal of Dermatology, Oxford University Press (OUP), Vol. 187, No. 3 ( 2022-09-01), p. 401-410
    Abstract: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. Objectives To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. Methods Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. Results In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50–57% vs. 20%, 95% CI 13–28%; adjusted P & lt; 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7–20·3 vs. 5·4 months, 95% CI 4·5–7·0; adjusted P & lt; 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48–6·81; adjusted P & lt; 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46–0·74; adjusted P & lt; 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. Conclusions Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.
    Type of Medium: Online Resource
    ISSN: 1365-2133 , 0007-0963
    URL: Article
    DOI: 10.1111/bjd.21241
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2004086-6
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  • 3
    Online Resource
    Online Resource
    Prognostic models for advanced melanoma patients treated with anti-PD-1 monotherapy.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 8_suppl ( 2019-03-10), p. 133-133
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 8_suppl ( 2019-03-10), p. 133-133
    Abstract: 133 Background: Anti-PD-1 monotherapy has dramatically improved the outcomes of patients with advanced melanoma, yet the majority of patients develop therapeutic resistance. A prognostic model is needed to optimally select patients who are most and least likely to benefit. Methods: We performed a retrospective analysis of 141 advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. Demographic and clinical characteristics, baseline and early-on-treatment (median 3 weeks after anti-PD-1 monotherapy initiation) routine laboratory variables, and prognostic data were collected and correlated in both univariate and multivariate analyses. Results: Median progression free survival (PFS) and overall survival (OS) were 7.6 months (95% CI 2.3-12.9) and 57.3 months (95% CI 33.3-81.3), respectively. In multivariate analyses, significant independent prognostic variables ( P 〈 0.05) in favor of longer PFS included cutaneous subtype, low baseline lactic acid dehydrogenase (LDH); low early-on-treatment derived neutrophil-to-lymphocyte ratio (dNLR); high early-on-treatment albumin, basophil, and red blood cell counts (RBCs); those in favor of longer OS included BRAF V600 mutation; low baseline LDH and neutrophil-to-lymphocyte ratio (NLR); low early-on-treatment LDH; high early-on-treatment total protein, basophil, and lymphocyte counts. Prognostic scoring models (total scale: 0-6) were established based on these independent prognostic factors as dichotomous variables, for both PFS (HR 0.555, 95% CI 0.481-0.641, P 〈 0.001) and OS (HR 0.411, 95% CI 0.326-0.519, P 〈 0.001), respectively. For patients with PFS scores of ≤ 2, 3, 4, 5, and 6, rates without progression at 6 months were 0%, 9.4%, 31.0%, 67.3%, and 80.0%, respectively. For patients with OS scores of ≤ 2, 3, 4, 5, and 6, survival rates at 12 months were 25.0%, 68.4%, 79.3%, 97.1%, and 100% ; at 24 months were, 0%, 45.6%, 69.1%, 82.6%, and 100%, respectively. Conclusions: A scoring system based on clinical characteristics and easily accessible routinely tested biomarkers may be used to help predict outcomes of anti-PD-1 monotherapy treated advanced melanoma patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.8_suppl.133
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    The use of cryoablation to overcome resistance to PD-1 blockade in unresectable melanoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9538-9538
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9538-9538
    Abstract: 9538 Background: Percutaneous image-guided cryoablation (cryo) is an established minimally invasive oncologic treatment that modulates the immune microenvironment. We hypothesized that cryo can augment anti-tumor responses in melanoma patients progressing on immune checkpoint inhibitors (ICI). Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryo of an enlarging lesion and ICI continuation for a minimum of 2 additional cycles. Computed tomography was performed at 6-8 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-12 weeks. The primary endpoint was safety and feasibility. Secondary endpoints were overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analyses on pre- and post-cryo tumor biopsy and blood samples were performed. Results: From May 2018 through July 2020, 20 pts were screened, 18 enrolled and 17 treated per protocol. All pts received prior PD-1/PD-L1 monotherapy and 12 (67%) experienced primary resistance to ICI. Median follow-up was 8.5 months. Ablated lesions included lymph nodes (n = 4), lung/pleura (n = 4), soft tissue/bone (n = 3), adrenal (n = 3), chest wall (n = 1), and kidney (n = 1). Peri-procedural events occurred in 3 cases (pneumothorax, diaphragm puncture, osteomyelitis). One pt. with underlying ICI-induced hypophysitis experienced an adrenal crisis post-procedure, which rapidly corrected with stress-dose steroid administration; there were no de novo immune-related adverse events post-ablation and there were no grade 4/5 events. In evaluable pts (n = 17), ORR was 18% and DCR was 47% (3 PR, 5 SD). To investigate the inflammatory state of the tumor microenvironment prior to cryo, PD-1, CD8+ TIL IHC, was performed and will be presented at the meeting. Additional exploratory analyses (serial ctDNA analysis, single cell RNA sequencing, HLA-subtyping) are ongoing. Conclusions: Cryoablation in patients with unresectable melanoma following progression on ICI is feasible with an acceptable side effect profile. Efficacy data of this potentially synergistic approach in metastatic melanoma is encouraging. Correlative analyses are underway to identify biomarkers of response to this novel strategy. Clinical trial information: NCT03290677. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9538
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Organ site-specific radiological responses in anti-PD-1 monotherapy treated advanced melanoma patients.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 9552-9552
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 9552-9552
    Abstract: 9552 Background: Melanoma is notorious for its high degree of heterogeneity with the implication that metastases in different sites react differently to immunotherapy. We aimed to explore the site-specific response pattern in anti-PD-1 monotherapy treated advanced melanoma patients. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital (MGH) from Sept 2009 to Dec 2017. Radiological evaluations were carried out by radiologists from the MGH Tumor Imaging Metrics Core using irRECIST 1.1. Statistical analysis was carried out using ANOVA test. Results: Among 61 evaluated patients, 56 (91.8%) had at least one measurable target lesion(s) at baseline, including 35 (57.4%) patients with measurable lymph nodes (LN)/subcutaneous lesion(s), 25 (50.0%) with lung lesion(s), and 21 (34.4%) with liver lesion(s). At week-12 radiological evaluation after anti-PD-1 monotherapy initiation, lesions at different sites responded differently at marginal statistical significance (P = 0.071), namely mean percent changes compared with baseline were 3.75%, 5.12%, and -30.95% for LN/subcutaneous, liver, and lung lesions, respectively. Among patients who had disease under control (CR/PR/SD) (n = 37, 60.7%) by week-12 evaluation, the mean tumor percentage change at week-24 compared with week-12 were -8.94%, -12.18%, and -5.91% for LN/subcutaneous, liver, and lung lesions, respectively (P = 0.479). Conclusions: Although our small sample size limits definitive discrimination in organ site-specific response differences, it appears that lung lesions respond more quickly and to a greater extent compared with LN/subcutaneous and liver lesions in advanced melanoma patients treated with anti-PD-1 monotherapy. We will explore this in a larger, multicenter cohort.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.9552
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    A phase II study of cryoablation (cryo) of an enlarging tumor in patients (pts) with advanced lung cancer or melanoma receiving post-progression immune checkpoint inhibition (ICI).
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14243-e14243
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14243-e14243
    Abstract: e14243 Background: Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment. Through direct modulation of the tumor, it is theorized that this local therapy may modify the immune microenvironment. We hypothesized that it can augment an anti-tumor response when used concurrently with ICI. Methods: In this phase II single-arm study, pts with advanced lung cancer or melanoma progressing on ICI undergo cryo of an enlarging lesion and ICI is continued for a minimum 2 additional cycles. Computed tomography is performed at 4-6 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-10 weeks. The primary endpoint is safety and feasibility. Secondary endpoints are overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analysis on pre- and post-cryo biopsy specimen, when evaluable, will be performed. A planned analysis to document preliminary safety and feasibility in the first 11 patients was performed. Results: 11 pts (out of planned 40) have been enrolled. 8 with melanoma, 3 with lung cancer. All pts received prior PD-1/PD-L1 monotherapy with 8 pts treated with pembrolizumab, 2 with nivolumab and 1 with atezolizumab. Treated lesions were in lung (n = 4), bone (n = 3), lymph nodes (n = 2), liver (n = 1) and adrenal gland (n = 1). No immune related adverse events occurred. There was one treatment-related CTCAE grade 3 event (osteomyelitis) but no grade 4/5 events. One pt. experienced grade 3 hyponatremia, unrelated to cryo. In evaluable pts (n = 10), ORR was 10% and DCR was 50% (4 SD, 1 PR). Conclusions: During this scheduled safety analysis, cryo following progression on ICI was feasible and had an acceptable side effect profile. Early efficacy data of this potentially synergistic approach is encouraging but warrants further investigation. Clinical trial information: NCT03290677. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14243
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
    Online Resource
    Predictable early onset high-dose-glucocorticoid-associated-irAE and its predictive role in anti-PD-1 monotherapy treated advanced melanoma patients.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 9544-9544
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 9544-9544
    Abstract: 9544 Background: Though uncommon, a subgroup of patients with melanoma develop early-onset severe immune-related adverse effects (irAEs) that require immunosuppressive treatment with high-dose glucocorticoids (HD-GCCs). We aimed to examine the impact of early onset HD-GCC-associated-irAE (EO-HGA-irAE) in the setting of anti-PD-1 monotherapy initiation on prognosis and to develop a predictive scoring system. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. The relationship between EO-HGA-irAE and PFS (defined as time from anti-PD-1 monotherapy initiation to PD) was assessed using 8-week conditional landmark analysis (Kaplan-Meier curves, log-rank test) and time-dependent COX regression model (multivariate analysis). Demographic characteristics and baseline routine laboratory variables were collected and correlated with occurrence of EO-HGA-irAE using logistic regression modeling. Best cutoff values were identified using ROC curve (Youden index) to dichotomize continuous variables. Results: Among 146 patients, 13 (8.9%) developed EO-HGA-irAE. In 8-week landmark analysis, median PFS was 2.9 (95% CI, 2.8-3.0) and 17.5 (95% CI, 10.8-24.2) months (P = .001) for patients with and without EO-HGA-irAE, respectively. Multivariate analysis revealed that EO-HGA-irAE was independently correlated with significantly higher risk of disease progression with hazard ratio of 2.4 (95% CI 1.4-4.0) (P = .001). Potential predictive variables (P 〈 .25 for continuous variables, P 〈 .1 for dichotomous variables) in favor of the occurrence of EO-HGA-irAE included age, baseline glucose, and neutrophil, eosinophil, and WBC count. After dichotomization and further validation using a logistic regression model, a scoring system (score range 0-3) composed of 3 dichotomized predictors, including age, baseline glucose, and baseline neutrophil count was developed with odds ratio of 3.4 (95% CI, 1.6-8.8) (P = .001). The probabilities of patients scoring 0,1,2,3 of developing EO-HGA-irAE were 1.1%, 3.5%, 11.1%, and 29.9%, respectively. Conclusions: Development of EO-HGA-irAE is correlated with shorter PFS in advanced melanoma patients treated with anti-PD-1 monotherapy. A scoring system based on age and simple, easily accessible, routinely tested biomarkers can be used to help predict the risk of EO-HGA-irAE occurrence. Validation with a larger sample size is required.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.9544
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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