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  • 1
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    Clinical outcomes of patients with stage IV cancer receiving immune checkpoint inhibitors in the inpatient setting.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 6634-6634
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 6634-6634
    Abstract: 6634 Background: Immune checkpoint inhibitors (ICI) represent a major leap in the treatment of many cancers. Use has rapidly expanded in recent years, yet it is unknown whether hospitalized patients, who are often sicker than those who were studied in clinical trials, derive benefit from ICI. The primary objectives of this study were to characterize the clinical features and outcomes of inpatients receiving ICI at a single institution, and to identify predictors of survival. Methods: After IRB approval, we conducted a retrospective chart review of inpatients with Stage IV solid tumors receiving ICI between 2015 – 2018 at a tertiary care referral hospital. Patients receiving ICI on clinical trial were excluded. We examined the clinical characteristics, readmission rate, and post-discharge survival. We then conducted a Cox multivariable regression analysis to identify predictors of post-discharge survival. Results: A total of 103 patients with Stage IV solid tumors were treated with ICI as inpatients between 2015 – 2018. Average age was 57 years (range = 26 to 85); 57% were male; 27% had ECOG performance status (PS) 3-4; average Charlson Comorbidity Index score was 8.3. Most common tumor types were melanoma (35%) and lung (22%). Seventy-six percent began ICI as an inpatient and 24% received ICI as continuation of outpatient therapy. Seventeen percent experienced an immunotherapy related adverse event, most commonly colitis and pneumonitis. The 30 day readmission rate was 41%. The median post-discharge survival was 31 days; 47% of patients died during admission or within 30 days of discharge; 14% survived more than 6 months. Factors predictive of shorter post-discharge survival were PS of 3-4 relative to PS 0-2 (HR 2.0, p 〈 0.004), and lung cancer (HR 2.0, p 〈 0.024) and other tumor types (HR 2.1, p 〈 0.004) relative to melanoma. Conclusions: While the majority of inpatients receiving ICI died during admission or within 30 days of discharge, a subset of patients with stage IV disease were alive at 6 months. Tumor type and ECOG PS predict post-discharge survival and may be used to identify inpatients more likely to benefit from ICI. These novel findings, which are unique to a single institution, require additional validation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.6634
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 2
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    Phase II study of pembrolizumab in leptomeningeal carcinomatosis.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 2007-2007
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 2007-2007
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.2007
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Phase II trial of pembrolizumab in patients with brain metastases.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2006-2006
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2006-2006
    Abstract: 2006 Background: Brain metastases are an increasing challenge in oncology due to increasing incidence and limited treatments. Recent studies suggest that brain metastases harbor a tumor microenvironment characterized by immunosuppressive phenotypes, which contribute to treatment resistance. Therefore, a logical therapeutic strategy for brain metastases is to evaluate immune-based strategies that augment T cell cytotoxicity. Methods: This study was designed as an open-label, single-stage, single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases of diverse histologies. The target accrual was 58 patients to achieve at least 52 evaluable patients (i.e., received at least one dose of pembrolizumab). The primary endpoint was intracranial benefit, defined as a best response of complete response, partial response, or stable disease by RANO criteria during treatment. The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among the total of 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study in this patient population. This design has a type-I error of 10% and power of 89% (target type-II error of 15%). Results: In the 57 evaluable patients, median age was 53 (range 28-80) and 81% were female. Tumor histologies included breast (n = 35), non-small cell lung cancer (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), ovarian (n = 1), pituitary carcinoma (n = 1), pituitary neuroendocrine tumor (n = 1), esophageal adenocarcinoma (n = 1), prostate (n = 1), renal cell carcinoma (n = 1), neuroendocrine carcinoma (n = 1), unknown primary (n = 1) and sinonasal adenocystic carcinoma (n = 1). For the patients with breast cancer, 16 patients had HER-2 positive disease, 17 patients had hormone receptor-positive disease, and 11 patients had the triple-negative subtype. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). In addition, seven patients, who had either breast cancer, melanoma or sarcoma, had durable intracranial anti-tumor activity ( 〉 2 years). The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (18/40; 90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema (n = 2). Thirteen patients discontinued treatment for adverse events. Conclusions: Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases. These results suggest that PD-1 blockade may serve as the backbone of therapeutic strategies for a select group of patients with brain metastases and warrants further evaluation. Clinical trial information: NCT02886585 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2006
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
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    Heterogeneous response and irAE patterns in advanced melanoma patients treated with anti-PD-1 monotherapy from different ethnic groups: Subtype distribution discrepancy and beyond.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 10020-10020
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 10020-10020
    Abstract: 10020 Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P 〈 .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.10020
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 5
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    A phase II study of ERK inhibition by ulixertinib (BVD-523) in metastatic uveal melanoma.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 10036-10036
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 10036-10036
    Abstract: 10036 Background: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. This has led to efforts to treat uveal melanoma with MEK inhibition with mixed results. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases which has undergone phase I testing. Methods: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a total sample size of 25 patients (pts) and an initial evaluation of efficacy after 13 pts. Two responses were required to continue to the second stage. Results: From April 2018 to April 2019 thirteen pts were enrolled. Pts were predominantly female (69%) with a median age of 64 yrs. (34 -76). Sites of metastasis included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with BVD-523 and other ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. The best response, per RECIST 1.1, was stable disease (SD) in 4 pts, and disease progression (PD) in 7 patients. Two patients were unevaluable for response due to withdrawing themselves from the study. Median time to progression was 2.0 months (90% CI: 1.8 – 3.6 mos.). There were eight deaths due to disease progression with a median survival time of 6.9 months (90%CI: 3.2 to 8.3 mos.). Analysis of correlative data from pre- and on-treatment biopsies exploring the change in expression of key signaling proteins relating to treatment is underway. Conclusions: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed on study were consistent with what would be expected with MAPK pathway inhibition. Clinical trial information: NCT03417739.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.10036
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 6
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    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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  • 7
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    Predictive plasma proteomic biomarkers of immunotherapy toxicity in patients (pts) with metastatic melanoma (MM).
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. e21569-e21569
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. e21569-e21569
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.e21569
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Investigating the tumor immune infiltrate for populations that predict immune-related adverse events (irAEs) in patients receiving PD-1 inhibitors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3116-3116
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3116-3116
    Abstract: 3116 Background: The mechanistic relationship between clinical benefit and immune-related adverse events (irAEs) in response to immune checkpoint inhibitors (ICIs) remains unclear, with several clinical studies reporting that irAEs are biomarkers of responses. Single-cell RNA sequencing (scRNAseq) analysis of tumors from patients with advanced melanoma before and after treatment with ICIs have identified immune cells that correlate with response to ICIs. We sought to evaluate if these populations were also associated with irAEs. Methods: A published scRNAseq data set generated with the Smart-Seq2 protocol (Sade-Feldman M, et al. Cell 2018.) was re-analyzed, stratified by two definitions of irAEs: (1) toxicity requiring systemic immunosuppression (prednisone 〉 10mg/day) or (2) systemic immunosuppression and/or endocrinopathy. Unbiased single-cell analysis was performed, followed by sub-clustering of T cell populations. The percentage of cells in each cluster was determined on a per sample basis. Results: 13,184 immune cells from 39 samples collected from 25 patients were re-analyzed. 27 samples were from patients who did not respond to ICIs, while 12 samples came from responding patients. 21 samples came from patients who required immunosuppression, 5 samples from patients with isolated thyroiditis, and 13 samples from patients who met neither irAE criteria. Unsupervised scRNAseq analyses focused on ICI efficacy re-capitulated published associations between response and populations that included B-cells (p 〈 0.01) and TCF7 expressing T-cells (p 〈 0.01). While these cell populations were not associated with either definition of toxicity, we observed a non-Treg CD4 expressing T cell population (0.8-10.5% cells/sample) that positively correlated with either definition of toxicity (p 〈 0.05) but not efficacy. Conclusions: In a patient cohort with advanced melanoma, tumor-infiltrating immune cell populations associated with response to ICI therapy were not associated with irAEs. This suggests that biomarkers of ICI response may not function as biomarkers of irAEs, and ongoing analysis will seek to validate this result. Understanding the differences between ICI response and irAEs may identify new therapeutic targets for maximizing efficacy while mitigating toxicity.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3116
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 9
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    CTEP 9557: A dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF mutant solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3609-3609
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3609-3609
    Abstract: 3609 Background: Combination BRAF and MEK inhibitor therapy is associated with response in patients (pts) with BRAF mutant (mut) solid tumors; however critical limitations for the durable activity of these agents remains. Preclinically, the addition of heat shock protein 90 (HSP90) inhibitors improves the efficacy of BRAF inhibitor (BRAFi) therapy in both BRAFi -sensitive and resistant mutant cell lines. Methods: CTEP study 9557 (NCT02097225) is a phase I study designed to determine the safety and efficacy of the small molecule HSP90inhibitor, AT13387, in combination with dabrafenib (dab) and trametinib (tram) in patients with BRAF V600E/K mut solid tumors. Prior chemotherapy, immunotherapy, BRAF and/or MEK exposure was permitted. The primary objective was to determine the maximum tolerated dose (MTD). Results: From July 2015 to June 2018, 22 patients with previously treated, metastatic BRAF V600E/K mut solid tumors were enrolled using a 3 + 3 design at four dose levels (DL) (Table). Pts were predominantly female (59%) with a median age of 57.5yrs (37 -75). The most common tumor type was BRAF V600E mut colon cancer (N=12). Dose limiting toxicities (DLTs) occurred in one patient in DL3 and one in DL4, specifically grade 3 myelosuppression and fatigue, respectively. The MTD was Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. Twenty-one of 22 pts were eligible for efficacy assessment. Best response, per RECIST 1.1, was partial response (PR) in 2 pts – one with colon ca (TKI-naïve), one with melanoma (TKI-resistant) - stable disease (SD) in 8 pts, and disea se progression (PD) in 11 with a disease control rate (PR + SD) of 47.6% (90% CI: 29% - 67%). Median time to progression was significantly longer in DL3 (3.9 mths; 1.8-9.2) compared to DL1 (1.6mths; 0.9-1.7) or DL2 (1.5; 0.6-3.6). Median PFS and OS were 1.8mths (90% CI: 1.6 – 3.7mths) and 5.1 mths (90% CI: 2.5 -10.6mths), respectively. Median OS was not reached in DL3/4. Correlative data on the expression of the key signaling proteins relating to response will be presented at the meeting. Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was determined to be safe with evidence of disease control in a heavily pre-treated population of pts with BRAF V600E/K mut solid tumors. Clinical trial information: NCT02097225 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3609
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 10
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    Characterizing the tumor and immune landscape of melanoma patients treated with combined checkpoint blockade and MAPK targeted therapy.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9522-9522
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9522-9522
    Abstract: 9522 Background: Melanoma therapy has been revolutionized by two novel therapeutic approaches: mitogen activated protein kinase (MAPK) targeted therapy (MTT) and immune checkpoint blockade therapy (ICB). Less than half of patients respond to ICB monotherapy, in part due to non-responsive tumor microenvironment (TME). It previously has been shown that MTT enhances anti-tumor immunity within the TME, thus providing a strong rationale for its combination with immunotherapy. Regimens combining MTT with ICB have had mixed results, and which patients should be treated with these combinations is unknown. Methods: The first arm (NCT03149029) of a planned two stage design was to enroll 14 patients (pts) harboring BRAF V600 mutation treated with 2 weeks (wks) of MTT (dabrafenib plus trametinib) then 6 wks of concomitant MTT and pembrolizumab, followed by single-agent pembrolizumab thereafter. The primary endpoint is clinical benefit (CB) defined as partial/complete response or stable disease (per RECIST1.1) persisting at 24 wks. If 9 of 14 pts had CB, then 11 more pts would be enrolled for a total cohort of 25. Serial biopsies were performed prior to MTT, following the 2-week lead-in of MTT, and following six wks of combination immune therapy and MTT. Single-cell RNA-seq profiling of CD45 + and CD45 - cells was performed using both the smart-seq2 plate-based protocol and 10x genomics platform. Results: Sixteen pts were enrolled, with 14 receiving both MTT and ICB. Two pts did not receive ICB due to MTT toxicity. Only 5 had CB, and the second stage did not open. A 6 th pt had CB extracranially with a new small brain met at wk 24 scans was considered CB for tumor analysis. A clustering analysis of 25 samples (n = 9 pts) showed that following MTT the abundance of CD8 T-cells as well as tumor IFNγ levels were significantly elevated in CB vs. no CB (NCB) patients. In addition, tumor associated macrophages (TAM) in NCB patients possessed mainly an M2 phenotype and expressed a significantly higher level of immune suppressor genes, such as HLA-G and CD52. Interestingly, NCB pts had a significantly higher expression of tumor TGFβ, which is a strong inducer of M2 macrophages. In contrast, most of the TAMs occupying the tumor of the CB pts had the M1 phenotype, and significantly expressed CD9, CD81 and CD82, important factors during antigen recognition and immunological synapse formation. Conclusions: Abbreviated MTT with ICB did not lead to increased clinical benefit at 24 wks in this small study. It is theorized that the tumor’s ability to create a unique microenvironment by producing certain factors (e.g. TGFβ), modifies the immune system and may tilt its path into immune suppression thereby reducing the efficacy of this combinatorial therapy in melanoma pts with metastatic disease. These results may help identify pts most likely to benefit from combined MTT plus ICB and new targets to overcome resistance to these regimens. Clinical trial information: NCT03149029.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9522
    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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