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  • 1
    Online Resource
    Online Resource
    Pathologic response after induction chemo-immunotherapy with single or double immune checkpoint inhibition in locally advanced head and neck squamous cell carcinoma (HNSCC): Expansion cohorts of the CheckRad-CD8 trial.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 6064-6064
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 6064-6064
    Abstract: 6064 Background: Targeting the immune checkpoint CTLA-4 in addition to PD-1/PD-L1 alone did not increase efficacy in HNSCC, whereas this has not been studied in combination with chemotherapy. Induction chemo-immunotherapy followed by pathologic response-based patient selection for chemotherapy-free radioimmunotherapy was efficient in locally advanced HNSCC (J Immunother Cancer. 2022 Jan;10(1):e003747). The expansion cohorts of the CheckRad-CD8 trial studied safety and efficacy of induction chemo-immunotherapy with increased dose or without CTLA-4 inhibition. Methods: Patients with previously untreated stage III-IVB (AJCC 8 th edition) HNSCC were eligible for this multicenter phase II trial. Induction chemo-immunotherapy of the main cohort (MC) consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients in expansion cohort 1 (EC1) received this combination with high dose tremelimumab 300mg fix dose d5 and patients in expansion cohort 2 (EC2) received no tremelimumab. In EC1 and EC2 prophylactic G-CSF was recommended. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy entered chemotherapy-free radioimmunotherapy up to a total dose of 70Gy. The current analysis focuses on toxicity and pathologic response after induction chemo-immunotherapy. Results: Between Sep 2018 and Sep 2021, 80 patients were enrolled in the MC (one excluded), 20 in EC1 and 20 in EC2 (one excluded) subsequently. In the MC, EC1 and EC2 a total of 56%, 50%, 58% were stage IV and 29%, 30%, 26% had p16 positive oropharyngeal tumors. Baseline median intratumoral CD8+ immune cell density was 395/mm², 505/mm² and 763/mm² in MC, EC1 and EC2. After induction chemo-immunotherapy 41 (52%), 12 (60%) and 11 (58%) of the patients had pCR in the re-biopsy in MC, EC1 and EC2. Patients with residual tumor after induction therapy had a median intratumoral CD8+ immune cell density of 670/mm², 781/mm² and 1605/mm², which was a median increase by factor 3.0, 2.1 and 4.8 in the corresponding patients’ tissue samples. In the cohorts MC, EC1 and EC2 the overall rate of grade 3-4 adverse events per patient was 1.38, 1.35 and 0.58. The corresponding rate of non-hematologic adverse events per patient was 0.84, 0.95 and 0.37, respectively. Conclusions: Neither increase of tremelimumab dosage nor its omission did significantly affect pathologic response to induction chemo-immunotherapy with cisplatin/ docetaxel/ durvalumab. Non-hematologic toxicity was slightly increased for high dose tremelimumab and clearly decreased without tremelimumab. The role of concomitant administration of tremelimumab with radiotherapy cannot be assessed until the final study analysis. Clinical trial information: NCT03426657.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.6064
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
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    Development and validation of longitudinal c-reactive protein as dynamic response predictor for PD-L1 blockade in advanced NSCLC: Findings from four atezolizumab clinical trials.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e21113-e21113
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e21113-e21113
    Abstract: e21113 Background: Numerous studies suggested that pre-treatment C-reactive protein (CRP) is a survival predictive biomarker for cancer patients treated with anti-PD-(L)1 blockade. However, the application of longitudinal CRP levels as dynamic biomarker for advanced non-small cell lung cancer (NSCLC) patients treated with anti-PD-(L)1 remains unexplored. Methods: This study analyzed four international, multi-center clinical trials (OAK, BIRCH, POPLAR and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment. CRP test was performed ≤ 96 hours before Day 1 of each cycle. 1438 patients with more than 2 times CRP results (a total of 11,253 records) in all 3 collection timepoints. The primary endpoint was overall survival (OS). First, multivariate survival analysis was conducted to include clinical factors such as gender, ECOG-PS, race and metastases as contributing risk factors. Then, multivariate joint modelling of longitudinal and time-to-event data was used to establish the relationship between longitudinal CRP and OS in the OAK study, whereas external validation was performed by time-dependent AUC analysis on the BIRCH, POPLAR and FIR studies. Results: Log-transformed longitudinal CRP levels (log(CRP)) in combination with clinical factors in absence of PD-L1 expression emerged as independent predictors of worse OS in the OAK study (HR of jointed model = 2.08, 95% CI: 1.84-2.35, p 〈 0.001) with a high accuracy (AUC = 0.74) for predicting OS. The predictive value of longitudinal CRP was validated in the external validation cohorts with good performance in OS (BIRCH: HR = 2.77 (95% CI: 2.31-3.44), AUC = 0.76; POPLAR: HR = 1.95 (95% CI: 1.50-2.64), AUC = 0.76; and FIR: HR = 1.83 (95% CI: 1.46 -2.39), AUC = 0.72). Conclusions: The Bayesian multivariate joint model demonstrated that longitudinal CRP is a strong survival dynamic predictor for atezolizumab-treated NSCLC patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e21113
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy
    Elsevier BV ; 2020
    In:  European Journal of Cancer Vol. 140 ( 2020-11), p. 55-62
    Details
    In: European Journal of Cancer, Elsevier BV, Vol. 140 ( 2020-11), p. 55-62
    Type of Medium: Online Resource
    ISSN: 0959-8049
    URL: Article
    DOI: 10.1016/j.ejca.2020.09.001
    RVK:
    XA 42017.A
    RVK:
    XA 42017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1120460-6
    detail.hit.zdb_id: 1468190-0
    detail.hit.zdb_id: 82061-1
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  • 4
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    Online Resource
    Primary results of the phase II CheckRad-CD8 trial: First-line treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) with double checkpoint blockade and radiotherapy dependent on intratumoral CD8+ T-cell infiltration.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 6007-6007
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 6007-6007
    Abstract: 6007 Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC. Targeting the immune checkpoint CTLA-4 may be synergistic to radiotherapy. This trial studies feasibility and efficacy of combined PD-L1/CTLA-4 blockade concomitant to induction chemotherapy and radiotherapy. Methods: Patients with previously untreated stage III-IVB (AJCC 8 th edition) HNSCC were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy (performed on d22-26) entered radio-immunotherapy (RIT) up to a total dose of 70Gy. Patients received further three cycles of durvalumab/tremelimumab (q4w, two concomitant and one subsequent) followed by eight cycles of durvalumab mono (q4w). Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80% (i.e. dose limiting toxicity/DLT ≤20%; exclusion of patients with other reasons than DLT for treatment discontinuation; feasibility unacceptable if ≤65%). The calculated sample size was 57 patients to enter RIT. Main secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between Sep 2018 and Mai 2020, 80 patients were enrolled (one excluded). Median age was 60 years, 33 patients (42%) were current smokers, 43 patients (54%) had oropharyngeal tumors (53% p16 positive), 44 patients (56%) were stage IV. Median follow up was 12.5 months. After induction chemo-immunotherapy 41 patients had pCR and 31 an intratumoral CD8+ immune cell increase. Of 60 patients entering RIT (primary endpoint cohort), 10 received DLT and 4 discontinued for other reasons. The feasibility rate of the RIT cohort until cycle 6 was 82%, meeting the primary endpoint of ≥80% (95% confidence interval (CI), one-sided (lower boundary): 72%). The RIT cohort had a PFS rate at 1 year of 79% (CI 69-90%) and at 2 years of 73% (CI 61-87%) and an OS rate at 1 year of 89% (CI 81-98%) and at 2 years of 86% (CI 77-97%). The entire study cohort had a PFS rate at 1 year of 75% (CI 65-85%) and at 2 years of 68% (CI 58-81%) and an OS rate at 1 year of 86% (CI 78-95%) and at 2 years of 80% (CI 70-91%). Toxicity (treatment-related or un-related) ≥grade 3 appeared in 75 patients (95%) and mainly consisted of dysphagia (53%), leucopenia (48%) and infections (29%). DLT mainly consisted of hepatitis (10%). Conclusions: The trial met the primary endpoint feasibility. CD8+ T cell-based pathological patient selection after induction therapy identifies patients with promising PFS rates after chemotherapy-free RIT. Clinical trial information: nct03426657.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.6007
    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
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    A multicenter phase II trial of the combination cisplatin/ docetaxel/durvalumab/tremelimumab as single-cycle induction treatment in locally advanced HNSCC (CheckRad-CD8 trial).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 6519-6519
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 6519-6519
    Abstract: 6519 Background: PD-1/PD-L1 inhibitors are efficient in head and neck squamous cell cancer (HNSCC). Combination with anti-CTLA4 agents may enhance anti-tumor activity compared to anti-PD-1/PD-L1 monotherapy in different tumor types. In the CheckRad-CD8 trial the typical induction treatment consisting of Cisplatin/Docetaxel was combined with Durvalumab/Tremelimumab. Patients with pathological complete response (pCR) in the re-biopsy after induction treatment or at least 20% increase of intratumoral CD8 density in the re-biopsy compared to baseline entered radioimmunotherapy with concomitant Durvalumab/Tremelimumab. Methods: In this prospective multicenter phase II trial, patients with HNSCC stage III-IVB received a single cycle of Cisplatin 30mg/m² d1-3, Docetaxel 75mg/m² d1, Durvalumab 1500mg fix dose d5 and Tremelimumab 75mg fix dose d5. Objectives of this interim analysis were to quantify the effect of the induction treatment on intratumoral CD8 density and the pCR rate and to generate safety data. Results: Between Sep 2018 and Dec 2019, 57 patients were enrolled. Median age was 59 years, 22 patients (37%) were current smokers, 27 patients (47%) had oropharyngeal tumors (52% p16 positive). The median pre-treatment intratumoral CD8 density was 335 CD8+ cells/mm². After induction treatment 27 patients (47%) had a pCR in the re-biopsy and further 25 patients (44%) had a relevant increase of intratumoral CD8+ cells (median increase by factor 3.0). Response according to RECIST criteria was CR in 1 (2%), PR in 19 (33%) and SD in 20 patients (35%) (17 patients not evaluable). Adverse events (AE) grade 3-4 appeared in 39 patients (68%) and mainly consisted of leucopenia (43%) and infections (28%). 6 patients (11%) developed grade 3-4 immune-related AEs. In multivariable analysis the intratumoral CD8 density was the only independently significant predictor of pCR (odds ratio 1.0013 per cell/mm², 95%-CI 1.00023-1.0023, p=0.017). 42 patients (74%) continued with Durvalumab/ Tremelimumab concomitant to radiotherapy. Conclusions: Single cycle induction treatment with Cisplatin/Docetaxel/Durvalumab/Tremelimumab is feasible and achieves a high pCR rate. CD8 density may have a predictive role for further treatment planning in locally advanced HNSCC. Clinical trial information: NCT03426657 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.6519
    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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  • 6
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    Abstract 382: Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 382-382
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 382-382
    Abstract: Background: Numerus studies already proved C-reactive protein (CRP) in pre-treat is a predictive biomarkers to for cancer patients treated with anti-PD(L)-1 antibodies. However, there aren't any study has evaluated CRP levels longitudinally in patients with immune checkpoint inhibitors (ICIs). This study provides a comprehensive investigation of CRP levels as well as its longitudinal trajectories as a dynamic predictor of treatment response and survival outcome in metastatic cancer patients undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: A total number of 104 patients were prospectively enrolled. First, multivariate survival analysis for clinical factors, which including cancer types, line of treatment, PD-L1 expression, brain metastases (BM), etc. Then, used multivariate joint modelling of longitudinal and time to event data to establish the relationship between longitudinal CRP and the overall survival (OS). Results: 92/102 patients with more than 2 times CRP results in all of treatment timepoints. Longitudinal CRP levels combine with clinical factors emerged as independent predictors of worse OS (HR of jointed model= 1.82, 95% CI: 1.45-2.32, p & lt; 0.001), and this dynamic biomarker achieved a high accuracy (C-index 0.81) for predicting OS. However, those clinical factors didn't impact the dynamic CRP in this jointed model (HR of PD-L1= 1.68(0.79-3.65), HR of BM= 0.82(0.42-1.64), HR of PD-L1: BM=0.76(0.30-1.89)). Conclusion: Our study highlights longitudinal CRP serves as potential personalized dynamic predictions for immunotherapeutic benefit of metastatic cancer patients. Keywords: metastatic cancers, immune checkpoint inhibitors, C-reactive protein, dynamic predictor Trial registration: Prospectively registered in ClinicalTrials.gov (NCT03453892) on January 24, 2018. Citation Format: Jian-Guo Zhou, Hu Ma, Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau. Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 382.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-382
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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