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  • American Society of Clinical Oncology (ASCO)  (9)
  • Sauter, Jennifer L.  (9)
  • 1
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    Molecular correlates of PD-L1 expression in patients with non-small cell lung cancer.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 9018-9018
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 9018-9018
    Abstract: 9018 Background: PD-L1 expression is the only FDA-approved predictive biomarker for patients with NSCLC treated with immune checkpoint inhibitors. The impact of tumor molecular profiling on tumor PD-L1 expression is not known. We hypothesized that somatic mutations and copy number alterations may be associated with distinct patterns of PD-L1 expression in patients with NSCLC. Methods: We examined patients with NSCLC in whom PD-L1 testing and targeted next-generation sequencing (MSK-IMPACT) were performed on the same tissue sample. PD-L1 expression was determined by IHC using the E1L3N antibody clone and categorized as PD-L1 high (≥ 50%), intermediate (1-49%), or negative ( 〈 1%) expression. The association of PD-L1 with individual genes, pathways, tumor mutation burden, whole genome duplication (WGD), and aneuploidy (fraction of genome altered (FGA)) were evaluated. P-values 〈 0.05 and q-values 〈 0.15 were considered significant for individual genes. Results: 1023 patients with NSCLC had PD-L1 testing and MSK-IMPACT performed on the same tissue sample, 18% (n = 180) had high, 21% (n = 218) had intermediate, and 61% (n = 625) had negative PD-L1 expression. High PD-L1 expression was significantly enriched in metastatic vs primary lesions (p 〈 0.001). There was a minor correlation between PD-L1 and TMB (spearman rho = 0.195) and PD-L1 and FGA (spearman rho = 0.11). Similar rates of WGD were found among patients with high, intermediate, and negative PD-L1 expression (p = 0.38). Mutations in KRAS and TERT were significantly enriched in PD-L1 high compared to other groups (p = 0.001, q = 0.14; p 〈 0.001, q = 0.003). By contrast, mutations in EGFR and STK11 were associated with PD-L1 negativity (p 〈 0.001, q = 0.001; p = 0.001, q = 0.14). Pathway analysis showed DNA repair (p 〈 0.001), TP53 (p 〈 0.001), and SWI/SNF (p = 0.04) pathways significantly associated with PD-L1 high compared to PD-L1 negative expression. Conclusions: The genetic features of NSCLC are associated with distinct patterns of PD-L1 expression. This data may provide insight to how the molecular phenotype can interact with the immunologic phenotype of tumors.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.9018
    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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  • 2
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    Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 7 ( 2018-03-01), p. 633-641
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 7 ( 2018-03-01), p. 633-641
    Abstract: Treatment of advanced non–small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non–small-cell lung cancer treated with anti–programmed death-1 or anti–programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted 〉 6 months. Tumor mutation burden (TMB), fraction of copy number–altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P 〈 .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P 〈 .001; hazard ratio, 1.38; P = .024). The fraction of copy number–altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.75.3384
    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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    Outcomes to first-line pembrolizumab in patients with non-small cell lung cancer and a PD-L1 tumor proportion score ≥90%.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 9111-9111
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 9111-9111
    Abstract: 9111 Background: In non-small cell lung cancers with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of ≥50%, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared to platinum-doublet chemotherapy. Whether higher PD-L1 expression levels within the TPS range of 50-100% predict for even greater benefit to pembrolizumab is currently unknown. Methods: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment for advanced NSCLC with a PD-L1 TPS of ≥50%. Results: Among 196 patients with NSCLC treated with first-line pembrolizumab, the ORR was 43.8% (95%CI: 36.8-51.1). At a median follow-up of 12.6 months (95%CI: 11.6-13.7), the mPFS was 6.2 months (95% CI: 4.2-8.2) and the mOS was not reached. The median PD-L1 TPS among patients who experienced a response to pembrolizumab was significantly higher than in patients with stable or progressive disease (TPS 90% vs 70%, P 〈 0.001), so a TPS cut point of 90% was chosen for further analysis. Baseline clinicopathological characteristics were well-balanced between patients with a PD-L1 TPS of 50-89% vs 90-100%. Compared to patients with a PD-L1 TPS of 50-89% (N = 114, 58.2% of the cohort), patients with a TPS of 90-100% (N = 82, 41.8% of the cohort) had a significantly higher ORR (61.0% versus 31.6%, P 〈 0.001), a significantly longer mPFS (13.2 versus 3.7 months, HR: 0.48 [95% CI: 0.33-0.71], P 〈 0.001), and a significantly longer mOS (NR versus 16.0 months, HR: 0.38 [95% CI: 0.21-0.70], P = 0.002). After adjusting for ECOG performance status and smoking history, PD-L1 TPS of 90-100% was significantly associated with improved mPFS (HR: 0.51 [95% CI: 0.34-0.75] , P 〈 0.001) and mOS (HR: 0.38 [95% CI: 0.21-0.70], P = 0.001). Conclusions: Among patients with NSCLC and a PD-L1 TPS ≥50%, clinical outcomes are improved in the subgroup of patients with a PD-L1 TPS of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.9111
    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
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    Acquired resistance to PD-1 blockade in NSCLC.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 9621-9621
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 9621-9621
    Abstract: 9621 Background: Although durability is the trademark characteristic of response to PD-1 blockade, acquired resistance can occur. The frequency, patterns, and survival outcomes of patients with acquired resistance to PD-1 blockade are unknown. Methods: All patients with NSCLC treated with PD-1 blockade at MSKCC were examined. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo vs systemic patterns of acquired resistance were defined as progression in ≤ 2 sites of disease or ≥ 3 sites of disease, respectively. Results: Of 1201 patients treated with PD-1 blockade, 243 (20%) achieved initial response and 189 (78%, 95% CI 72-83%) eventually developed acquired resistance (AR). Onset of AR was variable and decreased with longer duration of response (53% within 1 year, 37% 1-2 years, 10% 〉 2 years). Patients with PD-L1 expression 〈 50% and TMB 〈 8mut/Mb were more likely to develop resistance compared those with PD-L1 expression ≥50% and TMB ≥8mut/Mb (OR 5.5, p = 0.02). Unlike organ sites of primary refractory disease, AR commonly occurred in lymph nodes (41%) and infrequently in the liver (6%). Patterns of AR were most commonly oligo rather than systemic (79/141 [56%], 39/141 [28%] ); some patients died without radiographic progression (23/141 [16%]). Oligo-AR occurred later (median onset 13 vs 5.6 mo) and associated with improved post-progression survival (median OS 55.2 vs 9.2 mo, HR 6.0, p 〈 0.001) compared to systemic-AR. Post-progression survival was highest in patients with AR compared to those with initial SD or PD to PD-1 blockade (median 18.9 vs 12.5 vs 4.4, p 〈 0.001). Of 49 patients treated initially with locally-directed therapy for AR, 28 (57%) remain alive and systemic therapy-free. Conclusions: Acquired resistance to PD-1 blockade is common in NSCLC. Risk of acquired resistance is lower in biomarker-enriched patients and with increased duration of response. Patterns of acquired resistance is commonly oligo in nature, which is amenable to locally-directed therapy and can be associated with improved survival. Differences in organ-site distribution and post-progression survival suggest distinct biology associated with acquired resistance vs primary refractory disease.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.9621
    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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    Long-term responders to PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 9549-9549
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 9549-9549
    Abstract: 9549 Background: Long-term response – the plateau of the survival curve – is the transcendent benefit from PD-1 blockade. However, only a subset of responses achieve substantial durability. The frequency, characteristics, and predictors of long-term responders (LTR) to PD-1 blockade are not well known and may differ from short-term responders (STR). Methods: Patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy from two institutions (MSK and DFCI) were examined. Responses were assessed by RECIST. LTR was defined as PR/CR lasting ≥ 24 months. STR was defined as PR/CR lasting 〈 12 months. Comparisons were also made to patients with progressive disease (PD). PD-L1 expression was assessed by IHC. TMB was assessed by targeted NGS; high TMB was defined as ≥ median of the cohort. A subset had detailed molecular profiling by MSK-IMPACT. Fisher’s exact and Mann-Whitney U tests were used to compare features, and the log-rank test was used to compare survival. Results: Of 2318 patients (MSK n = 1536, DFCI n = 782), 126 (5.4%, 95% CI 4.6-6.4%) achieved LTR, with similar rates in both cohorts. STR occurred in 139 (6%). Overall survival was longer in LTR compared to STR (median NR vs 19.6 months, HR 0.07, p 〈 0.001). LTR had deeper responses compared to STR (median best overall response -69% vs -46%, p 〈 0.001). Patients with LTR were younger ( 〈 65 years old) and had increased TMB (≥ median mut/Mb) compared to both STR and PD (p = 0.006, p = 0.03; p 〈 0.001, p 〈 0.001). The rate of LTR was enriched among patients with both high TMB/high PD-L1 compared to those with low TMB/low PD-L1 (9% vs 1%, OR 9.2, p 〈 0.001), while STR was similar in both groups (7% vs 6%). 2% of patients with sensitizing EGFR mutations (n = 243) achieved LTR. Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in LTR compared to STR (p 〈 0.05 for each). Among patients with KRAS mutations, the rate of LTR was higher in those with co-mutation with TP53 compared to STK11 (11% vs 2%, p = 0.01). Conclusions: Long-term response (LTR, ongoing response ≥ 24 months) to PD-1 blockade is an uncommon but profound clinical outcome in metastatic lung cancers. Younger age and high TMB correlate with LTR; the combination of high TMB/high PD-L1 enriches for LTR but not STR. Features predicting long term response may be distinct from those predicting initial response.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.9549
    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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    Response and durability of anti-PD-(L)1 therapy in never- or light-smokers with non-small cell lung cancer (NSCLC) and high PD-L1 expression.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 9011-9011
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 9011-9011
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.9011
    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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  • 7
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    Clinical and molecular features predicting long-term response (LTR) to anti-PD-(L)1 based therapy in patients with NSCLC.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 9022-9022
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 9022-9022
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.9022
    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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    Multimodal integration of radiology, pathology, and genomics for prediction of response to PD-1 blockade in patients with non–small cell lung cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 9064-9064
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 9064-9064
    Abstract: 9064 Background: Immunotherapy is now given to almost all patients with advanced non-small cell lung cancer (NSCLC). However, developing robust biomarkers to predict benefit remains challenging. We set out to evaluate the predictive capacity of integrating medical imaging, histopathologic, and genomic features to develop a multimodal biomarker for immunotherapy response. Methods: We used baseline data that is routinely obtained during diagnostic clinical workup at a single center in patients with NSCLC and known outcomes following immunotherapy. The multimodal dataset included DNA alterations from NGS, CT scan images, and digitized PD-L1 immunohistochemistry (IHC) slides. Guided by experts in each field, we developed a workflow to extract data for each patient and used an attention-gated machine learning approach to integrate the features into a risk prediction model. Results: Our cohort included 247 patients with advanced NSCLC who received immunotherapy and had complete radiology, pathology, genomic, and clinical data. The patient cohort was 54% female, had a median age of 68 years (range 38-93), and 88% patients had a smoking history. Responders (CR/PR) vs non-responders (SD/PD) showed a median PFS and OS of 2.7 months (95% CI 2.5-3.0) and 11.4 months (95% CI 10.3-12.8), respectively. Of all patients, 187 (76%) had segmentable disease on chest CT scans. We used a radiomics approach and aggregated the average individual lesion predictions to construct patient-level response predictions which resulted in an overall AUC = 0.65, 95% CI 0.57-0.73. We next studied digitized FFPE slides of pre-treatment PD-L1 IHC staining of tumor specimens. Overall, 52% of slides showed PD-L1 tumor proportion score (TPS) ≥ 1% and were used to extract IHC-texture, a novel spatial characterization of PD-L1 staining. Logistic regression modeling on IHC-texture resulted in prediction accuracy of AUC = 0.62 (95% CI 0.51-0.73) which was inferior to the pathologist-assessed PD-L1 TPS (AUC = 0.73, 95% CI 0.65-0.81). We next implemented a dynamic deep attention-based multiple instance learning model with masking to evaluate the impact of combining features from all modalities. Our multimodal model (AUC = 0.80, 95% CI 0.74-0.86) outperformed unimodal measures, including tumor mutational burden (AUC = 0.61, 95% CI 0.52-0.70) and PD-L1 TPS (AUC = 0.73, 95% CI 0.65-0.81). Conclusions: Our study is a proof of concept for using multimodal features to improve prediction of immunotherapy response over standard-of-care approaches in patients with NSCLC using expert-guided machine learning.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.9064
    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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  • 9
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    Association of BAP1 alterations with malignant pleural mesothelioma treated with trimodality therapy.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 8552-8552
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 8552-8552
    Abstract: 8552 Background: Trimodality therapy with pleurectomy/decortication, cytotoxic chemotherapy, and adjuvant pleural intensity modulated radiation therapy (IMPRINT) is an emerging standard of care for locally advanced epithelioid mesothelioma (Rimner, Zauderer et al. JCO 2016). Some patients, however, progress rapidly and we therefore sought to identify potential predictive markers of response to this treatment. Given the putative role of BAP1 in DNA damage repair, we hypothesized that alteration in BAP1 would be associated with improved local control after radiation therapy. Methods: We identified patients previously treated at our institution with IMPRINT to a median dose of 4680cGy in 26 fractions. Targeted next generation sequencing was performed with MSK-IMPACT on archival tissue samples. Chart review was undertaken for clinicopathologic features and outcome data. Results: MSK-IMPACT testing was successfully performed on 58 patients who completed IMPRINT. The majority were male with a median age of 70 years. Ninety-seven percent had epithelioid subtype while 3% were biphasic with predominantly epithelioid histology. Median overall survival was 30.2 months with a median follow-up of 45.3 months, consistent with prior reports. Somatic BAP1 mutations were identified in 34% of the specimens. Those with BAP1 mutant tumors had a median time to local failure of 22.4 months (IQR 10.9 – 36.9 months) while those with BAP1 wild type tumors only had a median of 12.1 months (IQR 8.7-15.85 months) to local failure (p = 0.057). We identified a trend towards improved overall survival among those with BAP1 altered tumors compared to those with BAP1 wild type (HR = 0.61, p = 0.14). Conclusions: BAP1 alteration may be associated with improved duration of local control and improved overall survival after IMPRINT therapy. Further analysis and validation in a large data set is needed and a platform for identifying and validating predictive biomarkers should be included in the planned NRG randomized trial of IMPRINT.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.8552
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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