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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e12070-e12070
    Abstract: e12070 Background: In triple negative breast cancer (TNBC), anti-PD-L1 is associated with gains in overall survival, however only in tumors with 〉 1% PD-L1+ ICs. Locoregional cytokine therapy is being evaluated as a method of priming and redirecting ICs to tumors, which may increase I-O benefit particularly in PD-L1 negative tumors. We report a sensitive method of quantifying I-O-related changes in PD-L1 and ICs using mIHC and single-cell hierarchical regression, which controls for within-tumor and across-patient PD-L1/IC heterogeneity. Methods: Pre-treatment and resection tissues from a phase Ib trial of locoregional cytokines (IRX-2, n = 16 subjects) in ESBC were analyzed. IRX-2 contains immunostimulatory cytokines (GM-CSF, IL-2, IFN-α, INF-γ, and IL-12) and was injected in peri-areolar tissue, which communicates directly with tumor-draining lymphatics. Specimens were analyzed for 1) H & E stromal TILs score; 2) clinical PD-L1 IC expression (Ventana SP142, 2 blinded pathologists); and 3) mIHC (PerkinElmer Vectra). InForm software was used to obtain geospatial outputs of tumor cells (CK+) and ICs (CD3, CD8, CD163) across multiple regions of interest (mean:18; range: 9-32). Mixed-effects modeling was used to evaluate for changes in PD-L1, ICs, and IC/tumor distance metrics. Results: PD-L1 and IC quantity by mIHC was highly concordant with clinical PD-L1 IC classification (JT test = 211, p 〈 .001) and TIL score (r = 0.77). Cytokine therapy was associated with higher PD-L1 IC classification in 9/13 tumors, and increased PD-L1 ICs by mIHC in 14/15 (+337%, 95% CI: 120,769%). After adjusting for heterogeneity, cytokine therapy increased CD3+CD8+ ICs (+173%, CI: 93,287%) and CD3+CD8- ICs (+120%, CI: 21,301%). Therapy was also associated with increased effector-helper T-cell clustering (nearest-neighbor distance, -40%, CI: -29,-50%) and effector cell tumor localization (stromal-tumor interface CD8+ density +90%, Cl: 74, 305%). Conclusions: Our method is concordant with clinical PD-L1 and sTILs scores, and can additionally quantify IC and IC distances. This assay may allow for comparative I-O assessments with increased resolution, and will be used in a randomized phase II trial of pembrolizumab, chemo +/- IRX-2 in stage II/III TNBC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 1015-1015
    Abstract: 1015 Background: Atezolizumab (anti-PD-L1) plus nab-paclitaxel was shown to improve outcomes in mTBNC in a phase III clinical trial. Subjects were required to be 〉 12 months from curative-intent therapy in this trial. It remains unknown whether non-taxane chemo + anti-PD-1/L1 will be beneficial in mTNBC, or whether this approach is effective in rapidly-progressing patients ( 〈 12 mo from curative-intent therapy). Methods: mTNBC patients were enrolled in a phase Ib study of anti-PD-1 (pembro, 200mg IV q3w) plus physician’s choice chemo (cape: n = 14, 2000mg BID, 7d on/7d off; or taxol: n = 14, 80mg/m2 q1w). Primary/secondary objectives were to evaluate safety/tolerability (primary) and RECIST1.1 response (w12). The exploratory objective was to explore for differences in immunomodulation according to chemo choice. Mixed effects models were employed to compare the longitudinal effects of chemo on peripheral immune cells (flow cytometry) and T-cell diversity (Immunoseq assay). Results: Enrollment of the trial is complete (n = 28), with 100% of evaluable patients tolerating therapy (n = 22) as of 2/1/2019. Cape ORR was 43% (5 PR, 1 CR, 2 SD) with median PFS = 155d. Taxol ORR was 25% (1 CR, 1 PR, 3 SD) with median PFS = 99d. Subjects enrolled 〈 12 months from curative-intent therapy had numerically lower response (ORR = 27%, 1 CR, 2 PR, 3 SD) than subjects without rapid progression (ORR = 45%, 1 CR, 4 PR, 2 SD). No significant differences in immunomodulation were observed according to chemo type, however both cape & taxol were associated with declines in T-cell quantity (CD4 p 〈 .02, CD8 p 〈 .04) and Immunoseq T-cell fraction over time. Conclusions: Pembro plus cape or taxol is safe with encouraging efficacy, however activity may be lower in the setting of rapid progression following curative-intent chemo. Cape+pembro efficacy is favorable with no measurable differences in immunomodulation, and therefore cape may be preferred as a chemo backbone in selected patients. Both cape and taxol are associated with iatrogenic declines in T-cell quantity, which may explain the observed dropoff in anti-PD-1/L1 activity in later lines. Clinical trial information: NCT02734290.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 1033-1033
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 604-604
    Abstract: 604 Background: The addition of pembro to neoadjuvant chemotherapy (NACT) improves pathological complete response (pCR) rate and recurrence-free survival in stage II/III TNBC, albeit with substantial chemotherapy-attributed toxicity. We hypothesize that locoregional cytokine therapy could be combined with pembro to optimize immune response and clinical outcome. In a phase Ib early-stage breast cancer trial, we previously demonstrated that peri-lymphatic cytokine injection (IRX-2 regimen, comprised of physiologic doses of IL-2, IFNg, and other cytokines derived from activated donor lymphocytes, given with low-dose cyclophosphamide) is well tolerated and associated with increased intratumoral lymphocytes, T-cell activation, and PD-L1 expression. Here, we report preliminary outcomes of neoIRX, a phase II trial evaluating induction IRX-2 + pembro preceding NACT + pembro. Methods: Subjects with stage II/III TNBC were randomized to receive induction pembrolizumab (all subjects: 200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of NACT + pembro. The primary endpoint was pCR rate following NACT + pembro (n = 15 subjects/arm planned); secondary endpoints were safety and tolerability. We explored post-induction/pre-NACT radiographic (ultrasound) and histologic outcomes (TILs, tumor regression) as a biomarker strategy to predict pCR. Results: The trial terminated after n = 12 subjects due to withdrawal of drug support for IRX-2. The IRX-2 arm achieved 83% pCR (n = 5/6, CI 36-100%) compared to 33% pCR with pembro alone (n = 2/6, CI 4-78%). The regimen was well-tolerated with minimal IRX-2-attributed toxicities (67% grade I skin bruise). Toxicities during NACT + pembro were similar to Keynote-522. 67% (n = 4/6) of IRX-2 subjects experienced week 3 radiographic regression, with evidence of brisk lymphocyte infiltration on week 3 biopsy, and with 100% pCR rate (n = 4/4) following NACT + pembro. n = 2/6 subjects receiving pembro+IRX-2 experienced pCR on week 3 biopsy, versus n = 0/3 evaluable in control arm. Conclusions: Induction IRX-2 + pembro is well tolerated and is associated with encouraging outcomes, supporting further study of peri-lymphatic induction cytokine therapy in stage II/III TBNC. Post-induction radiographic and histologic outcomes may identify patients with immune-responsive tumors, for whom NACT de-escalation may be a promising therapeutic approach to mitigate toxicity. Clinical trial information: NCT04373031 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 10000-10000
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 10019-10019
    Abstract: 10019 Background: Cancer and its treatment frequently impact QoL in patients. In older cancer patients, a small decrement in QoL is associated with significant functional impairment, disability, treatment discontinuation and decreased survival. Little is known about the role of exercise in improving QoL in older cancer patients undergoing active chemotherapy and the mechanistic association between inflammation and QoL. We conducted a secondary analysis of a nationwide phase III RCT to assess the effect of exercise on QoL in older cancer patients. Methods: We included 198 older cancer patients (aged ≥60 years) who were randomized to receive chemotherapy alone (C) or with EXCAP (Exercise for Cancer Patients). EXCAP is a home–based progressive aerobic and resistance training program. We used ANCOVA to evaluate the effect of EXCAP on QoL (measured by the Functional Assessment of Cancer Therapy-General, FACT-G, and -Cognitive Function, FACT-Cog). Baseline values, gender and chemotherapy duration were adjusted. We assessed associations between changes in QoL and changes in inflammatory cytokines. Results: Median age was 66.7 ± 2.3 years, 92% were female and 77% had breast cancer. In terms of chemotherapy, 3-week and 2-week regimens were used for 72% and 28%, respectively. EXCAP group had better social (p=0.02), emotional (p=0.04) and physical (p=0.03) well-being post-intervention than the C group. There was also a positive trend for improvement in functional, cognitive and overall well-being (Table 1). In the EXCAP group, improved social well-being was associated with decreases in the pro-inflammatory cytokine, IL-8 (r=0.30, p=0.03). Conclusions: Our analysis showed that exercise improves QoL in older cancer patients receiving active chemotherapy. Improvement in social well-being may be mediated by reducing inflammation. Physicians should consider incorporating exercise when prescribing chemotherapy for older adults with cancer. Clinical trial information: NCT00924651. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 10045-10045
    Abstract: 10045 Background: Cancer related fatigue (CRF) is commonly reported among breast cancer survivors and can negatively impact quality of life and treatment adherence. Large, prospective, longitudinal studies assessing CRF in breast cancer survivors compared to matched non-cancer controls are rare. Methods: Breast cancer survivors (n = 581, stage I-IIIBC, mean age 53.4) from community oncology clinics and age-matched controls (n = 364, mean age 52.6) completed the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI, scores range -24 to 96) prior to chemotherapy (T1), at chemotherapy completion (T2) and six-months after chemotherapy (T3). Linear mixed models compared trajectories of CRF over time in survivors compared to controls, adjusting for age, education, race, BMI, marital status, menopausal status, and depressive symptoms. Results: Survivors reported greater CRF compared to controls at all time points (mean total score T1 9.4 vs. -3.7, T2 17.0 vs. -3.3, and T3 8.5 vs. -3.1, all p 〈 0.001; all subscales p 〈 0.001). From T1 to T2 survivors experienced a significant increase in CRF as shown in the total score (mean change (MC) = 8.3; effect size (ES) = 0.4 , p 〈 0.001), and general, mental, and physical sub-scales (MC = 4.3, 2.1, 3.2 , ES = 0.7, 0.5, 0.7, respectively, all p 〈 0.001), while controls experience minimal changes (MC = 0.1-0.3, ES 〈 0.09, p 〉 0.05). At T3 survivors total score returned to T1 values (MC = -0.1, ES = 0.01, p = 0.461), which was, however, still greater than controls ( p 〈 0.001), while general, mental, and physical CRF subscale scores remained significantly higher than T1 values (MC = 1.2, 1.7, 1.9, ES = 0.2, 0.4, 0.3, respectively, all p 〈 0.001; controls no change). Group by time interactions indicated changes over time were greater in the survivors than controls (p 〈 0.001). In multivariate analyses of survivors, age, BMI, performance status, and baseline depression significantly predicted change in CRF. Conclusions: These results from the largest well-controlled study to date showed that breast cancer survivors experience significantly more CRF prior to and after chemotherapy compared to healthy controls. Further research should aim to identify subgroups of survivors most susceptible to CRF.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 12043-12043
    Abstract: 12043 Background: Impaired nutrition is associated with greater treatment toxicity and reduced overall survival in patients with advanced cancer. We aimed to evaluate the association of impaired nutrition with psychological health and quality of life among older adults with advanced cancer who were starting cancer treatment with palliative intent. Methods: This secondary analysis was performed on baseline data from a nationwide cluster randomized clinical trial (ClinicalTrials.gov identifier: NCT02107443; PI: Mohile; funding NCI UG1CA189961). Adults age ≥70 with advanced cancer and≥1 geriatric assessment impairment were enrolled from 2014 to 2017. Patients with BMI 〈 21 kg/m 2 , 〉 10% involuntary weight loss in the past 6 months, or Mini Nutritional Assessment Short Form (MNA-SF) score of ≤11 were considered to have impaired nutrition. We used separate multivariable linear regressions to evaluate the association of impaired nutrition with each measure of psychological health and quality of life, which included Geriatric Depression Scale (GDS-15, range 0-15), Generalized Anxiety Disorder-7 (GAD-7, range 0-21), NCCN Distress Thermometer (NCCN DT, range 0-10) and Functional Assessment of Cancer Therapy-General (FACT-G, range 0-108). Analyses were adjusted for baseline patient demographics, clinical characteristics, and geriatric assessment. Results: Among 541 patients, mean age was 77 (range 70-96) and 60% had impaired nutrition. Among the 326 patients with impaired nutrition, 95% had MNA-SF ≤11, 23% had 〉 10% weight loss in the last six months, and 20% had BMI 〈 21 kg/m 2 . Mean baseline GDS-15 was 3.1 (standard deviation [SD] 2.7), GAD-7 was 2.9 (SD 4.0), NCCN DT was 2.9 (SD 2.7), and FACT-G was 80 (SD 14). In the adjusted model, compared to those with normal nutrition, older adults with impaired nutrition had greater depression (mean 0.65 points higher on the GDS-15, p 〈 0.01) and lower quality of life (mean 6.0 points lower on the FACT-G, p 〈 0.01). There was insufficient evidence of an association between nutrition and anxiety (β = 0.67, p = 0.06) or distress (β = 0.26, p = 0.28). Conclusions: Recognition of malnutrition by oncology providers is crucial for older adults with advanced cancer. Impaired nutrition is associated with greater depression and lower quality of life among older adults with advanced cancer. Tailored resources to improve psychological health and quality of life are needed to support older adults with impaired nutrition receiving cancer treatment.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 1082-1082
    Abstract: 1082 Background: The IO score is a is a 27-gene signature developed to classify the tumor immune microenvironment derived from the 101-gene TNBCtype genomic classifications. The IO score predicts clinical outcome following immune checkpoint inhibitor therapy in NSCLC and bladder cancer, and recently was shown to predict benefit by pCR of atezolizumab plus CT over neoadjuvant CT alone in early stage TNBC (NeoTRIPaPDL1 trial). The IO score has not yet been evaluated in mTNBC or with pembro in breast cancer. Methods: We report preliminary associations of IO score with response from a phase Ib trial (NCT02734290). mTNBC subjects received 1st/2nd line pembro (200mg IV q3wk) plus investigator’s choice paclitaxel (80mg/m2 IV q1wk, n = 15) or capecitabine (2000mg PO BID x 7d, q2wk, n = 14). Baseline (n = 23) and on-treatment (at wk 6, n = 10) biopsies were analyzed for IO score and genomic subtype by RNA exome sequencing. Objective response rate (ORR, partial or complete response, 12 weeks) and survival was determined among response-evaluable subjects (n= 21). Tumor PD-L1 was assessed by IHC (combined positive score, CPS 〉 10%). The IO signature was analyzed as a binary classifier (IO+/IO-) and as a continuous variable (IO score). Results: 39% of evaluable subjects were IO+ (n =9/23). IO+ was associated with improved clinical outcome, including ORR (IO+ 43%, IO- 29%), median progression free survival (mPFS, IO+ 138d, IO- 79d), and median overall survival (mOS, IO+ 687d, IO- 305d). IO+/IO- classification and IO scores were stable across serial biopsies (Cohen’s kappa = 0.74, r = 0.84). IO score was not strongly correlated with PD-L1 CPS (r = 0.27) or sTILs (r =.09). PD-L1-/IO+ tumors constituted 31% (n = 5/16) of PD-L1- cases and exhibited favorable outcome (ORR 40%, mPFS 162d, mOS 556d). IO score and ORR varied across TNBCtype classifications (BL1 subtype: 50% ORR, 66% IO+; BL2 subtype: 0% ORR, 66% IO+; LAR subtype: 50% ORR, 0% IO+, MSL subtype: 33% ORR, 60% IO+). Conclusions: IO score is associated with favorable outcome following pembro + CT, and may identify PD-L1-negative cases that respond to pembro + CT. Further investigation in larger datasets is warranted to ascertain the clinical utility of IO score in this setting. Funding: Drug support and funding provided by Merck Sharpe & Dohme as part of the Merck Investigator Studies Program. Clinical trial information: NCT02734290.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 513-513
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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