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V. Villaflor
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.03 - Circulating Tumor DNA Mutant Allele Frequency and Tumor Burden as Biomarkers for Response to Immune Checkpoint Blockade (ID 9606)
16:05 - 16:15 | Author(s): V. Villaflor
- Abstract
- Presentation
Background:
Identifying biomarkers to select patients who respond to immune checkpoint blockade in non-small cell lung cancer (NSCLC) remains a challenge. Cell-free circulating tumor DNA (ctDNA) has emerged as a non-invasive, quantitative method of monitoring genomic alterations in the peripheral blood. We evaluated the clinical utility of ctDNA mutant allele frequency (MAF) and tumor burden based on imaging as biomarkers for response to immune checkpoint blockade in NSCLC.
Method:
From a cohort of 136 patients with ctDNA samples, 20 patients were retrospectively identified with ctDNA testing before initiation of anti-PD-1/PD-L1 treatment or within 90 days of therapy initiation. ctDNA testing was performed by Guardant360 (Guardant Health, Redwood City, CA). MAF of the dominant clone was identified quantitatively for each patient. In addition, baseline tumor burden was estimated using RECIST version 1.1. MAF and tumor burden were correlated with progression free survival (PFS) and overall survival (OS). Logistic regression of response rate (RR) and clinical benefit rate (CBR) was also performed.
Result:
Higher median ctDNA MAF was correlated with significantly shorter PFS and OS (hazard ratio (HR) 3.4, p=0.03 and HR 10.4, p=0.03, respectively) (Figure 1). There was no significant association between tumor burden estimation and PFS and OS. However, tumor burden was significantly correlated with MAF (r=0.58, p=0.007). MAF and tumor burden estimation did not correlate with RR or CBR in this small sample. Figure 1
Conclusion:
ctDNA MAF appears to be a promising, non-invasive, prognostic biomarker for response to immune checkpoint blockade in NSCLC with higher MAF associated with shorter PFS and OS. ctDNA MAF may also serve as a surrogate for tumor burden. Prospective studies with serial ctDNA sampling are necessary to further validate these findings.
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-004 - Phase I/Ib Study of Nivolumab and Veliparib in Advanced Solid Tumors and Lymphoma with and without Alterations in Selected DNA Repair Genes (ID 8357)
09:30 - 09:30 | Author(s): V. Villaflor
- Abstract
Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been a successful treatment strategy in a minority of patients with many different tumor histologies (non-small cell lung cancer, squamous cell head and neck cancer, melanoma, Hodgkin lymphoma, renal cell carcinoma, urothelial carcinoma). An increase in the proportion of patients that benefit from this emerging mechanism is needed. Veliparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), and it has been shown in preclinical models and in patients with BRCA mutant ovarian cancer to exert anti-tumor effects through lethal exacerbation of DNA repair defects. Extensive genomic sequencing of tumors of varying histologies has revealed that approximately 5% of all tumors harbor defects in DNA repair genes such as BRCA1/2, RAD51, CHEK1, ATM, ATR, CHEK2, FANCD2, FANCA. We propose combining PD-1 inhibition with nivolumab with PARP inhibition with veliparib in patients with DNA repair gene defects in order to maximize the proportion of patients with clinical responses to these novel treatment strategies.
Method:
We are currently enrolling patients on this phase I/Ib clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. The study schema is shown below. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.04-005 - Phase 2 Study of Nivolumab and Metformin in Advanced Non-Small Cell Lung Cancer with and without Prior Treatment with PD-1/PD-L1 Inhibitors (ID 8505)
09:30 - 09:30 | Author(s): V. Villaflor
- Abstract
Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been proven to be a successful treatment strategy in a minority of patients with non-small cell lung cancer. An increase in the proportion of patients that benefit from this emerging mechanism is needed, and many novel combination therapies are being tested. Furthermore, many patients with non-small cell lung cancer are excluded from further clinical trials if they have received prior checkpoint inhibitor therapy, so this trial provides for this additional unmet need. Epidemiologic studies have consistently demonstrated an association between decreased cancer incidence and mortality in patient treated with metformin. Preclinical models have demonstrated that this anti-cancer effect is potentially mediated by inhibition of insulin like growth factor-1 (IGF-1) and mTOR, as well as activation of AMPK and tuberous sclerosis complex (TSC1, TSC2). Also, metformin has recently been found to exert immunomodulatory functions, inhibiting the exhaustion of CD8+ tumor infiltrating lymphocyte (TIL) function, thereby upregulating tumor-specific immune function. It accomplishes this by preventing apoptosis of CD8+ TILs and converting CD8+ TILs from quiescient central memory T cells to effector memory T cells with active anti-tumor effects. In vivo, the addition of metformin to vaccination enhances the generation of effector memory T cells, congruent with the overall hypothesis. We propose a proof-of-concept parallel phase 2 trial using the combination regimen of nivolumab and metformin. We hypothesize that the combination of nivolumab and metformin will be synergistic and can overcome resistance to single agent PD-1/PD-L1 inhibitors.
Method:
We are currently enrolling patients in this phase II clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-034 - Pretreatment Neutrophil & Platelet Count as a Predictor for Unfavorable Clinical Outcome in Non-Small Cell Lung Cancer (NSCLC) (ID 10250)
09:30 - 09:30 | Author(s): V. Villaflor
- Abstract
Background:
The importance of tumor immune microenvironment in disease outcomes has already been established. We can speculate that markers present in patients’ complete blood count (CBC) such as absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) could potentially help predict clinical benefit. In addition, given the recently discovered T cell inhibitory role of platelets, we hypothesized that increased platelet counts may lower the efficacy of T cell mediated immune checkpoint inhibitors. Here, we explored how well the information obtained from the simple non-invasive peripheral blood CBC can predict clinical outcome to immunotherapy in NSCLC.
Method:
ANC, ALC, AMC, neutrophil lymphocyte ratio (NLR) and platelet values were collected for twenty NSCLC patients at two times points; pretreatment (t1) & approximately 2-3 weeks after first treatment (t2). Response to immune checkpoint inhibitors based on RECIST criteria (response rate (RR) and clinical benefit rate (CBR)), progression-free survival (PFS) and overall survival (OS) were examined. Cox regression analyses were performed for baseline and delta (t2-t1) CBC values while controlling for various other clinical variables.
Result:
Baseline ANC and AMC were significantly associated with both worse PFS and OS, respectively (ANC; HR= 1.30, p=0.004 & HR= 1.31, p=0.020, AMC; HR= 13.75, p=0.030 & HR= 38.14, p=0.042). Platelets showed significance for only worse OS (HR= 4.45, p=0.036). Delta hematological profiles did not show any significant differences in clinical outcome. In multivariate analyses adjusting for clinical variables, ANC remained as an independent predictor of unfavorable PFS. None of the above variables examined were predictive of RR or CBR. Figure 1
Conclusion:
Elevated pretreatment ANC appears to strongly predict shorter PFS and OS in patients with NSCLC treated with immunotherapy. Pretreatment platelets greater than 400K was linked with poor survival outcome. Further studies with a larger cohort and serial CBC collection during treatment are warranted to validate this study.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-013 - Prognostic Role of Circulating Tumor DNA (ctDNA) and Immune Cell Biomarkers in Non-Small Cell Lung Cancer (NSCLC) (ID 10358)
09:30 - 09:30 | Author(s): V. Villaflor
- Abstract
Background:
Peripheral blood biomarkers can provide valuable information in a relatively non-invasive manner. In solid tumors, it has been suggested that ctDNA mutant allele frequency (MAF) and immune cell counts from peripheral blood complete blood count (CBC) at baseline may be associated with survival outcome. Here, we investigated the role of ctDNA MAF and immune cells as prognostic biomarkers that may predict overall survival in patients with NSCLC.
Method:
A retrospective cohort of 128 patients with ctDNA sample testing performed by ctDNA NGS test (Guardant360) were selected. ctDNA MAF of the dominant clone was collected. CBC’s drawn within a 1-2 week window (baseline) of ctDNA were reported for absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), neutrophil lymphocyte ratio (NLR) and platelet count. Platelets and MAF were analyzed by quartiles (lower 75% vs highest 25%). Survival analyses and Cox regression analyses were performed on these variables.
Result:
A significant association was found for ANC (hazard ratio (HR) = 1.17, p<0.001), AMC (HR=1.98, p=0.037), MAF (HR=2.53, p=0.005), NLR>5(HR=2.98, p<0.001), and platelet counts (HR=2.49, p=0.006) with overall survival (OS), but not ALC. In multivariate analyses adjusting for clinical variables including age, sex, smoking status, histology, disease stage, number of prior lines of treatment, prior radiation, history of other cancers and ALK/EGFR mutation status, ANC remained as an independent predictor of OS(HR= 1.19, p<0.001). Figure 1
Conclusion:
Higher ANC, AMC, NLR, platelet counts and MAF were associated with poor overall survival. Further studies are required to validate our findings in patients with NSCLC.
