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Luis E. Raez
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.12 - Brain Necrosis in Patients With Metastatic Lung and Breast Cancer Successfully Treated With Bevacizumab (ID 1689)
00:00 - 00:00 | Presenting Author(s): Luis E. Raez
- Abstract
Introduction
Patients (pts) develop brain radionecrosis (BRN) as a result of radiation therapy for brain tumors or metastatic brain lesions. This is seen more often now with the use of stereotactic radiosurgery (SRS). BRN is characterized by an increase in permeability and disruption of the blood brain barrier (BBB). The mechanism of BRN is currently unknown, however it is hypothesized that there is an inflammatory reaction of the local tissue to radiation which results in a continuous process involving endothelial cell dysfunction. This leads to tissue hypoxia and increased vascular endothelial growth factor (VEGF) which in turn causes capillary leakage, progressive BBB dysfunction, and cerebral edema. There are currently no standard treatment options for BRN. Bevacizumab (BEV), a humanized monoclonal antibody with action against VEGF, has recently been used in some reports for the treatment of BRN. BEV essentially blocks VEGF from reaching its targets on the endothelium, thus making it an interesting treatment modality for BRN.
Methods
We identified BRN in 15 pts with brain metastasis treated with SRS at our institution (14 diagnosed with lung cancer and one with breast cancer). We assessed the efficacy and safety of BEV for the treatment of BRN. A demographic review was conducted, analyzing pts’s age, sex, ethnicity, etc. We evaluated the BEV dose, dosing frequency, number of treatments received, medication-related adverse effects (AE), and clinical benefit. Brain imaging, mainly MRI and PET scan, were completed pre-treatment and after four cycles of therapy to evaluate the efficacy of BEV. Pts who exhibited clinical benefit, defined as complete response (CR), partial response (PR), or stable disease (SD), received an additional four cycles of treatment.
Results
The median age was 65y (range 49-78y) and 9/14 (64%) pts were female. Clinical benefit was achieved in 13/15 (87%) pts. Pts experienced improvement of cognitive function, headaches, weakness and other symptoms. MRIs showed improvement in edema and a reduction or stabilization of the brain lesions. The most frequent dosing regimen administered was 10 mg/kg of BEV every two weeks and the median number of cycles given was eight cycles (1-12). Treatment with BEV was well tolerated with eight pts (53%) experiencing BEV-related grade two or less AE including hypertension (21%), proteinuria (14%), thrombocytopenia (7%) and mild nose bleeds (7%). There were no Grade 3-5 AE.
Conclusion
This study demonstrates that there is a clinical benefit when administering BEV for the treatment of BRN in lung cancer pts with metastatic brain lesions. BEV was well tolerated and had an acceptable safety profile.
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.04 - cfRNA from Liquid Biopsies Is More Abundant Than cfDNA, Informs Treatment Outcome and Is Concordant with Tissue (ID 1203)
00:00 - 00:00 | Presenting Author(s): Luis E. Raez
- Abstract
Introduction
The most analyzed nucleic acid in liquid biopsies is cfDNA due to its presumed greater stability compared with cfRNA. However, sometimes it is difficult to isolate sufficient tumor cfDNA from blood for analyses. In theory, cfRNA representing a particular gene expression should be present at much higher levels than the corresponding gene in cfDNA because a single gene is normally transcribed many times. cfRNA should contain only those mutations that are consequential for tumor development and also allows the measurement of tumor gene expressions. Here, we compared levels of cfDNA and cfRNA isolated from patients’ blood, to assess the stability of the cfRNA and its utility as a biomarker to follow therapy outcomes in non-small cell lung (NSCLC) cancer.
Methods
137 blood samples (20cc) from 54 pts with stage IIIB/IV NSCLC were drawn into both RNA and DNA BCT Tubes (Streck) pre-treatment and at three month intervals or progression. Levels of cfRNA, cfDNA, KRAS and PD-L1 gene expression were quantitated by qPCR and correlated with pts response (CR/PR/SD/PD), as determined by CT scans at the same time. Whole transcriptome RNA seq analysis was performed on 87 tissue-plasma paired samples in a separate study.
Results
There was a strong association of PD-L1 with Outcome to Immunotherapy in Tissue and Blood. 80% of pts positive for PD-L1 in tissue (9/11) were positive for PD-L1 in blood; 83% of these patients responded to immunotherapy with a PR. Also 46% of pts negative for PD-L1 in tissue (6/13) were also negative in blood. Pts negative for PD-L1 in blood only did not respond to immunotherapy with a PR.
Changes in cfRNA and cfDNA as surrogates for monitoring disease status were seen when levels of cfDNA were significant. Levels of these nucleic acids exuded into the blood stream increased as patients progressed (PD) and decreased or remained stable as patients responded to therapy with a PR or SD. However, when cfDNA levels were at the limit of detection, changes in cfRNA levels still accurately predict patient outcome to disease. In 87% of treatment segments (55/63), changes in cfRNA levels were concordant with CT scans, whereas cfDNA levels were concordant with CT scans in 62% (24/63) of treatment segments.
Finally our concordance analysis of NGS done in cfRNA in Tissue and Blood compare representative biomarker expressions (CD86, PD-L1, TIGIT, CD28, TIM3, CTLA4, LAG3 PDL2, PD1, FOXP3, IDO, OX40) in paired tissue and plasma samples using RNAseq whole transcriptome analysis (WTA). The qualitative and quantitative concordance between tissue and plasma gene expressions reached 84% and 76% respectively.
Conclusion
CfRNA levels average 20 x higher than cfDNA levels and can track treatment outcome similarly to cfDNA even when cfDNA is limiting. cfRNA yields data on specific gene expression drug targets such as PD-L1 and is concordant with IHC. PD-L1 gene expression from cfRNA can accurately monitor response to immunotherapy in NSCLC. Levels of gene expressions in tissue and blood measured by RNAseq WTA are concordant.
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P33 - Pathology - Immunotherapy Biomarker (ID 101)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P33.14 - STK11/LKB1, KRAS Mutations and Immune-Related Adverse Events as Predictors of Response to Immunotherapy in Lung Cancer (ID 1674)
00:00 - 00:00 | Presenting Author(s): Luis E. Raez
- Abstract
Introduction
Programmed death-ligand 1 (PD-L1) and tumor mutational burden (TMB) might help us predict responses to check point inhibitors (CPI), but we don’t have biomarkers that can predict resistance. Preliminary reports of mutations (mut) in STK11/LKB1 have suggested that they can confer CPI resistance. We investigated the role of STK1/LKB11, KRAS mut as markers of poor response to CPI in patients (pts) with non-small cell lung cancer (NSCLC). Additionally, we previously reported evidence that immune-related adverse events (irAEs) and its utility in identifying potential responders to CPIs. We investigated the role of STK11/LKB1 mut, KRAS mut and irAEs as predictors of response to CPIs in patients (pts) with non-small cell lung cancer (NSCLC).
Methods
Pts with stage IIIB-IV NSCLC who were treated with CPI were prospectively tested (NGS) for KRAS and STK11/LKB1 mut were evaluated for progression free survival (PFS) and overall survival (OS). Log-rank tests were used to compare OS and PFS, chi-squared tests were used to compare 1-year survivals and proportions among different variables, and Kaplan-Meier survival curves were used to report OS and PFS. Furthermore, since Hispanics (H) are often not stratified in clinical trials, we sought to evaluate if incidence of irAEs and STK11 mut were similar between H and non-Hispanic (NH) pts.
Results
Of the 127 pts: 31 pts had an STK11 mut and 14 had an STK11+KRAS mut. Median age was 65y (27-88y). Males comprised 54% of the total pts and 24% of pts were H. STK11 mut pts had an inferior median PFS (5.6 vs 6.28 months; p-value 0.35) and significant difference in median OS (8.6 vs 12.1months; p-value 0.035) compared with STK11 wt pts. OS at 12 months was significantly higher in the STK11 wt group versus the STK11 mut group (73% vs 55%; p-value 0.03). Pts with STK11+KRAS mut had shorter OS and PFS than patients with wt (5m vs 11m and 3m vs 5m) but the differences were not significant, however the 1-year survival was better for wt pts compare with pts with both mutations (70% vs 40%) p-0.03. 48 pts experienced an irAE and 77 did not. The irAEs positive group had increased median PFS (9.5 vs 4.4 months; p-value 0.0047) and OS (14.2 vs 7.3 months; p-value < 0.001) compared to the irAEs negative group. OS at 12 months was 85% in the irAEs positive group compared to 60% in the irAEs negative group (p-value 0.001). There were no significant differences in incidence of irAEs and STK11/LKB1 mut status for H vs. NH pts.
Conclusion
STK11/LKB1 mut pts and pts carrying KRAS mut concomitantly had shorter OS, PFS and 1-year survival compared with similarly treated pts with wt, however some numbers are not significant. CPIs treated NSCLC pts that experienced irAE had improved survival outcomes compared to those without irAEs. These findings are consistent with other studies that have reported STK11/LKB1 muts as a major genomic driver of primary resistance to CPI, and validate our previous report that described the utility of irAEs in predicting response to CPIs.
