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J. Lewis
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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 07.02 - Characteristics of Lung Cancer Cell-Free Tumor DNA (CfDNA) Shedding and Correlation with Tumor Burden as Measured by RECIST (ID 9663)
15:55 - 16:05 | Author(s): J. Lewis
- Abstract
- Presentation
Background:
cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.
Method:
We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.
Result:
There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1
Conclusion:
In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.05 - Identification of Novel Potentially Targetable Genomic Alterations in Paired Tumors with Acquired EGFR TKI Resistance by NGS (ID 9088)
11:45 - 11:55 | Author(s): J. Lewis
- Abstract
- Presentation
Background:
While previous reports have established MET and HER2 amplification as two mechanisms of non-T790M driven EGFR TKI resistance in EGFR mutant NSCLC, resistance occurs in the absence of these modifications in a significant number of patients. Therefore, there exists an unmet need to define additional mechanisms of resistance to EGFR TKIs. We hypothesized that targeted next-generation sequencing could detect additional targetable activating mutations in paired tumor samples from patients with acquired resistance to first or second generation EGFR TKIs.
Method:
We conducted an analysis of clinical and molecular data prospectively collected from 285 EGFR-mutant NSCLC patients enrolled into the MD Anderson Lung Cancer GEMINI database. Of 157 patients treated with first-line therapy (erlotinib, gefitinib, or afatinib), we identified 75 patients with TKI-acquired resistance with matched pre/post-TKI tumor samples. Matched tumor samples were analyzed with targeted gene sequencing. Recurrent alterations were defined as an alteration occurring more than 2 times. Recurrent acquired mutations were expressed in Ba/F3 and EGFR mutant (T790M+/-) NSCLC cells. Mutation expressing Ba/F3 cell lines were assayed for IL-3 independence, and mutation expressing NSCLC cell were screened against combination targeted TKIs.
Result:
EGFR mutant NSCLC patients treated with first-line therapy had a median PFS of 14 months; and, of the patients with pre/post-TKI tumor molecular data, 47% of patients were T790M negative. There were 30 recurrent acquired alterations identified in 13 different genes. Genes included ARAF, BRAF, EGFR, FGFR, GNAS, JAK2, MCL1, PDGFRα, PIK3CA, RAF1, RB1, SMAD4, and TP53. Of the alterations identified, most occurred in 1 of 4 targetable genes: BRAF (N=3), FGFR (N=5), PDGFRα (N=3), or PIK3CA (N=2). Both previously reported and novel mutations were identified, and preliminary screening of mutant expressing Ba/F3 cell lines found that of the mutations tested (BRAF WT & G469H, FGFR2 A371G, PDGFRα WT & L682F, and PIK3Ca E545K) all grew independent of IL-3. HCC827 and H1975 cell lines expressing acquired mutations in BRAF, FGFR, PDGFRα, or PIK3CA were more sensitive to combination targeted therapy compared to EGFR TKIs or mutation specific TKIs alone unlike control cell lines, supporting the possibility that targeting these mutations would be of therapeutic benefit.
Conclusion:
Analysis of patient data identified 30 recurrent genomic alterations in 13 different genes including novel alterations in BRAF, EGFR, FGFR, PDGFRα, RB1, and SMAD4, many of which were found to be activating mutations. Our analysis identified potentially targetable mutations of BRAF, FGFR, PDGFRα, and PIK3CA which merits further pre-clinical and clinical investigation.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-014 - Computing the Impact of Immunotherapy on NSCLC Landscape: The Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) (ID 9505)
09:30 - 09:30 | Author(s): J. Lewis
- Abstract
Background:
Anti-PD-1 and anti-PD-L1 antibodies including pembrolizumab, nivolumab and atezolizumab have entered clinical practice in the management of metastatic NSCLC as monotherapy and immunotherapy-based combinations. We have established a real-world Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) to understand how the emergence of immunotherapy impacts choice of treatment, clinical outcomes, and patient reported outcomes (PROs) in the different histo-molecular subtypes of metastatic NSCLC. The objectives of ANCHoR are to determine the treatment choice and treatment sequence by PD-L1 status in the various histo-molecular categories of NSCLC and to understand the impact of such treatment choice on response rates, progression-free survival (PFS), and overall survival (OS). Additionally we will measure the impact the treatment choices have on the PROs by utilizing the validated instruments, EuroQol-5D version 5L (EQ-5D-5L) and MD Anderson Symptom Inventory module specific to lung cancer (MDASI-LC).
Method:
The study will enroll patients with metastatic NSCLC diagnoses who are treated at MD Anderson Cancer Center (MDA) between January 1, 2017 and December 31, 2020. The study period will end on June 30, 2021 to allow a minimum of six months of follow-up. Trained abstractors will collect demographic, diagnostic, clinical, molecular (biomarker and PD-L1), treatment (regimens utilized in sequence and reason for discontinuation), response and survival (including PFS and OS), health care resource utilization and PRO (EQ-5D-5L and MDASI-LC) information that will be integrated in a comprehensive database. Information from the MDA electronic medical record will be extracted and populated in the GEnomic Marker-guided therapy INItiative (GEMINI) database and the PRO database which are linked. EQ-5D-5L followed by MDASI-LC will be completed directly by the patients and these will be automatically populated in the web-based PRO database at treatment initiation, at the time of response assessments and when switching lines of therapy.
Result:
Interim analysis will be conducted every six months to measure the impact of immunotherapy over time. Study results will be presented using descriptive statistics for continuous variables (mean, standard deviation, median, and interquartile range), categorical variables (frequency and proportions), and time-to-event variables (Kaplan-Meier). Regression models will be used for estimating the relationship between dependent variable and one or more predictors. Cox proportional hazards model will be used to estimate hazard ratios for time-to-event outcomes.
Conclusion:
The ANCHoR study is the first comprehensive registry of its kind that will enable the quantification of the changing impact of immunotherapy on the real-world NSCLC treatment landscape.
