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A. Futreal
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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)
11:00 - 12:30 | Author(s): A. Futreal
- 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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OA 13 - Immuno-Biology (ID 677)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Hiroyuki Suzuki, Scott N. Gettinger
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 301 + 302
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OA 13.05 - Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues (ID 8766)
11:00 - 12:30 | Author(s): A. Futreal
- Abstract
- Presentation
Background:
Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.
Method:
We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.
Result:
Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.
Conclusion:
These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.
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